|Year : 2014 | Volume
| Issue : 1 | Page : 27-65
Distribution of genetic polymorphisms of genes encoding drug metabolizing enzymes & drug transporters - a review with Indian perspective
Gurusamy Umamaheswaran, Dhakchinamoorthi Krishna Kumar, Chandrasekaran Adithan
ICMR Centre for Advance Research in Pharmacogenomics, Department of Pharmacology,Jawaharlal Institute of Postgraduate Medical Education & Research, Puducherry, India
|Date of Submission||06-Aug-2012|
|Date of Web Publication||6-Mar-2014|
Senior Professor & Head, ICMR Centre for Advance Research in Pharmacogenomics, Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education & Research, Puducherry 605 006
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Phase I and II drug metabolizing enzymes (DME) and drug transporters are involved in the absorption, distribution, metabolism as well as elimination of many therapeutic agents, toxins and various pollutants. Presence of genetic polymorphisms in genes encoding these proteins has been associated with marked inter-individual variability in their activity that could result in variation in drug response, toxicity as well as in disease predisposition. The emergent field pharmacogenetics and pharmacogenomics (PGx) is a promising discipline, as it predicts disease risk, selection of proper medication with regard to response and toxicity, and appropriate drug dosage guidance based on an individual's genetic make-up. Consequently, genetic variations are essential to understand the ethnic differences in disease occurrence, development, prognosis, therapeutic response and toxicity. For that reason, it is necessary to establish the normative frequency of these genes in a particular population before unraveling the genotype-phenotype associations. Although a fair amount of allele frequency data are available in Indian populations, the existing pharmacogenetic data have not been compiled into a database. This review was intended to compile the normative frequency distribution of the variants of genes encoding DMEs (CYP450s, TPMT, GSTs, COMT, SULT1A1, NAT2 and UGTs) and transporter proteins (MDR1, OCT1 and SLCO1B1) with Indian perspective.
Keywords: Cytochrome P450 - drug metabolizing enzymes - Indians - pharmacogenetics - pharmacogenomics - polymorphism - SNP - transporters
|How to cite this article:|
Umamaheswaran G, Kumar DK, Adithan C. Distribution of genetic polymorphisms of genes encoding drug metabolizing enzymes & drug transporters - a review with Indian perspective. Indian J Med Res 2014;139:27-65
|How to cite this URL:|
Umamaheswaran G, Kumar DK, Adithan C. Distribution of genetic polymorphisms of genes encoding drug metabolizing enzymes & drug transporters - a review with Indian perspective. Indian J Med Res [serial online] 2014 [cited 2016 Apr 29];139:27-65. Available from: http://www.ijmr.org.in/text.asp?2014/139/1/27/128312
| Introduction|| |
Patients or individuals may not respond in similar ways when administered with the same drug in a standard dose. Both genetic and non-genetic factors including age, gender, nutrition, concomitant medications, organ function, co-morbidness and drug interactions can modulate the efficacy of pharmacotherapy  . However, to a great extent the inter-individual variability in drug response is attributable to the presence of single nucleotide polymorphisms (SNPs) in the sequence of the genes encoding proteins that are involved in the absorption, distribution, metabolism and excretion (ADME) of many therapeutic agents, toxins and various pollutants , . The pharmacogenetics and pharmacogenomics (PGx) predicts disease risk, selection of proper medication with regard to response and toxicity, and appropriate drug dosage guidance based on an individual's genetic make-up  . Genetic variations in genes encoding ADME proteins have been associated with marked inter-individual variability in drug response, toxicity as well as disease susceptibility. The variation can occur at various levels of ADME as well as in drug action. Presence of SNPs in genes encoding drug metabolizing enzymes (DME) can cause the alteration of the enzyme leading to normal, reduced, increased or absence of activity. Based on this level of enzyme activity, patients can be divided into four phenotypes: (i) Poor metabolizer (PM) - no activity; (ii) Intermediate metabolizer (IM) - reduced activity; (iii) Extensive metabolizer (EM) - normal activity; and (iv) Ultra-extensive or Ultrarapid metabolizer (UM) - increased activity , . Polymorphisms exhibited by these DMEs and transporters are well known and their prevalence varies among different ethnic populations  . Therefore, the knowledge of genetic variations is essential to understand the ethnic differences in disease occurrence, development, prognosis, therapeutic response and toxicity. Before unraveling the genotype-phenotype associations in a particular population, it is of paramount importance to establish the normative frequency of these genes. In recent years we have performed pharmacogenetic studies on clinically important genes and established their normative frequencies in south Indian populations ,,,,,,,,, . Since the Indian populations are highly heterogeneous in nature, our results could not be extrapolated to the entire Indian population.
India is the world's second most populous country and inhabited by more than 1.21 billion humans comprising 4,693 communities, 325 languages and 25 scripts , . There is extreme diversity in terms of culture, biological, social characteristics, language and religion in Indians and genetically they are unique from other races. Based on their ethnic origin, Indian populations are morphologically classified into four groups viz., Caucasoid, Mangoloid, Protoaustraloid and Negrito. The Caucasoid and Protoaustraloid are the most predominant populations, mostly confined to northern and southern India. The Mangoloids live along the Himalayan fringe of Jammu and Kashmir and north-eastern region of the country, whereas the Negritos limited to Andaman Islands alone. In the same way, on the basis of their linguistic lineages the languages spoken in India belong to four major families: Austro-Asiatic (Central & East India), Dravidian (South India), Indo-European (North India) and Tibeto-Burman (North-East India) , . The Indian populations have been characterized as ancestral North Indians (ANI) and ancestral South Indians (ASI) on the basis of their ancestry components  . The authors have also shown that unlike the ANI, the ASI are not genetically close to any of the contemporary population outside India  . A recent Indian genome variation consortium (IGVC) study of genetic markers in 55 diverse Indian populations revealed high heterogeneity among the Dravidian populations and showed dissimilarity with HapMap populations  . The Indian population comprised multiple ethnic groups but there have been no published data available on the allele frequencies of these genes for Indians. Hence, we compiled the frequency distribution of the variants of genes encoding drug metabolizing enzymes and drug transporters, with Indian perspective. We compiled the normative frequency data of DME and transporters in various geographical regions of India reported from different studies and pooled them as North Indians (NI), South Indians (SI) and North East Indians (NEI) based on their ancestral ethnicity. Furthermore, we also compared the pooled mean allele frequency of Indian populations with the data from previous reports in Africans, Asians and Caucasians.
| Literature search and data collection|| |
A keyword literature search of the articles published (up to June 2012) on genes encoding drug metabolizing enzymes and drug transporters in Indian populations was done from databases such as PubMed, Medline and Google Scholar. The following search terms were used: "CYP450", "CYP1A1", "CYP1A2", "CYP2A6", "CYP2C8", "CYP2C9", "CYP2C19", "CYP2D6", "CYP2E1", 0"CYP3A", "CYP3A4", "CYP3A5", "GSTs", "GSTM1", "GSTT1", "GSTP1", "UGTs", "UGT1A1", "UGT1A7", "TPMT", "SULT1A1", "SULT1A2", "COMT", "NAT1", "NAT2", "MDR1 or ABCB1", "OCT1 or SLC22A1", "SLCO1B1 or OATP1B1" "transporters", DME and ADME in combinations with words "polymorphism" or "variation", "pharmacogenetics", pharmacogenomics", "India", "South Indian", "North Indian" and "Population" using the limit Human. Studies with the following inclusion criteria were included (i) original papers carried out in native Indians, (ii) studies containing data on unrelated healthy individuals, (iii) with information on normative genotype or allele frequency distribution, and (iv) well defined ethnicity. Accordingly, the related reference articles were also searched to identify other relevant publications. The reasons for exclusion of studies, were (i) overlapping data, (ii) family-based studies, (iii) meta-analysis, (iv) studies on non-residential Indians, and (v) studies that did not report genotype or allele frequency. Ethnicities were categorized as NI, SI, and NEI based on their geographical origin. When more than one publication was available for a gene SNP frequency for the same population from the same group, only the study with highest total number of subjects was included to avoid bias and overlapping data.
| Drug metabolizing enzymes|| |
Phase I enzymes
Enzymes involved in phase I drug metabolism largely belong to the cytochrome P450 (CYP) super family of drug metabolizing enzymes which catalyze the reactions such as hydrolysis, oxidation and reduction in which the functional groups of a substrate are added or deleted. This CYP450 system is divided into 18 families and 44 subfamilies consisting of 57 genes and 58 pseudo genes. Among them, the oxidative metabolism of 90 per cent drugs has been controlled by CYP1, CYP2 and CYP3 subfamilies  . The allele frequency distribution of phase I enzymes in various Indian populations is described in [Table 1] ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, .
|Table 1: Allele frequencies (%) of genes encoding phase I drug metabolizing enzymes (DME) in various Indian populations|
Click here to view
CYP1A (CYP1A1 & CYP1A2): Human CYP1A belongs to the group of phase I DME CYP450 isoforms. It consists of two members, CYP1A1 and CYP1A2. These are the key enzymes in the biotransformation of estrogens, polycyclic aromatic hydrocarbons and aromatic amines. In addition, CYP1A2 is also involved in the metabolism of a number of therapeutic drugs including caffeine, clozapine, olanzapine, amitriptyline, R-warfarin, veramapil, theophylline, propranolol, clomipramine, imipramine, haloperidol and acetaminophen. The gene encoding CYP1A1 is located at 15q22-q24, spanning 5,810 bp with seven exons and six introns. While the gene encoding CYP1A2 is located at 15q22, extending 7.8 kb with six exons and so far, more than 150 variant alleles have been described worldwide ,, . Polymorphisms in these genes lead to variability in the enzyme activity and is shown to be associated with various cancers such as colon, ovarian, breast, lung, oral and acute lymphoblastic leukaemia (ALL). The most common being CYP1A1*2A or m1 (3798T > C), also known as Msp1, CYP1A1*2C or m2 (2455A > G), CYP1A1*3 or m3 (3204T > C) and CYP1A1*4 or m4 (2452C > A) polymorphisms for CYP1A1. For CYP1A2, CYP1A2*1F (163C > A) is the most common variant. The frequency of the mutant alleles CYP1A1*2A and CYP1A1*2C were significantly ( P < .05) different among the Indian populations as well as in comparison with other populations (P < .0001) ,,,,,,,,,,,,,,,,,,,,,,,,, . CYP1A1*3 was absent in Indians, while CYP1A1*2B (9.5%) was determined only in NEI  , which was significantly different from other populations (P < .0001). The CYP1A1*4 frequency in NEI  was different from NI, Caucasians and Africans but absent in Asians (P < .0001). Similarly, CYP1A1*4 frequency in NI was in agreement with Caucasians but different from Africans (P < .0001). Conversely, the frequency of CYP1A2 polymorphisms is available only in NI population. The distribution of CYP1A2 alleles were 8, 24.5, 9.5, 50.7 and 0 for *1C, *1D, *1E, *1F & *2, respectively. Significant interethnic differences were observed between NI and other major populations, P < .001 [Table 2] ,,,,,,, .
|Table 2: Summary of normative allele frequency distribution of genes encoding major human Phase I and II drug metabolizing enzymes (DME) and drug transporters in different ethnics|
Click here to view
CYP2A6: Human CYP2A6 is the major hepatic CYP2A enzyme and its role in the metabolism of drugs is small (3%) but it is important in the oxidative metabolism of nicotine. In addition, it is involved in the catalytic metabolism of valproic acid, fadrozole, methoxyflurane, artesunate, coumarin, disulfiram, halothane, losigamone, tegafur and letrozole. It also metabolizes environmental toxins, procarcinogens, retinoic acids and steroids  . The gene encoding CYP2A6 spans about 6kb with 9 exons and is mapped on chromosome 19q13.2 with other CYP2A sub-family (CYP2A7 and CYP2A13) members. Importance of CYP2A6 had risen considerably after the finding of a relationship between defective CYP2A6 alleles, smoking behaviour and cigarette consumption, drug clearance as well as tobacco related cancer risk. The CYP2A6 gene is extremely polymorphic and up to now, more than 81 variant alleles have been known , . Besides the normal type allele designated as CYP2A6*1, three non-functional alleles which result in absence of CYP2A6 activity *2 (1799T > A, Leu160His), *4A (gene deletion), and *5 (1436G > T and 6582G > T, Gly479Val) have been well known. The frequency data of CYP2A6*1B polymorphisms are available only for NI  and similarly CYP2A6*2 and *5 are available only in SI populations  . Among the CYP2A6 variants, *1B is the most prevalent allele followed by *4, whereas *2 and *5 were found to be rare [Table 1]. The comparison of CYP2A6*1B between NI (32.7%) and other populations indicates similarity with Caucasians (27.6%) and significant difference with Africans
11.2 per cent and Asians 42.8 per cent (P < .001). The prevalence of the defective allele CYP2A6*4A was higher in NI (11.3%), SI (8.9%) and Asians (11%) but significantly lower in Africans (0.5%) and Caucasians 3 per cent (P < .0001). In contrast, the other variant CYP2A6*2 was lower in SI (1%), Africans (0.3%), Caucasians (2.3%) and absent in Asians. Similarly, CYP2A6*5 were lower in SI (0.7%), Asians (0.5%) and virtually absent in Africans and Caucasians [Table 2] ,,, .
CYP2C8: The enzyme CYP2C8 comprises approximately 7 per cent of the total hepatic cytochrome system, which metabolizes around 5 per cent of drugs in phase I metabolism  . CYP2C8 plays significant role in metabolizing antidiabetics (troglitazone, pioglitazone, rosiglitazone & repaglinide), anticancer (paclitaxel), antihypertensive (veramapil), non-steroidal anti-inflammatory drugs (NSAID) (ibuprofen), 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase inhibitor (cerivastatin), antimalarial (chloroquine, amodiaquine) and antiarrhythmic (amiodarone) drugs. Additionally, it is the principal enzyme responsible for the metabolism of retinoic and arachidonic acid in the kidneys  . The human CYP2C8 gene which encodes CYP2C8 enzyme is localized in the long (q24.1) arm of the chromosome 10, consists of 9 exons and spans about 31 kilo base. CYP2C8 gene exhibits several polymorphisms and so far, more than 20 polymorphisms have been reported in different populations  . Among them, the most commonly studied SNPs that lead to decreased enzyme activity are CYP2C8*2 in exon 5 (805A > T, I269F), CYP2C8*3 in exons 3 and 8 (416G > A/1196A > G, R139K/K399R), CYP2C8*4 in exon 5 (792C > G, I264M) and CYP2C8*5 (475delA). The enzymes encoded by these variant alleles impair the metabolism of several drug substrates of CYP2C8. Subjects who are homozygous (*2/*2 or *3/*3) have lower intrinsic clearance of CYP2C8 substrates than those who are heterozygous (*1/*2 or *1/*3). Further, the polymorphisms of CYP2C8 have been associated with diseases such as myocardial infarction (MI)  . The only study which determined the frequency distribution of CYP2C8 alleles in any of the Indian population was carried out in SI Tamilians  with a frequency of about 0.8 per cent (95% CI 0.2-2.1) and 2.9 per cent (95% CI 1.6-4.7) for CYP2C8*2 and *3, respectively [Table 1]. Population studies from around the world in different populations indicate that CYP2C8*2 variant is rare in SI and Caucasians, whereas it is a common variant among Africans. Allele CYP2C8*3 is a common variant in Caucasians while it occurs either at small frequency or not present in SI and Africans. With regard to Asians subjects, the CYP2C8 polymorphism was monomorphic for CYP2C8*1 allele [Table 2] , .
CYP2C9: Drugs undergoing oxidative metabolism such as S-warfarin, rosiglitazone, tolbutamide, phenytoin, glyburide, glibenclamide, glimepiride, glipizide, losartan, irbesartan, torsemide, tamoxifen, fluvastatin, fluoxetine, amitriptyline and other commonly used anti-inflammatory drugs (diclofenac, ibuprofen, naproxen, piroxicam, aceclofenac, celecoxib) have been described to be principally metabolized by CYP2C9 ,, . It is encoded by the gene CYP2C9, which is located on chr10q24.2. Among the CYP2C isoforms, CYP2C9 is the most abundant one and constitutes about 20 per cent of total CYP450 hepatic content  . The gene CYP2C9 is known to be polymorphic and inter-individual differences in the enzyme activity of CYP2C9 categorize subjects into EMs, IMs and PMs. Currently, 41 different variant alleles are known for CYP2C9 gene  . Among the many variants, CYP2C9*2 (430C > T, Arg144Cys) in exon 3 and CYP2C9*3 (1075A > C, Ile359Leu) in exon 7 are the most characterized alleles and individuals with these variant alleles are reported to have decreased CYP2C9 activity. These variants are reported to be associated with acute MI, hypertension, colorectal cancer and major depressive disorders; also with certain adverse drug reactions including gingival hyperplasia, hypoglycaemia and gastrointestinal bleeding. In addition, a number of other alleles such as CYP2C9*5 (1080C > G, D360E), *6 (818Adel), *9 (752A > G, H251R), *11 (1003C > T, R335W) and *12 (1465C > T, P489S) may cause impaired metabolism, which may give rise to life threatening drug toxicity and may have impact on drug metabolism and disease susceptibility ,, . The prevalence of CYP2C9*2 was significantly different between NI and SI (9% vs. 3.6%, P < .0001) ,,,, , whereas CYP2C9*3 (9.7% vs. 8%) allele was equally distributed among the Indian populations [Table 1]. With regard to CYP2C9*2, NI showed similarity with Caucasians but difference with Africans (P < .0001) ,,,,, . In contrast, the SI showed similarity with Africans but different from Caucasians (P < .0001). Indians had higher frequency of CYP2C9*3, as compared to Africans and Asians (P < .0001) but no difference was observed with Caucasians [Table 2] ,, .
CYP2C19: CYP2C19 is a polymorphically expressed CYP450 enzyme, constitutes about 16 per cent of the CYP2C family in liver and it is encoded by the gene CYP2C19 located on chr10q24. It is involved in the metabolism of a broad range of clinically important drugs including antimalarial (proguanil), oral anticoagulants R-warfarin, anti-epileptics (S-mephenytoin, diazepam, phenobarbitone), antivirals (nelfinavir), antiplatelets (clopidogrel), chemotherapeutic agents (cyclophosphamide), proton pump inhibitors (omeprazole, pantoprazole, lansoprazole, rabeprazole) as well as several antidepressants (amitriptyline, clomipramine) , . Upto now, 35 polymorphisms have been identified. The frequencies of these alleles in different ethnic populations were extremely variable. Carriers of the non-functional alleles such as CYP2C19*2 in exon 5 (681G > A) and CYP2C19*3 in exon 4 (636G > A) have diminished ability to metabolize therapeutic agents that are substrates of CYP2C19 , . The CYP2C19*2 allele notably occurred at a higher frequency among the Indian populations (NI 33.1% and SI 36.8%) than Africans 16 per cent, Caucasians 13.3 per cent and slightly higher than Asians 28.4 per cent (P < .001). The CYP2C19*3 alleles in Indians were 1.9 and 1.1 per cent in NI and SI, respectively [Table 1]. Marked inter- and intra-ethnic variations were observed among the Indian populations (P < .05) and as compared to other major ethnics such as Asians and Caucasians (P < .001) individually with regard to the distribution of the polymorphic allele CYP2C19*3,,,,,,,, . On the other hand, a novel variant allele in the regulatory region defined as CYP2C19*17 (-806C > T, -340C > T) increases the activity of CYP2C19 protein resulting in ultrarapid metabolism of CYP2C19 substrates  . The ultrarapid metabolizer CYP2C19*17 was studied only in SI Tamilians  with a frequency of about 19.2 per cent [Table 1]. The comparison of SI subjects with Asian individuals indicates significant difference in UM allele, P < .0001 [Table 2] ,,, .
CYP2D6: Cytochrome P450 2D6 (CYP2D6) is responsible for the metabolism of clinically important drugs, namely anticancer, antiarrhythmic, antihistamines, antipsychotics, β-blockers, opioids, antihypertensives and antidepressants. Of the total CYP450 content, CYP2D6 constitutes approximately 2-4 per cent and involved in the elimination of 25 per cent currently prescribed drugs, . The CYP2D6 gene consists of 9 exons and 8 introns and is located on chromosome 22q13.2. The sequence of CYP2D6 is highly polymorphic. Up till now, over 135 allelic variants have been reported and CYP2D6*2 (2850C > T;4180G > C) in exon 2 and 6, *3 (2549delA) in exon 5, *4 (1846G > A in intron 3 - exon 4 junction), *5 (whole gene deletion), *10 in exon 1(188C > T, P34S), *14 (1758G > A), *17 (1023C > T; 2850C > T) in exon 2 and *41 (2988G > A) variants were the most characterized alleles of CYP2D6 . The frequencies of the defective alleles in different races vary widely. Apart from PMs, IMs individuals also had been classiﬁed as UMs of CYP2D6 substrates depending upon the presence of CYP2D6 allele combinations. PMs are those who carry two defective alleles (inactive enzyme), resulting in increased concentrations of the parent drug in plasma, whereas in the case of UMs, as a result of gene duplication individuals carry more than two copies of the functional gene leading to increased enzyme activity, resulting in decreased parent drug concentration in blood  .
The dosage recommendation is based upon the CYP2D6 genotype for drugs that are substrates of CYP2D6 in order to avoid both treatment failure and adverse drug reaction. Of the five variants which contribute to the loss of CYP2D6 activity (*3,*4, *5, *6 and *14), only *14 was not detected in Indian populations. Similarly, the other variants (*9, *17 and *29) leading to diminished enzyme activity were also not found in Indians. The functional allele CYP2D6*2 was most prevalent in Indians which was found at comparable frequencies between NI (29.3%) and SI (34.8%). Both the Indian populations showed significant difference compared with Asians and Caucasians (P < .0001, [Table 2] ,, . Although the NI showed similarity with Asians, SI showed significant difference (P < .0001). The CYP2D6*3 allele was found only in NI 9.2 per cent (95% CI 6.9-11.8) and it was absent in SI. Its frequency in NI was significantly higher as compared to Africans 0.4 per cent, Asians 1 per cent and Caucasians 2.8 per cent (P < .0001) ,,,,,, . Likewise, the polymorphism CYP2D6*5 which leads to gene deletion was determined with a frequency of about 1.9 and 1.8 per cent in NI and SI, respectively. It was significantly lower than those observed in Africans 6.6 per cent, Asians 7 per cent and Caucasians 6.9 per cent (P < .0001). On the other hand, CYP2D6*4 was evenly distributed in SI (7.3%), NEI (8.7%) and Africans (6.8%), while it was higher in NI (11.5%) and Caucasians (14%) and lower in Asians (4%), (P < .0001) [Table 2] ,,,,,,, . The occurrence of the CYP2D6 allele *10 which confers partially decreased activity, was found at higher frequencies (27.2%) in NI than (10.2%) SI and the difference was significant (P < .0001). With regard to CYP2D6*10, both the Indian populations showed significant difference when compared with other populations, P < .001
[Table 2] ,,,,, . The frequency of allele *41 showed high frequency in NI 12.5 per cent, Caucasians 8.5 per cent and lower in Asians 1.9 per cent (P < .0001). The active gene duplication alleles of CYP2D6 were studied only in NI Gujarati population  . Alleles associated with ultra-rapid metabolism (1xN and 2xN) and loss of enzyme activity (4xN) were found at fewer frequencies in NI and major ethnics. On the contrary, abridged activity alleles (10xN and 41xN) were absent in NI [Table 2] ,,,, .
CYP2E1: CYP2E1 is toxicologically important enzyme, which is present mostly in liver, and at lower levels in several extrahepatic tissues. Its levels are increased during fasting, diabetes, and exposure to alcohol. It catalyses the bioactivation of several procarcinogens and protoxins including N-nitrosodimethylamine, styrene, benzene and N-alkylformamides and also chlorzoxazone, acetaminophen, and the volatile anaesthetics (enflurane, sevoflurane, halothane, methoxyflurane and isoflurane) drugs  . The gene encoding CYP2E1 protein is located on chr10q26.3 and until now 12 different SNPs have been reported  . The polymorphisms of CYP2E1 have been linked to many chemically induced cancers and to alcoholic liver disease, in particular liver cirrhosis. Any functional polymorphism of this enzyme might be an important factor in determining the relative risk of alcohol-mediated hepatotoxicity, cancer or susceptibility to drug toxicity  . Polymorphic alleles with mutation in intron 7 CYP2E1*1B, in the 5'flanking region CYP2E1*5B (C1/C2, Rsa I) and intron 6 CYP2E1*6 (C/D, Dra I) are the common variants associated with altered gene function and expression. Their prevalence has been related to the occurrence of alcoholic liver disease and lung cancer. The frequency of CYP2E1*1B was equally distributed in NI, SI and Caucasians, while it was significantly higher in Asians, 18.1 per cent (P < .05) and relatively highest in Africans, 65.9 per cent (P < .001) ,,,, . With regard to CYP2E1*5B, similarity was observed between SI and NEI  (1.3% vs. 0.8%) but different in NI, 8.4 per cent (P < .001). Likewise, similarity was observed between NI and SI (17.7% vs. 22.2%) but different in NEI  , 0.8 per cent (P < .001) with respect to CYP2E1*6 [Table 2]. The frequency of CYP2E1*5B in NI was different from other ethnic populations whereas *6 was similar to Asians but different from Africans and Caucasians (P < .0001). The SI were different from other major populations (P < .0001) for CYP2E1*5B but similar to Asians and different when compared with Africans and Caucasians for CYP2E1*6 (P < .0001). The comparison of the frequency of CYP2E1*5B and *6 alleles in NEI with other ethnicities indicates significant dissimilarity (P < .01) ,, .
CYP3A (CYP3A4 & CYP3A5): The CYP3A isoenzymes metabolizes about 50-60 per cent of all currently prescribed drugs. Its subfamily consists of homologous proteins encoded by four different CYP3A genes namely CYP3A4, CYP3A5, CYP3A7 and CYP3A43 . These are located adjacent to each other on chromosome 7q21. Among these, CYP3A4 is the largest portion of CYP3A protein present in the adult liver and its catalytic activity may show up to 90 fold variation. Till now, 41 CYP3A4 alleles have been identified and characterized  , Out of these *1B (4713G > A) is the only defining variant of CYP3A4 reported at present. Subjects carrying the defective alleles of CYP3A4 have been implicated in disease predisposition to prostate cancer, estrogen receptor negative breast cancer and type 2 diabetes mellitus  . The frequency of CYP3A4*1B was available in NI (1.2%) only and the comparison between NI and other populations indicates significant variations (P < .01) , . The other CYP3A4 variants such as *2, *4, *5, *6 and *10 were not detected in NI  [Table 1]. On the contrary, CYP3A5 is polymorphically expressed in about 10-30 per cent adult livers and along with CYP3A4, metabolizes > 50 per cent of currently used drugs. It shares about 85 per cent of amino acid sequence identity with CYP3A4 but it has different degrees of catalytic activity and regioselectivity towards substrates  . Kuehl et al have demonstrated that at least one CYP3A5*1 allele is needed for expressing CYP3A5 protein. They have identified CYP3A5*3 (A to G at 6986) in intron 3 and CYP3A5*6 (G to A at 14690) in exon 7, which led to the absence of CYP3A5 protein 6986A allele (CYP3A5*1) was before correlated with high expression  . Further, two more variants in the coding regions viz.,*2 (27289C > A, Thr398Asn) in exon 12 and *4 (14665A > G, Gln200Arg) in exon 8 were identified. CYP3A5 may represent upto 50 per cent of the total hepatic CYP3A content in people expressing CYP3A5, . This gene may be an important contributor to individual and inter-racial variation in CYP3A mediated metabolism of drugs including antipsychotics (olanzapine), antiestrogen (tamoxifen), anticancer (irinotecan, docetaxel, vincristine), antimalarial (mefloquine, artemether, lumefantrine), immunomodulators (tacrolimus, cyclosporine), antihistamines (chlorpheniramine, terfenadine, astemizole), antiplatelets (clopidogrel), antihypertensives (nifedipine, amlodipine, felodipine, verapamil), antivirals (indinavir, nelfinavir, ritonavir, saquinavir), HMG-CoA reductase inhibitors (atorvastatin, cerivastatin, lovastatin) antibiotics (clarithromycin) and steroids (testosterone, estradiol, progesterone and androstenedione).
The presence of non-functional polymorphic alleles of CYP3A5 has been associated with blood pressure, MI, breast cancer and acute myeloid leukemia (AML) or ALL  . In Indians, CYP3A5*3 is the only variant allele present in NI and SI. None of the other variants *2, *4 and *6 were identified in Indians [Table 1]. The frequency of CYP3A5*3 in SI 56 per cent (95% CI 53.5-58.5) was significantly different (P < .0001), as compared to NI 68.2 per cent (95% CI 64.5-71.9). Similarly, both the Indian populations were statistically different compared with Caucasians 91.6 per cent, Asians 80.6 per cent and Africans 15 per cent (P < .0001) ,,, . Further, a promoter polymorphism -44A > G was observed only in NI  34.7 per cent which was higher than Caucasians 9.2 per cent (P < .0001) and similar to Asians 28.2 per cent [Table 2] ,,,,,,,,, .
Phase II enzyme
Phase II enzymes are involved in sulphation, acetylation, conjugation and glucuronidation reactions which may lead to the excretion of drugs by increasing the hydrophilicity of the substrate or deactivation of highly reactive substrates. Glutathione S-transferases (GSTs), N-acetayltransferases 1 and 2 (NAT1 and NAT2), thiopurine S-methyltranferase (TPMT), uridine disphosphate glucoronosyl transferases (UGTs), catechol methyl trasferase (COMT) and sulphotransferases (SULT) are the main phase II enzymes  . [Table 3] illustrates the allele frequency distribution of phase II enzymes in various Indian populations ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, .
|Table 3: Distribution of genes encoding phase II drug metabolizing enzymes (DME) allele frequencies in different Indian populations|
Click here to view
GST (GSTM1, GSTT1 & GSTP1): The polymorphic cytosolic glutathione S-transferase (GST) isoenzymes GSTM1, GSTT1 and GSTP1 are the predominant class of phase II drug metabolizing enzymes. The chromosome location of the genes encoding GSTM1 (mu), GSTT1 (theta) and GSTP1 (pi) are chr1p13.3, chr22q11.2 and chr11q13.2, respectively. They play a significant role in the biotransformation and detoxification of a wide range of xenobiotics and endogenous substances including carcinogens (halomethanes and methyl bromide). GSTs protect cells against reactive oxygen metabolites by the conjugation of glutathione with electrophilic compounds , . Both the genetic polymorphisms and expression pattern of GST genes may have a major impact on cancer susceptibility, inter-individual variability in the prognosis, drug effects and toxicity  . Of all the human GSTs, GSTM1 and GSTT1 isoenzymes are highly polymorphic. Those who carry the respective null genotypes termed as GSTM1*0/*0 and GSTT1*0/*0 due to homozygous gene deletions do not have these enzymes. On the other hand, single base pair substitution 313A > G of GSTP1 (Ile105Val) in exon 5 marks reduced enzyme activity. In addition, individually or in combination the null genotypes of GSTM1 and GSTT1 genes increase the risk of gastric, colon, bladder and lung cancers  .
The frequencies of GSTM1 and GSTT1 null
alleles were found to be 30.6 and 16.7 per cent in NI; 28.8 and 14.8 per cent in SI and 34.4 and 19.7 per cent in NEI ,,,,,,,,,,,,,,,,, . On the whole, a general uniformity was observed between NI vs. SI and NI vs.
NEI with regard to GSTM1 and GSTT1 null polymorphisms. Conversely, it was significantly different between SI and NEI (P < .04) ,,,,,,, . The frequency distribution of GSTM1 null variant in Indian populations was significantly different
from Africans, Asians and Caucasians (P < .03). Similarly, the frequency of GSTT1 null polymorphism in SI was in line with NI and different from NEI (P < .01) ,,,,,,,,,,,,,,, . Further, its frequency in Indian populations was significantly less prevalent as compared to Africans and Asians (P < .001), but showed similarity with Caucasians [Table 2]. The GSTP1 105Val allele was equally distributed at a frequency of 23.8 and 21.7 per cent in NI and NEI, respectively [Table 3]. However, it was significantly different in SI 14.6 per cent (P < .001), as compared to NI, NEI, Africans (36.8%), Asians (20.6%) and Caucasians
(25.9%) ,,,,,,,, . Likewise, a significant difference was observed in Africans (P < .0001) as compared to NI and NEI. As the distribution of GSTM1*0 (null), GSTT1*0 (null) and GSTP1 (105Val) alleles occurs at high frequencies in different populations, their genotyping becomes necessary [Table 2] ,,,, .
UGT1A1: The uridine diphosphate glucuronosyl transferase1A1 (UGT1A1) is a major phase II drug metabolizing enzyme belonging to UGT1A family. It is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics, carcinogens and drugs. UGT1A1 catalyzes glucoronidation of a variety of compounds including estrogens, bilirubin and therapeutic drugs , . Genetic polymorphism has been described for six of the 16 functional human UGT genes characterized to date, namely UGT1A1, 1A6, 1A7, 2B4, 2B7 and 2B15 . Polymorphisms of UGT1A1 gene causes decrease in enzyme activity which ultimately results in interpatient differences in the pharmacokinetics of irinotecan, an anticancer drug  . Human UGT1A1 enzyme is encoded by UGT1A1 gene, which is located on chromosome 2q37 and spans about 160 kb  . To date, more than 50 variants in the promoter and coding regions of UGT1A1 gene are known to disrupt enzyme activity. The most common being UGT1A1 (TA) 6 > 7 (UGT1A1*28) polymorphism in the TATA element of the 5'promoter region. It is characterized by (TA) 7 repeats instead of more common (TA) 6 repeats, resulting in lower promoter activity. It is the genetic basis for several clinical conditions such as, mild unconjugated hyperbilirubinemia associated with reduced hepatic bilirubin glucuronidation (Gilbert syndrome) and irinotecan mediated toxicity , . Irinotecan, an inhibitor of intracellular topoisomerase-I is metabolized to form active SN-38, which is further conjugated and detoxified by UGT1A1 enzyme  . The only study which determined the frequency of UGT1A1*28 in native Indians was carried out in SI  namely, Andhra Pradesh 32.2 per cent, Karnataka 29 per cent, Kerala 46.5 per cent and Tamil Nadu 52.8 per cent [Table 3]. Significant differences in the frequencies of this variant were observed in SI 39.7 per cent, as compared to Africans 55.3 per cent, Asians 13.1 per cent and Caucasians 29.6 per cent, P < .0001 [Table 2]  .
UGT1A7: The uridine 5'-diphosphate-glucuronosyltransferase 1A7 (UGT1A7) is an extrahepatic phase II DME expressed in pancreas, lung, stomach, oropharynx and oesophagus. It catalyzes the glucoronidation and detoxification of a wide variety of endogenous and exogenous compounds such as bilirubin, drugs, steroid hormones, phenols, coumarin and environmental carcinogens including nitrosamines and benzo[a]pyrene present in tobacco , . The gene UGT1A7 is highly polymorphic and localized on chromosome 2q37 and 11 missense variants have been characterized till now. The common being UGT1A7*1 (N129 R131 W208), UGT1A7*2 (K129-K131-W208), UGT1A7*3 (K129-K131-R208), and UGT1A7*4 (N129-R131-R208)144,145. Population epidemiological studies have suggested that individuals carrying UGT1A7 genetic variations which confer low detoxification activity are associated with the development of cancer of the liver, colon, oral, gastrointestinal, pancreas and chronic pancreatitis  . The frequencies of UGT1A7 gene polymorphisms were available only in NI  which have not been studied in other Indian populations [Table 3]. Overall, the variant of UGT1A7 seems to be more common in NI. The UGT1A7* 2, *3 and *4 alleles shows significant interethnic variability as compared to Africans, Asians and Caucasians (P < .01). In contrast, no interethnic differences were observed for UGT1A7*12 polymorphism [Table 2] ,,, .
TPMT: The gene thiopurine S-methyltransferse (TPMT) encodes the cytosolic enzyme TPMT which catalyzes S-methylation of thiopurine drugs such as 6-mercaptopurine (6-MP), azathioprine (AZA) and 6-thioguanine (6-TG). These drugs are commonly used for the treatment of ALL, autoimmune disorders, dermatological conditions and as an immunosuppressant in graft transplantations  . Polymorphism of TPMT alters the enzymatic activity of TPMT which is a major factor influencing interindividual differences in toxicity and therapeutic efficacy of thiopurine drugs. The TPMT enzyme activity in erythrocytes shows trimodal distribution in Caucasians  . Individuals with TPMT*1/*1 wild type show high enzyme activity (89-94%), while carriers of heterozygotes and homozygotes of TPMT mutant alleles show intermediate (6-11%) and low enzyme activity (33%) respectively. In contrast, Southeast Asians have unimodal distribution, which is perhaps due to the absence or low frequency of TPMT*3A .
The gene TPMT has 10 exons spreading over 27kb of genomic DNA on chromosome 6p22.3  . Till date, more than 24 polymorphisms have been reported for TPMT gene. Amongst these, TPMT*2 (238G>C),*3A (460G > A and 719A > G),*3B (460G > A) and *3C (719A > G) are the four major variant alleles that cause 80-95 per cent intermediate and low enzyme activity. Carriers of theses alleles have been shown to have clinical implications with respect to metabolism, toxicity and therapeutic efficacy of thiopurine drugs. TPMT*2, *3A and *3B were rare, while TPMT*3C appears to be the most common variant in Indians. Another variant allele, the African specific TPMT*8 (644G > A) in exon 9 which is responsible for intermediate activity, was absent in Indians  . The mutant allele TPMT*3A which causes the largest decrease in TPMT activity was detected only in NI (0.4%) but it was absent in SI, Similarly TPMT*2 and TPMT*3B was present only in SI (0.1% and 0.1%) but not in NI [Table 3]. With regard to TPMT*3A, the NI were different from Caucasians (P < .004) and similar to Asians and Africans  . With regard to TPMT*3C, the NI and SI were different from Caucasians, Africans (P < .01) and similar to Asians  . On the whole, the Indians have relatively low frequency of TPMT variant and it shows that they have higher TPMT activity and are likely to be at a lower risk of developing toxicity when treated with thiopurine drugs compared to Africans, Asians and Caucasians  [Table 2].
SULT1A1: Human sulphotransferase 1A1 (SULT1A1) is the most widely expressed of the SULTs isoform which catalyzes the sulphate conjugation of hormones, neurotransmitters, drugs (tamoxifen) and other xenobiotics. Differences in the ability of the SULT1A1 protein to catalyze the sulphonation reaction lead to altered therapeutic efficacy, toxicity and disease process (carcinogenesis) ,,[ . The gene encoding SULT1A1 is mapped to the short arm of the chromosome 16p12.1-p11.2. The SULT1A1*2 variant was the most common of the two common non-synonymous SNPs observed namely SULT1A1*2 (638G > A, Arg213His) and SULT1A1*3 (667A > G, Met223Val). Individuals carrying the variant allele SULT1A1*2 will have diminished capacity to sulphate the substrates of SULT1A1 due to shorter protein life and more susceptible to cancer risk as well. Gene duplication and deletion was more common in SULT1A1 gene and a correlation between the enzymatic activity and SULT1A1 gene copy numbers has been observed by Hebbring et al in an in vitro study. The frequency of SULT1A1*2 in Indian populations was established in SI , (22.6%) and NEI  (27.2%) but not in NI [Table 3]. It was significantly higher than those reported in Asians 8.7 per cent and lower than Caucasians 41.5 per cent (P < 0.0001), however, it was similar between SI, NEI and Africans 28.5 per cent [Table 2] , .
COMT: The enzyme catechol-O-methyltrasferase (COMT) is involved in the metabolism of catecholamines (adrenaline and noradrenaline), catecholestrogens, dopamine and their hydroxlated metabolites. The gene encoding COMT is located on chromosome 22q11.2 and produces two diverse proteins i.e. low affinity soluble COMT (S-COMT) and high affinity membrane bound (MB-COMT) by alternative transcription. Polymorphism in the human COMT is an important cause for the inter-individual variation in the enzyme activity of COMT. Further evidence has shown that the existence of COMT variants in individuals contributes to schizophrenia, breast cancer, endometrial cancer, Parkinson's disease, variation in pain sensitivity and therapeutic response (analgesics, levodopa) , . However, the results were not consistent and to date, approximately more than 30 SNPs have been described for COMT gene  . Among these, the most common being the COMT rs4680 (472G > A) in exon 4, where the nucleotide change A to G results in the replacement of valine with methionine at codon 158 in MB-COMT and 108 in S-COMT leading to 3-4 fold decrease in methylation activity. Except the SNP rs4680, the frequency of the other reported alleles such as rs3788319, rs737865, rs6269, rs4818, rs4633, rs165599 were available only in SI  [Table 3]. The frequency of rs4680 was significantly different between NI and SI (49 vs. 41.6%), P < 0.001 , . As compared to NI population, significant difference was obtained with Africans and Asians (P < 0.0001). The difference in the frequencies of COMT rs4680, rs737865 and rs4633 in SI were significant, as compared to Africans, Asians and Caucasians, P < 0.01[Table 2] ,,, .
NAT2: Human genome consists of two acrylamine N-acetyltransferase enzymes 1 (NAT1) and 2 (NAT2), which catalyze the metabolism of N-acetylation of arylamines, arylhydroxylamines and arylhydrazines , . The genes encoding both the isoforms, NAT1 and NAT2 localized on chromosome 8p21.3-23.1 and exhibit numerous polymorphisms. Based on NAT genotype, individual phenotype (acetylation activity) can be divided into slow, intermediate and rapid acetylator ,,[ . Genetic variations of NAT1 were not determined in native Indians. The common defective alleles of NAT2 are 191G > A (Arg64Gln), 282C > T (Tyr94Tyr), 481C > T (Leu161Leu), 341T > C (Ile114Thr), 590G > A (Arg197Gln), 803A > G (Arg268Lys) and 857G > A (Gly286Glu)  . Among these, the most studied alleles were NAT2*5, NAT2*6 and NAT2*7 at positions 341, 590 and 857, respectively.
The variant NAT2*6 corresponding to inactive enzyme was detected with a frequency of 37 per cent in SI  which was similar to 31.5 per cent in NI and different from NEI  26 per cent, (P < .003). Likewise, NAT2*7 accounts to 13.3 per cent in NI and it was similar to NEI (11.1%) but different from SI, 25 per cent (P < .0001). The other variants NAT*5 and *13 were studied only in SI and occurred with a frequency of 30 and 44 per cent, respectively, while *14 was virtually absent  . The NAT gene polymorphic frequency of *11 was different between NI and SI (29.2 vs. 22%), whereas *12 was equally distributed among them [Table 3]. A comparison of NAT2 allele frequencies of Indians with Africans, Asians and Caucasians reveals significant interethnic difference [Table 2]  . Carriers of these alleles will have variation in the metabolism of isoniazid, hydralazine, ribavirin, retigabine, sulphamethoxazole and may influence susceptibility to some cancers , .
Drug transporters are those proteins that carry either endogenous compounds or xenobiotics across the biological membranes. These play an important role in the uptake, bioavailability, efficacy, toxicity and clearance of drugs  . Generally, transporters that influence ADME of drugs are classified into (i) adenosine triphosphate (ATP)-binding cassette (ABC) family, and (ii) solute carrier (SLC) family , . The ABC transporters are efflux transporters, consisting of seven subfamilies and 49 genes, whereas the SLC are influx transporters with 360 genes and 46 subfamilies. The allele frequency of drug transporter genes in different Indian populations is shown in [Table 4] ,,,,,,,,, .
|Table 4: Frequency distribution of drug transporter genes in diverse Indian populations|
Click here to view
MDR1: The multidrug resistance 1 gene MDR1, also known as ABCB1, is localized at chromosome 7q21.1, consisting of 29 exons ranging in size from 49 to 209 bp, encoding an mRNA of 4.5 kb. P-glycoprotein (P-gp), the product of MDR1 gene is a 170 kDa transmembrane protein, belongs to ABC super family of transporter proteins which is well recognized for its role in drug transport and chemoresistance. It protects the tissues from toxic xenobiotics and other endogenous substances by exporting the substrates from intracellular to extracellular space , . The amount of expression, regulation and activity of P-gp influenced by MDR1 gene polymorphisms can directly affect the pharmacokinetics and pharmacodynamics of drugs that are substrates of P-gp, leading to inter-individual variation in drug response and toxicity  .The substrate specificity of P-gp is broad including clinically relevant agents, i.e. anti-neoplasmics (doxorubicin, actinomycin D, paclitaxel), antibiotics (erythromycin, levofloxacin, sparfloxacin, rifampicin), antihypersentives (losartan), antivirals (nelfinavir, indinavir, efavirenz), analgesics (morphine), antiepileptics (phenytoin, phenobarbital), antidepressants (amitriptyline), immunosuppressants (cyclosporin A, tacrolimus, rapamycin), antiarrthythmics (digoxin, verapamil), antilipidemic (atorvastatin) and steroids (aldosterone, cortisol, dexamethasone)  . In addition, the polymorphism exhibited by MDR1 gene is one of the factors responsible for individual susceptibility to various diseases such as breast cancer, colorectal cancer, Parkinson's disease and ulcerative colitis  .
Human MDR1 gene is highly polymorphic and over 50 SNPs have been identified. Among these, variants 2677G > T/A/C in exon 21, 3435C > T in exon 26 and 1236C > T in exon 12 are the most studied alleles of MDR1 gene  . MDR1 gene is extensively explored in Indian populations except NEI. In general, the Indians have at least one variant allele of MDR1. Among the Indian populations, the lowest 42.4 per cent and the highest 60 per cent frequency of 2677T/A allele were observed in NI and SI, respectively  . Similarly, the frequency distribution of the synonymous SNP 3435C > T was found to be 53.6 per cent in NI and 59.5 per cent in SI [Table 4]. A significant inter- and intra-ethnic difference was observed when these two alleles were compared among Indians and with other major populations [Table 2] ,, . On the other hand, the frequency of 1236C > T was available only in NI populations (51.9%) and it was different from other populations, P < 0.0001 [Table 4].
SLC22A1: SLC22A1 belongs to the solute carrier, SLC22, super family of transporters, and these are also known as organic cation transporter 1 (OCT1). These translocate a wide variety of endogenous substances, environmental toxins and therapeutic drugs of cationic nature , . There are three important isoforms of OCTs namely - OCT1, OCT2 and OCT3 with similar membrane topology consisting of 12 transmembrane domains  . Of these, OCT1 is one of the most highly expressed transporters in the hepatocytes and plays a significant role in the hepatic uptake, elimination, distribution and renal transport of several xenobiotics including therapeutic agents (e.g. metformin, levodopa, amantadine, pramipexole and imatinib) ,, . Animal studies have shown that the concentration of metformin in liver was greatly decreased in OCT1 gene knockout mice than in mice with normal OCT1 transporter activity , . The gene encoding human SLC22A1 is mapped onto chromosome 6q25.3, spanning 37kb with 11 exons. Numerous polymorphisms have been described for SLC22A1 gene in various populations leading to differences in transporter function  . Studies across the globe have evaluated the association between genetic variations of SLC22A1 gene and the pharmacokinetics and clinical consequences of metformin, levodopa, imatinib with inconsistent results ,, .
In Indians, the frequency of the three variants rs2282143 in exon 6 (Pro341Leu, 1022C > T), rs628031 in exon 7 (Met408Val, 1222A > G) and rs622342 (1386C > A) located in an intron between exon 8 and exon 9 were described in Tamilian healthy subjects  . No data are available in any of the other Indian populations. Genetic variants of OCT1 were common in SI Tamilians with a frequency of 8.9 per cent (95% CI 5.6-13.5), 80.3 per cent (95% CI 75.2-85.6) and 24.5 per cent (95% CI 18.9-30.2) for the alleles rs2282143 (T), rs628031 (G) and rs622342 (C), respectively  . It was different to the frequencies observed from those in Caucasians, P < 0.004 [Table 2] and [Table 4]. However, the frequency was similar to Africans and other Asian populations for rs628031. With regard to rs2282143, similarity was observed for Africans but not with Asians (P < 0.05), and for rs622342, similarity was shown for Asians but not with Africans (P < 0.05)  . The available data indicate significant delineation in the allele frequencies of the OCT1 gene variants between different ethnic groups leading to dissimilarity in the pharmacokinetics and clinical consequences of the substrates of OCT1.
SLCO1B1: Organic anion transporting polypeptide 1B1 (OATP1B1) is a transmembrane protein with 12 domains, and plays important role in the hepatocellular uptake of various exogenous and endogenous substances of anionic nature including therapeutic drugs such as statins (simvastatin, rosuvastatin, pravastatin, and atorvastatin), methotrexate, repaglinide, irinotecan and rifampin  . It is encoded by the gene OATP1B1, also known as SLCO1B1, and consists of 14 coding and one non-coding exons and spans 108.59 kb, located on chromosome 12p12.2. Polymorphisms in the SLCO1B1 gene decreases the transporter function and ultimately influencing the pharmacokinetics, toxicity and efficacy of OATP1B1 substrates. The variants of SLCO1B1 increase the risk of statin-induced myopathy; methotrexate induced gastrointestinal toxicity and also susceptibility to gallstone disease ,, . The most common polymorphisms were SLCO1B1*1B in exon 5 (388A > G), SLCO1B1*4 (463C > A) and SLCO1B1*5 in exon 6 (521T > C). The prevalence of these variants were available only in NI  population and its frequency was reported to be 45, 2.6 and 1.4 per cent for *1B, *4 and *5, respectively [Table 4]. The comparison of *1B allele frequency showed significant difference with being higher in Africans 87 and Asians 64 per cent but lower in Caucasians 37 per cent (P < 0.001) , . Similarly, the other variants (*4 and *5) were higher in other populations but Asians showed similarity with NI with regard to SLCO1B1*4 [Table 2]  .
| Future directions|| |
Currently, there are studies in India which established the normative frequency of clinically important genes, but most of these analyzed a limited number of individuals from south and north Indian populations. As Indian populations are highly heterogeneous in nature, these results may not be applied to the entire country population. Further, the frequency and impact of these gene polymorphisms on the enzyme activity are available for other major populations of the world (Celera, dbSNP, HapMap, HGVbase, JSNP and Refargen), but there are no such data for Indians. The Indian Genome Variation Consortium (IGVC) has generated a database IGVBrowser which harbours allele and genotype frequency for 4,229 SNPs from over 900 genes in distinct Indian populations, but it focused largely on disease predisposition biomarkers and lacks information on ADME genes  . Considering this along with the endogamous and polygenetic nature of Indian populations and being deficient in functional studies of these polymorphisms in Indians, there is a need for the systematic study to identify and functionally characterize clinically important ADME gene polymorphisms. In doing so, eventually we will have an opportunity to create an Indian database, perhaps an IndMap with the establishment of a nation-wide network among the Indian PGx researchers. This would provide information which would aid the researchers as well as the health care professionals for understanding the ethnic genetic diversity of the Indian population and its impact on drug pharmacokinetics and pharmacodynamics.
Additionally, the ultimate benefit of PGx studies is the usage of personalized medicine in clinical practice. One of the major problems in India is the non-availability of a cost-effective PGx testing method which is specific for Indian populations. Henceforth, it becomes imperative to develop a PGx chip in India and multicentre studies are required to validate the utility and clinical benefit of such chip. Finally, it can be concluded that understanding the role of genetics in influencing the pharmacodynamics and pharmacokinetics of clinically used drugs might help in tailoring pharmacotherapy. Therefore, information regarding the frequency distribution of the defective alleles of genes encoding enzymes concerned with ADME within particular populations is essential in adapting PGx.
| Acknowledgment|| |
The authors acknowledge the Indian Council of Medical Research (ICMR), New Delhi, India, for financial support to various studies conducted in pharmacogenomics. The authors thank Shri A. Naveen, Drs Rosemary, S.S. Soya, R. Padmaja, U.S. Chakradhara Rao, Shri A.S. Arunkumar and Ms. D. Anichavezhi, who contributed to the studies from JIPMER addressed in this review.
| References|| |
|1.||Evans DA, Manley KA, Mc KV. Genetic control of isoniazid metabolism in man. Br Med J 1960; 2 : 485-91. |
|2.||Chowbay B, Zhou S, Lee EJ. An interethnic comparison of polymorphisms of the genes encoding drug-metabolizing enzymes and drug transporters: experience in Singapore. Drug Metab Rev 2005; 37 : 327-78. |
|3.||Sissung TM, Troutman SM, Campbell TJ, Pressler HM, Sung H, Bates SE, et al. Transporter pharmacogenetics: transporter polymorphisms affect normal physiology, diseases, and pharmacotherapy. Discov Med 2012; 13 : 19-34. |
|4.||Ma Q, Lu AY. Pharmacogenetics, pharmacogenomics, and individualized medicine. Pharmacol Rev 2011; 63 : 437-59. |
|5.||Naveen AT, Adithan C, Padmaja N, Shashindran CH, Abraham BK, Satyanarayanamoorthy K, et al. Glutathione S-transferase M1 and T1 null genotype distribution in South Indians. Eur J Clin Pharmacol 2004; 60 : 403-6. |
|6.||Soya SS, Padmaja N, Adithan C. Genetic polymorphisms of CYP2E1 and GSTP1 in a South Indian population--comparison with North Indians, Caucasians and Chinese. Asian Pac J Cancer Prev 2005; 6 : 315-9. |
|7.||Jose R, Chandrasekaran A, Sam SS, Gerard N, Chanolean S, Abraham BK, et al. CYP2C9 and CYP2C19 genetic polymorphisms: frequencies in the south Indian population. Fundam Clin Pharmacol 2005; 19 : 101-5. |
|8.||Naveen AT, Adithan C, Soya SS, Gerard N, Krishnamoorthy R. CYP2D6 genetic polymorphism in South Indian populations. Biol Pharm Bull 2006; 29 : 1655-8. |
|9.||Sam SS, Thomas V, Reddy SK, Surianarayanan G, Chandrasekaran A. CYP1A1 polymorphisms and the risk of upper aerodigestive tract cancers in an Indian population. Head Neck 2008; 30 : 1566-74. |
|10.||Umamaheswaran G, Praveen RG, Arunkumar AS, Das AK, Shewade DG, Adithan C. Genetic analysis of OCT1 gene polymorphisms in an Indian population. Indian J Hum Genet 2011; 17 : 164-8. |
|11.||Arun Kumar AS, ChakradharaRao US, Umamaheswaran G, Ramu P, Kesavan R, Shewade DG, et al. Haplotype structures of common variants of CYP2C8, CYP2C9, and ADRB1 genes in a South Indian population. Genet Test Mol Biomarkers 2011; 15 : 407-13. |
|12.||Umamaheswaran G, Krishna Kumar D, Kayathiri D, Rajan S, Shewade DG, Dkhar SA, et al. Inter and intra-ethnic differences in the distribution of the molecular variants of TPMT, UGT1A1 and MDR1 genes in the South Indian population. Mol Biol Rep 2012; 39 : 6343-51. |
|13.||Krishnakumar D, Gurusamy U, Dhandapani K, Surendiran A, Baghel R, Kukreti R, et al. Genetic polymorphisms of drug-metabolizing phase I enzymes CYP2E1, CYP2A6 and CYP3A5 in South Indian population. Fundam Clin Pharmacol 2012; 26 : 295-306. |
|14.||Anichavezhi D, Chakradhara Rao US, Shewade DG, Krishnamoorthy R, Adithan C. Distribution of CYP2C19*17 allele and genotypes in an Indian population. J Clin Pharm Ther 2012; 37 : 313-8. |
|15.||Government of India. Census of India. Provisional Population Totals of 2011. Available from: http://www.censusindia.gov.in/2011-prov-results/PPT_2.html, accessed on June 10, 2012. |
|16.||Indian Genome Variation Database. Available from: http://www.igvdb.res.in/references.php, accessed on June 10, 2012. |
|17.||Reich D, Thangaraj K, Patterson N, Price AL, Singh L. Reconstructing Indian population history. Science 2009; 461 : 489-94. |
|18.||Zanger UM, Turpeinen M, Klein K, Schwab M. Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal Bioanal Chem 2008; 392 : 1093-108 |
|19.||Sobti RC, Sharma S, Joshi A, Jindal SK, Janmeja A. Genetic polymorphism of the CYP1A1, CYP2E1, GSTM1 and GSTT1 genes and lung cancer susceptibility in a north indian population. Mol Cell Biochem 2004; 266 : 1-9. |
|20.||Sharma R, Ahuja M, Panda NK, Khullar M. Combined effect of smoking and polymorphisms in tobacco carcinogen-metabolizing enzymes CYP1A1 and GSTM1 on the head and neck cancer risk in North Indians. DNA Cell Biol 2010; 29 : 441-8. |
|21.||Vibhuti A, Arif E, Mishra A, Deepak D, Singh B, Rahman I, et al. CYP1A1, CYP1A2 and CYBA gene polymorphisms associated with oxidative stress in COPD. Clin Chim Acta 2010; 411 : 474-80 |
|22.||Kumar V, Singh S, Yadav CS, Ahmed RS, Gupta S, Pasha ST, et al. CYP1A1 and CYP3A4 polymorphic variations in Delhi population of Northern India. Environ Toxicol Pharmacol 2010; 29 : 126-30. |
|23.||Ahmad ST, Arjumand W, Seth A, Nafees S, Rashid S, Ali N, et al. Risk of renal cell carcinoma and polymorphism in phase I xenobiotic metabolizing CYP1A1 and CYP2D6 enzymes. Urol Oncol 2012; 31 : 1350-7. |
|24.||Singh N, Mitra AK, Garg VK, Agarwal A, Sharma M, Chaturvedi R, et al. Association of CYP1A1 polymorphisms with breast cancer in North Indian women. Oncol Res 2007; 16 : 587-97. |
|25.||Singh V, Rastogi N, Sinha A, Kumar A, Mathur N, Singh MP. A study on the association of cytochrome-P450 1A1 polymorphism and breast cancer risk in north Indian women. Breast Cancer Res Treat 2007; 101 : 73-81. |
|26.||Srivastava DS, Mandhani A, Mittal RD. Genetic polymorphisms of cytochrome P450 CYP1A1 (*2A) and microsomal epoxide hydrolase gene, interactions with tobacco-users, and susceptibility to bladder cancer: a study from North India. Arch Toxicol 2008; 82 : 633-9 |
|27.||Anantharaman D, Chaubal PM, Kannan S, Bhisey RA, Mahimkar MB. Susceptibility to oral cancer by genetic polymorphisms at CYP1A1, GSTM1 and GSTT1 loci among Indians: tobacco exposure as a risk modulator. Carcinogenesis 2007; 28 : 1455-62. |
|28.||Shaffi SM, Shah MA, Bhat IA, Koul P, Ahmad SN, Siddiqi MA. CYP1A1 polymorphisms and risk of lung cancer in the ethnic Kashmiri population. Asian Pac J Cancer Prev 2009; 10 : 651-6. |
|29.||Malik MA, Upadhyay R, Mittal RD, Zargar SA, Modi DR, Mittal B. Role of xenobiotic-metabolizing enzyme gene polymorphisms and interactions with environmental factors in susceptibility to gastric cancer in Kashmir Valley. J Gastrointest Cancer 2009; 40 : 26-32. |
|30.||Suryanarayana V, Deenadayal M, Singh L. Association of CYP1A1 gene polymorphism with recurrent pregnancy loss in the South Indian population. Hum Reprod 2004; 19 : 2648-52. |
|31.||Vani GT, Mukesh N, Siva Prasad B, Rama Devi P, Hema Prasad M, Usha Rani P, et al. Association of CYP1A1*2A polymorphism with male infertility in Indian population. Clin Chim Acta 2009; 410 : 43-7. |
|32.||Joseph T, Chacko P, Wesley R, Jayaprakash PG, James FV, Pillai MR. Germline genetic polymorphisms of CYP1A1, GSTM1 and GSTT1 genes in Indian cervical cancer: associations with tumor progression, age and human papillomavirus infection. Gynecol Oncol 2006; 101 : 411-7. |
|33.||Syamala VS, Syamala V, Sheeja VR, Kuttan R, Balakrishnan R, Ankathil R. Possible risk modification by polymorphisms of estrogen metabolizing genes in familial breast cancer susceptibility in an Indian population. Cancer Invest 2010; 28 : 304-11. |
|34.||Suneetha KJ, Nancy KN, Rajalekshmy KR, Rama R, Sagar TG, Rajkumar T. Role of glutathione-s-transferase and CYP1A1*2A polymorphisms in the therapy outcome of south Indian acute lymphoblastic leukemia patients. Indian J Med Paediatr Oncol 2011; 32 : 25-9. |
|35.||Majumdar S, Mondal BC, Ghosh M, Dey S, Mukhopadhyay A, Chandra S, et al. Association of cytochrome P450, glutathione S-transferase and N-acetyl transferase 2 gene polymorphisms with incidence of acute myeloid leukemia. Eur J Cancer Prev 2008; 17 : 125-32. |
|36.||Ihsan R, Chauhan PS, Mishra AK, Yadav DS, Kaushal M, Sharma JD, et al. Multiple analytical approaches reveal distinct gene-environment interactions in smokers and non smokers in lung cancer. PLoS One 2011; 6 : e29431. |
|37.||Parveen F, Faridi RM, Das V, Tripathi G, Agrawal S. Genetic association of phase I and phase II detoxification genes with recurrent miscarriages among North Indian women. Mol Hum Reprod 2010; 16 : 207-14. |
|38.||Surekha D, Sailaja K, Rao DN, Padma T, Raghunadharao D, Vishnupriya S. Association of CYP1A1*2 polymorphisms with breast cancer risk: a case control study. Indian J Med Sci 2009; 63 : 13-20. |
|39.||Tiwari AK, Deshpande SN, Rao AR, Bhatia T, Mukit SR, Shriharsh V. Genetic susceptibility to tardive dyskinesia in chronic schizophrenia subjects: I. Association of CYP1A2 gene polymorphism. Pharmacogenomics J 2005; 5 : 60-9. |
|40.||Singh AP, Pant MC, Ruwali M, Shah PP, Prasad R, Mathur N, et al. Polymorphism in cytochrome P450 1A2 and their interaction with risk factors in determining risk of squamous cell lung carcinoma in men. Cancer Biomark 2010-2011; 8 : 351-9. |
|41.||Tiwari AK, Deshpande SN, Lerer B, Nimgaonkar VL, Thelma BK. Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: V. Association of CYP1A2 1545 C > T polymorphism. Pharmacogenomics J 2007; 7 : 305-11. |
|42.||Singh V, Upadhyay G, Rastogi N, Singh K, Singh MP. Polymorphism of xenobiotic-metabolizing genes and breast cancer susceptibility in North Indian women. Genet Test Mol Biomarkers 2011; 15 : 343-9 |
|43.||Ruwali M, Pant MC, Shah PP, Mishra BN, Parmar D. Polymorphism in cytochrome P450 2A6 and glutathione S-transferase P1 modifies head and neck cancer risk and treatment outcome. Mutat Res 2009; 669 : 36-41. |
|44.||Sistonen J, Fuselli S, Palo JU, Chauhan N, Padh H, Sajantila A. Pharmacogenetic variation at CYP2C9, CYP2C19, and CYP2D6 at global and microgeographic scales. Pharmacogenet Genomics 2009; 19 : 170-9 |
|45.||Singh S, Kumar V, Vashisht K, Singh P, Banerjee BD, Rautela R, et al. Role of genetic polymorphisms of CYP1A1, CYP3A5, CYP2C9, CYP2D6, and PON1 in the modulation of DNA damage in workers occupationally exposed to organophosphate pesticides. Toxicol Appl Pharmacol 2011; 257 : 84-92 |
|46.||Yadav SS, Ruwali M, Pant MC, Shukla P, Singh RL, Parmar D. Interaction of drug metabolizing cytochrome P450 2D6 poor metabolizers with cytochrome P450 2C9 and 2C19 genotypes modify the susceptibility to head and neck cancer and treatment response. Mutat Res 2010; 684 : 49-55. |
|47.||Rathore SS, Agarwal SK, Pande S, Mittal T, Mittal B. Frequencies of VKORC1 -1639 G > A, CYP2C9*2 and CYP2C9*3 genetic variants in the northern Indian population. Biosci Trends 2010; 4 : 333-7. |
|48.||Paul S, Pant MC, Parmar D, Verma J. Association and treatment response to capecitabine-based chemoradiotherapy with CYP2C9 polymorphism in head and neck cancer. Indian J Cancer 2011; 48 : 223-9. |
|49.||Lamba JK, Dhiman RK, Kohli KK. CYP2C19 genetic mutations in North Indians. Clin Pharmacol Ther 2000; 68 : 328-35. |
|50.||Ghodke Y, Joshi K, Arya Y, Radkar A, Chiplunkar A, Shintre P, et al. Genetic polymorphism of CYP2C19 in Maharashtrian population. Eur J Epidemiol 2007; 22 : 907-15. |
|51.||Siddapuram SP, Banerjee R, Tandan M, Prathap N, Mitnal S, Duvvuru NR. CYP2C19 polymorphism as a predictor of personalized therapy in South Indian population. J Assoc Physicians India 201; 59 : 490-3. |
|52.||Yadav SS, Ruwali M, Shah PP, Mathur N, Singh RL, Pant MC, et al. Association of poor metabolizers of cytochrome P450 2C19 with head and neck cancer and poor treatment response. Mutat Res 2008; 644 : 31-7. |
|53.||Singh M, Khanna VK, Shukla R, Parmar D. Association of polymorphism in cytochrome P450 2D6 and N-acetyltransferase-2 with Parkinson's disease. Dis Markers 2010; 28 : 87-93. |
|54.||Shukla P, Gupta D, Pant MC, Parmar D. CYP2D6 polymorphism: A predictor of susceptibility and chemoradiotherapy in head and neck cancer. J Cancer Res Ther 2012; 8 : 40-5 |
|55.||Soundararajan CC, Adhin A, Tripathi M, Prasad HK, Jain S, Vivekanandhan S. Association of CYP2D6 100 C > T and 2850 C > T polymorphisms with generalized tonic clonic seizures among Indians. J Neural Transm 2006; 113 : 1873-6. |
|56.||Arif E, Vibhuti A, Alam P, Deepak D, Singh B, Athar M, et al. Association of CYP2E1 and NAT2 gene polymorphisms with chronic obstructive pulmonary disease. Clin Chim Acta 2007; 382 : 37-42 |
|57.||Balaji L, Singh KB, Bhaskar LV. Genetic polymorphisms of the CYP2E1 gene do not contribute to oral cancer susceptibility in south Indians. Asian Pac J Cancer Prev 2011; 12 : 1523-7. |
|58.||Sameer AS, Nissar S, Qadri Q, Alam S, Baba SM, Siddiqi MA. Role of CYP2E1 genotypes in susceptibility to colorectal cancer in the Kashmiri population. Hum Genomics 2011; 5 : 530-7. |
|59.||Deka M, Bose M, Baruah B, Bose PD, Medhi S, Bose S, et al. Role of CYP2E1 gene polymorphisms association with hepatitis risk in Northeast India. World J Gastroenterol 2010; 16 : 4800-8. |
|60.||Rais N, Chawla YK, Kohli KK. CYP3A phenotypes and genotypes in North Indians. Eur J Clin Pharmacol 2006; 62 : 417-22. |
|61.||Ashavaid T, Raje H, Shalia K, Shah B. Effect of gene polymorphisms on the levels of calcineurin inhibitors in Indian renal transplant recipients. Indian J Nephrol 2010; 20 : 146-51. |
|62.||Bajpai P, Tripathi AK, Agrawal D. Genetic polymorphism of CYP3A5 in Indian chronic myeloid leukemia patients. Mol Cell Biochem 2010; 336 : 49-54. |
|63.||Sailaja K, Rao DN, Rao DR, Vishnupriya S. Analysis of CYP3A5*3 and CYP3A5*6 gene polymorphisms in Indian chronic myeloid leukemia patients. Asian Pac J Cancer Prev 2010; 11 : 781-4. |
|64.||Wojtczak A, Skretkowicz J. Clinical significance of some genetic polymorphisms of cytochromeP-450: family CYP1 and subfamilies CYP2A, CYP2B and CYP2C. Pol Merkur Lekarski 2009; 26 : 248-52 |
|65.||Zhou SF, Wang B, Yang LP, Liu JP. Structure, function, regulation and polymorphism and the clinical significance of human cytochrome P450 1A2. Drug Metab Rev 2010; 42 : 268-354. |
|66.||Cypalleles.ki.se. The Human Cytochrome P450 (CYP) Allele Nomenclature Database. Available from: http://www.cypalleles.ki.se/, accessed on June 1, 2012. |
|67.||Garte S, Gaspari L, Alexandrie AK, Ambrosone C, Autrup H, Autrup JL, et al. Metabolic gene polymorphism frequencies in control populations. Cancer Epidemiol Biomarkers Prev 2001; 10 : 1239-48. |
|68.||Li Y, Millikan RC, Bell DA, Cui L, Tse CK, Newman B, et al. Cigarette smoking, cytochrome P4501A1 polymorphisms, and breast cancer among African-American and white women. Breast Cancer Res 2004; 6 : R460-73. |
|69.||Duell EJ, Holly EA, Bracci PM, Liu M, Wiencke JK, Kelsey KT. A population-based, case-control study of polymorphisms in carcinogen-metabolizing genes, smoking, and pancreatic adenocarcinoma risk. J Natl Cancer Inst 2002; 94 : 297-306. |
|70.||Zhang J, Deng J, Zhang C, Lu Y, Liu L, Wu Q, et al. Association of GSTT1, GSTM1 and CYP1A1 polymorphisms with susceptibility to systemic lupus erythematosus in the Chinese population. Clin Chim Acta 2010; 411 : 878-81. |
|71.||San Jose C, Cabanillas A, Benitez J, Carrillo JA, Jimenez M, Gervasini G. CYP1A1 gene polymorphisms increase lung cancer risk in a high-incidence region of Spain: a case control study. BMC Cancer 2010; 10 : 463. |
|72.||Aklillu E, Carrillo JA, Makonnen E, Hellman K, Pitarque M, Bertilsson L, et al. Genetic polymorphism of CYP1A2 in Ethiopians affecting induction and expression: characterization of novel haplotypes with single-nucleotide polymorphisms in intron 1. Mol Pharmacol 2003; 64 : 659-69. |
|73.||Chida M, Yokoi T, Fukui T, Kinoshita M, Yokota J, Kamataki T. Detection of three genetic polymorphisms in the 5'-flanking region and intron 1 of human CYP1A2 in the Japanese population. Jpn J Cancer Res 1999; 90 : 899-902. |
|74.||Li D, Jiao L, Li Y, Doll MA, Hein DW, Bondy ML, et al. Polymorphisms of cytochrome P4501A2 and N-acetyltransferase genes, smoking, and risk of pancreatic cancer. Carcinogenesis 2006; 27 : 103-11. |
|75.||Di YM, Chow VD, Yang LP, Zhou SF. Structure, function, regulation and polymorphism of human cytochrome P450 2A6.Curr Drug Metab 2009; 10 : 754-80. |
|76.||Paschke T, Riefler M, Schuler-Metz A, Wolz L, Scherer G, McBride CM, et al. Comparison of cytochrome P450 2A6 polymorphism frequencies in Caucasians and African-Americans using a new one-step PCR-RFLP genotyping method. Toxicology 2001; 168 : 259-68. |
|77.||Kwon JT, Nakajima M, Chai S, Yom YK, Kim HK, Yamazaki H, et al. Nicotine metabolism and CYP2A6 allele frequencies in Koreans. Pharmacogenetics 2001; 11 : 317-23. |
|78.||Chen GF, Tang YM, Green B, Lin DX, Guengerich FP, Daly AK, et al. Low frequency of CYP2A6 gene polymorphism as revealed by a one-step polymerase chain reaction method. Pharmacogenetics 1999; 9 : 327-32. |
|79.||Totah RA, Rettie RE. Cytochrome P450 C8: substrates, inhibitors, pharmacogenetics and clinical relevance. Clin Pharmacol Ther 2005; 77 : 341-52. |
|80.||Rodenburg EM, Visser LE, Danser AH, Hofman A, van Noord C, Witteman JC, et al. Genetic variance in CYP2C8 and increased risk of myocardial infarction. Pharmacogenet Genomics 2010; 20 : 426-34. |
|81.||Kudzi W, Dodoo AN, Mills JJ. Characterisation of CYP2C8, CYP2C9 and CYP2C19 polymorphisms in a Ghanaian population. BMC Med Genet 2009; 10 : 124. |
|82.||Nakajima M, Fujiki Y, Noda K, Ohtsuka H, Ohkuni H, Kyo S, et al. Genetic polymorphisms of CYP2C8 in Japanese population. Drug Metab Dispos 2003; 31 : 687-90. |
|83.||Pechandova K, Buzkova H, Matouskova O, Perlik F, Slanar O. Genetic polymorphisms of CYP2C8 in the Czech Republic. Genet Test Mol Biomarkers 2012; 16 : 812-6. |
|84.||Garcia-Martin E, Martinez C, Ladero JM, Agundez JAG. Interethnic and intraethnic variability of CYP2C8 and CYP2C9 polymorhism in healthy individuals. Mol Diag Ther 2006; 10 : 29-40. |
|85.||Lee C.R., Goldstein J.A., Pieper J.A. Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics 2002; 12 : 251-63. |
|86.||Rosemary J, Adithan C. The pharmacogenetics of CYP2C9 and CYP2C19: ethnic variation and clinical significance. Curr Clin Pharmacol 2007; 2 : 93-109. |
|87.||Scott SA, Khasawneh R, Peter I, Kornreich R, Desnick RJ. Combined CYP2C9, VKORC1 and CYP4F2 frequencies among racial and ethnic groups. Pharmacogenomics 2010; 11 : 781-91 |
|88.||Yasar U, Eliasson E, Dahl ML, Johansson I, Ingelman-Sundberg M, Sjoqvist F. Validation of methods for CYP2C9 genotyping: frequencies of mutant alleles in a Swedish population. Biochem Biophys Res Commun 1999; 254 : 628-31. |
|89.||Yoon YR, Shon JH, Kim MK, Lim YC, Lee HR, Park JY, et al. Frequency of cytochrome P450 2C9 mutant alleles in a Korean population. Br J Clin Pharmacol 2001; 51 : 277-80. |
|90.||Desta Z, Zhao X, Shin JG, Flockhart DA. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 2002; 41 : 913-58. |
|91.||Santos PC, Soares RA, Santos DB, Nascimento RM, Coelho GL, Nicolau JC, et al. CYP2C19 and ABCB1 gene polymorphisms are differently distributed according to ethnicity in the Brazilian general population. BMC Med Genet 2011; 12 : 13. |
|92.||Kim KA, Song WK, Kim KR, Park JY. Assessment of CYP2C19 genetic polymorphisms in a Korean population using a simultaneous multiplex pyrosequencing method to simultaneously detect the CYP2C19*2, CYP2C19*3, and CYP2C19*17 alleles. J Clin Pharm Ther 2010; 35 : 697-703. |
|93.||Pedersen RS, Brasch-Andersen C, Sim SC, Bergmann TK, Halling J, Petersen MS, et al. Linkage disequilibrium between the CYP2C19*17 allele and wild type CYP2C8 and CYP2C9 alleles: identification of CYP2C haplotypes in healthy Nordic populations. Eur J Clin Pharmacol 2010; 66 : 1199-205. |
|94.||Dandara C, Lombard Z, Du Plooy I, McLellan T, Norris SA, Ramsay M. Genetic variants in CYP (-1A2, -2C9, -2C19, -3A4 and -3A5), VKORC1 and ABCB1 genes in a black South African population: a window into diversity. Pharmacogenomics 2011; 12 : 1663-70. |
|95.||Wang B, Yang LP, Zhang XZ, Huang SQ, Bartlam M, Zhou S. New insights into the structural characteristics and functional relevance of the human cytochrome P450 2D6 enzyme. Drug Metab Rev 2009; 41 : 573-643. |
|96.||Teh LK, Bertilsson L. Pharmacogenomics of CYP2D6: molecular genetics, interethnic differences and clinical importance. Drug Metab Pharmacokinet 2012; 27 : 55-67. |
|97.||Zhou Q, Yu XM, Lin HB, Wang L, Yun QZ, Hu SN, et al. Genetic polymorphism, linkage disequilibrium, haplotype structure and novel allele analysis of CYP2C19 and CYP2D6 in Han Chinese. Pharmacogenomics J 2009; 9 : 380-94. |
|98.||Li GC, Yang J, Zhou T, Chen ZG, Chen W. CYP2D6 genotypes and phenotypes in Chinese Han, Uygur and Kazakh populations. Yao Xue Xue Bao 2011; 46 : 238-42. |
|99.||Zuo LJ, Guo T, Xia DY, Jia LH. Allele and genotype frequencies of CYP3A4, CYP2C19, and CYP2D6 in Han, Uighur, Hui, and Mongolian Chinese populations. Genet Test Mol Biomarkers 2012; 16 : 102-8. |
|100.||Bozina N, Granic P, Lalic Z, Tramisak I, Lovric M, Stavljenic-Rukavina A. Genetic polymorphisms of cytochromes P450: CYP2C9, CYP2C19, and CYP2D6 in Croatian population. Croat Med J 2003; 44 : 425-8. |
|101.||Kharash ED, Thummel KE. Identification of cytochrome P4502E1 as the predominant enzyme catalyzing human liver microsomal defluorination of sevoflurane, isoflurane and methoxyflurane. Anesthesiologist 1993; 79 : 795-807. |
|102.||Bozina N, Bradamante V, Lovric M. Genetic polymorphism of metabolic enzymes P450 (CYP) as a susceptibility factor for drug response, toxicity, and cancer risk. Arh Hig Rada Toksikol 2009; 60 : 217-42. |
|103.||Lee MY, Mukherjee N, Pakstis AJ, Khaliq S, Mohyuddin A, Mehdi SQ, et al. Global patterns of variation in allele and haplotype frequencies and linkage disequilibrium across the CYP2E1 gene. Pharmacogenomics J 2008; 8 : 349-56. |
|104.||Wang SM, Zhu AP, Li D, Wang Z, Zhang P, Zhang GL. Frequencies of genotypes and alleles of the functional SNPs in CYP2C19 and CYP2E1 in mainland Chinese Kazakh, Uygur and Han populations. J Hum Genet 2009; 54 : 372-5. |
|105.||Daly AK. Significance of the minor cytochrome P450 3A isoforms. Clin Pharmacokinet 2006; 45 : 13-31. |
|106.||Lamba JK, Lin YS, Schuetz EG, Thummel KE. Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev 2002; 54 : 1271-94. |
|107.||Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat. Genet 2001; 27 : 383-91 |
|108.||Garsa AA, McLeod HL, Marsh S. CYP3A4 and CYP3A5 genotyping by Pyrosequencing. BMC Med Genet 2005; 6 : 19. |
|109.||Liu L, Yang L, Zhang YC, Ai XF, Wang JX, Xiao ZJ. Polymorphisms of drug-metabolizing enzymes genes in a Han Chinese population. Zhonghua Yi Xue Za Zhi 2009; 89 : 2675-81. |
|110.||Liu CH, Peck K, Huang JD, Lin MS, Wang CH, Hsu WP. Screening CYP3A single nucleotide polymorphisms in a Han Chinese population with a genotyping chip. Pharmacogenomics 2005; 6 : 731-47. |
|111.||Wen S, Wang H, Ding Y, Liang H, Wang S. Screening of 12 SNPs of CYP3A4 in a Chinese population using oligonucleotide microarray. Genet Test 2004; 8 : 411-6. |
|112.||Oliveira E, Marsh S, van Booven DJ, Amorim A, Prata MJ, McLeod HL. Pharmacogenetically relevant polymorphisms in Portugal. Pharmacogenomics 2007; 8 : 703-12. |
|113.||Kudzi W, Dodoo AN, Mills JJ. Genetic polymorphisms in MDR1, CYP3A4 and CYP3A5 genes in a Ghanaian population: a plausible explanation for altered metabolism of ivermectin in humans? BMC Med Genet 2010; 11 : 111. |
|114.||Hiratsuka M, Takekuma Y, Endo N, Narahara K, Hamdy SI, Kishikawa Y, et al. Allele and genotype frequencies of CYP2B6 and CYP3A5 in the Japanese population. Eur J Clin Pharmacol 2002; 58 : 417-21. |
|115.||Li D, Zhang GL, Lou YQ, Li Q, Wang X, Bu XY. Genetic polymorphisms in MDR1 and CYP3A5 and MDR1 haplotype in mainland Chinese Han, Uygur and Kazakh ethnic groups. J Clin Pharm Ther 2007; 32 : 89-95. |
|116.||Park SY, Kang YS, Jeong MS, Yoon HK, Han KO. Frequencies of CYP3A5 genotypes and haplotypes in a Korean population. J Clin Pharm Ther 2008; 33 : 61-5. |
|117.||Chou FC, Tzeng SJ, Huang JD. Genetic polymorphism of cytochrome P450 3A5 in Chinese. Drug Metab Dispos 2001; 29 : 1205-9. |
|118.||Jancova P, Anzenbacher P, Anzenbacherova E. Phase II drug metabolizing enzymes. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2010; 154 : 103-16. |
|119.||Singh S, Kumar V, Thakur S, Banerjee BD, Grover SS, Rawat DS. Genetic polymorphism of glutathione S-transferase M1 and T1 in Delhi population of Northern India. Environ Toxicol Pharmacol 2009; 28 : 25-9. |
|120.||Konwar R, Manchanda PK, Chaudhary P, Nayak VL, Singh V, Bid HK. Glutathione S-transferase (GST) gene variants and risk of benign prostatic hyperplasia: a report in a North Indian population. Asian Pac J Cancer Prev 2010; 11 : 1067-72. |
|121.||Ruwali M, Singh M, Pant MC, Parmar D. Polymorphism in glutathione S-transferases: susceptibility and treatment outcome for head and neck cancer. Xenobiotica 2011; 41 : 1122-30. |
|122.||Roy B, Dey B, Chakraborty M, Majumder PP.Frequency of homozygous null mutation at the glutathione-s-transferase M1 locus in some populations of Orissa, India. Anthropol Anz 1998; 56 : 43-7. |
|123.||Buch SC, Notani PN, Bhisey RA. Polymorphism at GSTM1, GSTM3 and GSTT1 gene loci and susceptibility to oral cancer in an Indian population. Carcinogenesis 2002; 23 : 803-7. |
|124.||Vettriselvi V, Vijayalakshmi K, Paul SF, Venkatachalam P. Genetic variation of GSTM1, GSTT1 and GSTP1 genes in a South Indian population. Asian Pac J Cancer Prev 2006; 7 : 325-8. |
|125.||Sreeja L, Syamala V, Hariharan S, Madhavan J, Devan SC, Ankathil R. Possible risk modification by CYP1A1, GSTM1 and GSTT1 gene polymorphisms in lung cancer susceptibility in a South Indian population. J Hum Genet 2005; 50 : 618-27. |
|126.||Sameer AS, Qadri Q, Siddiqi MA. GSTP1 I105V polymorphism and susceptibility to colorectal cancer in Kashmiri population. DNA Cell Biol 2012; 31 : 74-9. |
|127.||Mishra DK, Kumar A, Srivastava DS, Mittal RD. Allelic variation of GSTT1, GSTM1 and GSTP1 genes in North Indian population. Asian Pac J Cancer Prev 2004; 5 : 362-5. |
|128.||Sharma R, Ahuja M, Panda N, Khullar M. Polymorphisms in CYP2A13 and UGT1A7 genes and head and neck cancer susceptibility in North Indians. Oral Dis 2010; 16 : 760-8. |
|129.||Murugesan R, Vahab SA, Patra S, Rao R, Rao J, Rai P, et al. Thiopurine S-methyltransferase alleles, TPMT*2, *3B and *3C, and genotype frequencies in an Indian population. Exp Ther Med 2010; 1 : 121-7. |
|130.||Rai PS, Murali TS, Vasudevan TG, Prasada SK, Bhagavath AK, Pai P, et al. Genetic variation in genes involved in folate and drug metabolism in a south Indian population. Indian J Hum Genet 2011; 17 : S48-53. |
|131.||Semwal P, Prasad S, Varma PG, Bhagwat AM, Deshpande SN, Thelma BK. Candidate gene polymorphisms among North Indians and their association with schizophrenia in a case-control study. J Genet 2002; 81 : 65-71. |
|132.||Yadav S, Singhal NK, Singh V, Rastogi N, Srivastava PK, Singh MP. Association of single nucleotide polymorphisms in CYP1B1 and COMT genes with breast cancer susceptibility in Indian women. Dis Markers 2009; 27 : 203-10. |
|133.||Gupta M, Bhatnagar P, Grover S, Kaur H, Baghel R, Bhasin Y, et al. Association studies of catechol-O-methyltransferase (COMT) gene with schizophrenia and response to antipsychotic treatment. Pharmacogenomics 2009; 10 : 385-97. |
|134.||Anitha A, Banerjee M. Arylamine N-acetyltransferase 2 polymorphism in the ethnic populations of South India. Int J Mol Med 2003; 11 : 125-31. |
|135.||Singh S, Kumar V, Singh P, Banerjee BD, Rautela RS, Grover SS, et al. Influence of CYP2C9, GSTM1, GSTT1 and NAT2 genetic polymorphisms on DNA damage in workers occupationally exposed to organophosphate pesticides. Mutat Res 2012; 741 : 101-8. |
|136.||Ginsberg G, Smolenski S, Hattis D, Guyton KZ, Johns DO, Sonawane B. Genetic polymorphism in glutathione transferases (GST): Population distribution of GSTM1, T1, and P1 conjugating activity. J Toxicol Environ Health B Crit Rev 2009; 12 : 389-439. |
|137.||McIlwain CC, Townsend DM, Tew KD. Glutathione S-transferase polymorphisms: cancer incidence and therapy. Oncogene 2006; 25 : 1639-48. |
|138.||Piacentini S, Polimanti R, Porreca F, Martínez-Labarga C, De Stefano GF, Fuciarelli M. GSTT1 and GSTM1 gene polymorphisms in European and African populations. Mol Biol Rep 2011; 38 : 1225-30. |
|139.||Sivonova M, Waczulikova I, Dobrota D, Matakova T, Hatok J, Racay P, et al. Polymorphisms of glutathione-S-transferase M1, T1, P1 and the risk of prostate cancer: a case-control study. J Exp Clin Cancer Res 2009; 28 : 32. |
|140.||Li D, Dandara C, Parker MI. The 341C/T polymorphism in the GSTP1 gene is associated with increased risk of oesophageal cancer. BMC Genet 2010; 11 : 47. |
|141.||Jiang Y, Li N, Dong P, Zhang N, Sun Y, Han M, et al. Polymorphisms in GSTM1, GSTTI and GSTP1 and nasopharyngeal cancer in the east of China: a case-control study. Asian Pac J Cancer Prev 2011; 12 : 3097-100. |
|142.||Mackenzie PI, Miners JO, McKinnon RA. Polymorphisms in UDP glucuronosyltransferase genes: functional consequences and clinical relevance. Clin Chem Lab Med 2000; 38 : 889-92. |
|143.||Schulz C, Boeck S, Heinemann V, Stemmler HJ. UGT1A1 genotyping: a predictor of irinotecan-associated side effects and drug efficacy? Anticancer Drugs 2009; 20 : 867-79. |
|144.||Ginsberg G, Guyton K, Johns D, Schimek J, Angle K, Sonawane B. Genetic polymorphism in metabolism and host defense enzymes: implications for human health risk assessment. Crit Rev Toxicol 2010; 40 : 575-619 |
|145.||Zheng Z, Park JY, Guillemette C, Schantz SP, Lazarus P. Tobacco carcinogen-detoxifying enzyme UGT1A7 and its association with orolaryngeal cancer risk. J Natl Cancer Inst 2001; 93 : 1411-8. |
|146.||Feng FY, Liang G, Lu WF, Miao XP, Yu CY, Tan W, et al. Correlation of polymorphisms of UDP-glucuronosyltransferase 1A7 gene to genetic susceptibility of lung cancer. Ai Zheng 2005; 24 : 1085-90. |
|147.||Piepoli A, Gentile A, Valvano MR, Barana D, Oliani C, Cotugno R, et al. Lack of association between UGT1A7, UGT1A9, ARP, SPINK1 and CFTR gene polymorphisms and pancreatic cancer in Italian patients. World J Gastroenterol 2006; 12 : 6343-8. |
|148.||Lankisch TO, Vogel A, Eilermann S, Fiebeler A, Krone B, Barut A, et al. Identification and characterization of a functional TATA box polymorphism of the UDP glucuronosyltransferase 1A7 gene. Mol Pharmacol 2005; 67 : 1732-9. |
|149.||Sahasranaman S, Howard D, Roy S. Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol 2008; 64 : 753-67. |
|150.||Lindsay J, Wang LL, Li Y, Zhou SF. Structure, function and polymorphism of human cytosolic sulfotransferases. Curr Drug Metab 2008; 9 : 99-105. |
|151.||Hebbring SJ, Moyer AM, Weinshilboum RM. Sulfotransferase gene copy number variation: pharmacogenetics and function. Cytogenet Genome Res 2008; 123 : 205-10. |
|152.||Nowell S, Ratnasinghe DL, Ambrosone CB, Williams S, Teague-Ross T, Trimble L, et al. Association of SULT1A1 phenotype and genotype with prostate cancer risk in African-Americans and Caucasians. Cancer Epidemiol Biomarkers Prev 2004; 13 : 270-6. |
|153.||Liang G, Miao X, Zhou Y, Tan W, Lin D. A functional polymorphism in the SULT1A1 gene (G638A) is associated with risk of lung cancer in relation to tobacco smoking. Carcinogenesis 2004; 25 : 773-8. |
|154.||Tunbridge EM. The catechol-O-methyltransferase gene: its regulation and polymorphisms. Int Rev Neurobiol 2010; 95 : 7-27. |
|155.||Gupta M, Kaur H, Jajodia A, Jain S, Satyamoorthy K, Mukerji M, et al. Diverse facets of COMT: from a plausible predictive marker to a potential drug target for schizophrenia. Curr Mol Med 2011; 11 : 732-43. |
|156.||Le Marchand L, Donlon T, Kolonel LN, Henderson BE, Wilkens LR. Estrogen metabolism-related genes and breast cancer risk: the multiethnic cohort study. Cancer Epidemiol Biomarkers Prev 2005; 14 : 1998-2003. |
|157.||Wen W, Cai Q, Shu XO, Cheng JR, Parl F, Pierce L, et al. Cytochrome P450 1B1 and catechol-O-methyltransferase genetic polymorphisms and breast cancer risk in Chinese women: results from the shanghai breast cancer study and a meta-analysis. Cancer Epidemiol Biomarkers Prev 2005; 14 : 329-35. |
|158.||van Esch AA, de Vries E, Te Morsche RH, van Oijen MG, Jansen JB, Drenth JP. Catechol-O-methyltransferase (COMT) gene variants and pain in chronic pancreatitis. Neth J Med 2011; 69 : 330-4. |
|159.||Vargas-Alarcon G, Fragoso JM, Cruz-Robles D, Vargas A, Vargas A, Lao-Villadoniga J et al. Catechol-O-methyltransferase gene haplotypes in Mexican and Spanish patients with fibromyalgia. Arthritis Res Ther 2007; 9 : R110. |
|160.||Hein DW. Molecular genetics and function of NAT1 and NAT2: role in aromatic amine metabolism and carcinogenesis. Mutat Res 2002; 506-507 : 65-77. |
|161.||García-Martín E. Interethnic and intraethnic variability of NAT2 single nucleotide polymorphisms. Curr Drug Metab 2008; 9 : 487-97. |
|162.||Sharom FJ. ABC multidrug transporters: structure, function and role in chemo resistance. Pharmacogenomics 2008; 9 : 105-27. |
|163.||Choi MK, Song IS. Organic cation transporters and their pharmacokinetic and pharmacodynamic consequences. Drug Metab Pharmacokinet 2008; 23 : 243-53. |
|164.||Poduri A, Khullar M, Bahl A, Sharma YP, Talwar KK. A combination of proatherogenic single-nucleotide polymorphisms is associated with increased risk of coronary artery disease and myocardial infarction in Asian Indians. DNA Cell Biol 2009; 28 : 451-60. |
|165.||Grover S, Bala K, Sharma S, Gourie-Devi M, Baghel R, Kaur H, et al. Absence of a general association between ABCB1 genetic variants and response to antiepileptic drugs in epilepsy patients. Biochimie 2010; 92 : 1207-12. |
|166.||Jafar T, Prasad N, Agarwal V, Mahdi A, Gupta A, Sharma R, et al. MDR-1 gene polymorphisms in steroid-responsive versus steroid-resistant nephrotic syndrome in children. Nephrol Dial Transplant 2011; 26 : 3968-74. |
|167.||Ghodke Y, Chopra A, Shintre P, Puranik A, Joshi K, Patwardhan B. Profiling single nucleotide polymorphisms (SNPs) across intracellular folate metabolic pathway in healthy Indians. Indian J Med Res 2011; 133 : 274-9. |
|168.||Rao DN, Anuradha C, Vishnupriya S, Sailaja K, Surekha D, Raghunadharao D, et al. Association of an MDR1 gene (C3435T) polymorphism with acute leukemia in India. Asian Pac J Cancer Prev 2010; 11 : 1063-6. |
|169.||Jindal C, Kumar S, Choudhari G, Goel H, Mittal B. Organic anion transporter protein (OATP1B1) encoded by SLCO1B1 gene polymorphism (388A > G) & susceptibility in gallstone disease. Indian J Med Res 2009; 129 : 170-5. |
|170.||Srivastava A, Srivastava A, Srivastava N, Choudhuri G, Mittal B. Organic anion transporter 1B1 (SLCO1B1) polymorphism and gallstone formation: High incidence of Exon4 CA genotype in female patients in North India. Hepatol Res 2011; 41 : 71-8. |
|171.||Cascorbi I. P-glycoprotein: tissue distribution, substrates, and functional consequences of genetic variations. Handb Exp Pharmacol 2011; 201 : 261-83. |
|172.||Allabi AC, Horsmans Y, Issaoui B, Gala JL. Single nucleotide polymorphisms of ABCB1 (MDR1) gene and distinct haplotype profile in a West Black African population. Eur J Clin Pharmacol 2005; 61 : 97-102. |
|173.||Xu P, Jiang ZP, Zhang BK, Tu JY, Li HD. Impact of MDR1 haplotypes derived from C1236T, G2677T/A and C3435T on the pharmacokinetics of single-dose oral digoxin in healthy Chinese volunteers. Pharmacology 2008; 82 : 221-7. |
|174.||Cascorbi I, Gerloff T, Johne A, Meisel C, Hoffmeyer S, Schwab M, et al. Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects. Clin Pharmacol Ther 2001; 69 : 169-74. |
|175.||Koepsell H, Lips K, Volk C. Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm Res 2007; 24 : 1227-51. |
|176.||Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 2011; 50 : 81-98. |
|177.||Wang L, Giannoudis A, Lane S, Williamson P, Pirmohamed M, Clark RE. Expression of the uptake drug transporter hOCT1 is an important clinical determinant of the response to imatinib in chronic myeloid leukemia. Clin Pharmacol Ther 2008; 83 : 258-64. |
|178.||Becker ML, Visser LE, van Shaik RH, Hofman A, Uitterlinden AG, Stricker BH. OCT1 polymorphism is associated with response and survival time in anti-Parkinsonian drug users. Neurogenetics 2011; 12 : 79-82. |
|179.||Takane H. Genetic polymorphisms of SLCO1B1 for drug pharmacokinetics and its clinical implications. Yakugaku Zasshi 2011; 131 : 1589-94. |
|180.||Kalliokoski A, Niemi M. Impact of OATP transporters on pharmacokinetics. Br J Pharmacol 2009; 158 : 693-705. |
|181.||Aklillu E, Mugusi S, Ngaimisi E, Hoffmann MM, Konig S, Ziesenitz V, et al. Frequency of the SLCO1B1 388A > G and the 521T>C polymorphism in Tanzania genotyped by a new LightCycler®-based method. Eur J Clin Pharmacol 2011; 67 : 1139-45. |
[Table 1], [Table 2], [Table 3], [Table 4]