Metformin is an oral antidiabetic drug, commonly used for treating type 2 diabetes mellitus (T2DM) patients. It is transported into the hepatocytes by polyspecific organic cation transporter 1, which is encoded by the gene SLC22A1. It has been hypothesized that genetic variations of SLC22A1 gene will influence inter-individual variation in glucose lowering efficacy of metformin. Previous studies have demonstrated this in other populations with conflicting results, but it remains to be elucidated in Indian population. Henceforth, the objective of the study was to evaluate the impact of SLC22A1 rs622342 gene polymorphism on the clinical efficacy of metformin in South Indian T2DM patients. A total of 122 newly detected, treatment naive T2DM patients of either sex were included in this study. The patients were started on metformin monotherapy and followed up for 12 weeks. Genotype was determined using qRT-PCR. Before and after treatment with metformin, body mass index (BMI), serum lipid profile, glycated hemoglobin (HbA1c), fasting and postprandial glucose level, and blood pressure (BP) were measured. The study cohort mean age was 49.57 ± 9.88 years. Of the 122 T2DM patients, 93 were classified as responders and 29 as non-responders based on fall in HbA1c levels. Interestingly, carriers of one variant allele 'C' (AC) of rs622342 polymorphism were less among the responders than those who did not (44.8 vs. 22.6 %). The response was even lesser (13.8 vs. 4.3 %) in carriers of two copies of "C" allele (CC). On the contrary, patients with two copies of allele 'A' (AA) had 5.6 times greater chance of responding to metformin treatment. A similar trend was observed when the proportion was analyzed under different genetic models (OR 3.85, 95 % CI 1.61-9.19 for dominant; OR 3.56, 95 % CI 0.83-15.26 for recessive; OR 0.35, 95 % CI 0.14-0.86 for over-dominant; and OR 4.10, 95 % CI 1.78-9.43 for additive). Further, metformin showed significant beneficial effects on BMI, HbA1c, FPG, PPG, lipid parameters and BP. These data suggest that the allele and genotypes of SLC22A1 rs622342 gene polymorphism were associated with the therapeutic efficacy of metformin in South Indian patients with T2DM.

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The Arg16Gly and Gln27Glu polymorphisms do not determine the occurrence of asthma individually, but the GG-CG haplotype is associated with an increased risk of asthma. There is no effect of the genotypes on the response to nebulized salbutamol.

CYP2E1, CYP2A6 and CYP3A5 enzymes belong to phase I group of drug-metabolizing enzymes, which are involved in the metabolism of various compounds and xenobiotics. Presence of polymorphisms in the genes coding for these enzymes results in interindividual variations in drug metabolism, therapeutic response and susceptibility towards various diseases. The frequencies of these variants in genes differ considerably between ethnic groups. This study was carried out to estimate the allele and genotype frequencies of common variants in CYP2E1, CYP2A6 and CYP3A5 in South Indian population. Six hundred and fifty-two unrelated healthy volunteers of South Indian origin (Andhra Pradesh, Karnataka, Kerala and Tamil Nadu) were included in this study. Polymerase chain reaction-restriction fragment length polymorphism, allele-specific PCR, real-time PCR, SNaPshot and gene sequencing methods were used for the identification of gene polymorphisms. The frequencies of CYP2E1*1B, CYP2E1*5B and CYP2E1*6 alleles in South Indian population were 14.3, 1.3 and 22.4%, respectively. The frequencies of CYP2A6*2, CYP2A6*4A and CYP2A6*5 alleles were found to be 1, 8.9 and 0.7%, respectively. The distribution of CYP3A5*3 allele was 63.5%. There were no variant alleles of CYP3A5*2, CYP3A5*4 and CYP3A5*6 in South Indian population. The frequencies of CYP2E1, CYP2A6 and CYP3A5 in the South Indian population are distinct from Caucasians, Chinese, Japanese, African Americans and other compared populations. This is the first study conducted in the South Indian population with a larger sample size. The findings of our study provide the basic genetic information for further pharmacogenomic investigations in the population.

Reduced CYP2D6 activity is associated with poor treatment outcomes, in terms of increased risk of recurrence and shorter recurrence free survival, in breast cancer patients on adjuvant tamoxifen therapy.

BACKGROUND:Genetic variants of the organic cation transporter (OCT1) gene could influence interindividual variation in clinical response to metformin therapy. The genetic basis for the single-nucleotide polymorphism (SNP) of OCT1 gene has been established in other populations, but it remains to be elucidated in the Indian population. This study is focused on OCT1 gene variants rs2282143 (P341L, 1022C>T), rs628031 (M408V, 1222A>G) and rs622342 (1386C>A) frequency distributions in the South Indian Tamilian population.MATERIALS AND METHODS:A total of 112 unrelated healthy subjects of South Indian Tamilian origin, aged 18–60 years, of either sex were recruited for the study. Genotyping was determined using the quantitative real time-polymerase chain reaction and polymerase chain reaction followed by restriction fragment length polymorphism methods.RESULTS:Allele frequencies of rs2282143, rs628031and rs622342 polymorphisms were 8.9%, 80.3% and 24.5%, respectively. Interethnic differences in the genotype and allele frequencies of OCT1 gene polymorphism were observed when compared with other major populations. The SNPs rs2282143, T allele and rs628031, G allele were more common in Asians (5.5–16.8% and 76.2–81%) and African Americans (8.2% and 73.5%) than in Caucasians (0–2% and 57.4–60%).CONCLUSION:This is the first time the frequency of OCT1 gene polymorphism was determined in the Indian population, and is similar to the frequencies observed in African-Americans and other Asian populations but different from those in Caucasians. The data observed in this study would justify further pharmacogenetic studies to potentially evaluate the role of OCT1 gene polymorphism in the therapeutic efficacy of metformin.

Molecular variants of polymorphic drug metabolizing enzymes and drug transporters are attributed to differences in individual's therapeutic response and drug toxicity in different populations. We sought to determine the genotype and allele frequencies of polymorphisms for major phase II drug-metabolizing enzymes (TPMT, UGT1A1) and drug transporter (MDR1) in South Indians. Allelic variants of TPMT (*2,*3A,*3B,*3C & *8), UGT1A1 (TA)6>7 and MDR1 (2677G>T/A & 3435C>T) were evaluated in 450-608 healthy South Indian subjects. Genomic DNA was extracted by phenol-chloroform method and genotype was determined by PCR-RFLP, qRT-PCR, allele specific PCR, direct sequencing and SNaPshot techniques. The frequency distributions of TPMT, UGT1A1 and MDR1 gene polymorphisms were compared between the individual 4 South Indian populations viz., Tamilian, Kannadiga, Andhrite and Keralite. The combined frequency distribution of the South Indian populations together, was also compared with that of other major populations. The allele frequencies of TPMT*3C, UGT1A1 (TA)7, MDR1 2677T, 2677A and 3435T were 1.2, 39.8, 60.3, 3.7, and 61.6% respectively. The other variant alleles such as TPMT*2, *3A, *3B and *8 were not identified in the South Indian population. Sub-population analysis showed that the distribution of UGT1A1 (TA)6>7 and MDR1 allelic variants differed between the four ethnic groups. However, the frequencies of TPMT*3C allele were similar in the four South Indian populations. The distribution of TPMT, UGT1A1 and MDR1 gene polymorphisms of the South Indian population was significantly different from other populations.

Allele and genotype frequency of a genetic variant in ATM gene affecting glycemic response to metformin in South Indian population.Context:The novel polymorphism in ATM gene (rs11212617), which is implicated to have association with metformin response, exhibits inter-ethnic variability in the allele and genotype frequency distribution.Aims and Design:The objective of the present study is to establish the allele and genotype frequency of rs11212617 single nucleotide polymorphism in ATM gene, in South Indian population and to find if this variant has any role in the etiology of type 2 diabetes mellitus.Materials and Methods:The study was performed in 2 cohorts of populations, 112 healthy volunteers and 118 type 2 diabetes mellitus patients. Genomic deoxyribonucleic acid (DNA) was extracted from peripheral blood leucocytes by phenol-chloroform method and genotyping was performed by real-time polymerase chain reaction using TaqMan assay.Results:In South Indian population, the frequency of major A allele was 0.65 and the minor C allele was 0.35. AA and CC are the homozygous genotypes with frequency of 0.39 and 0.09 respectively. The frequency of heterozygous genotype AC (0.52) was found to be higher than the homozygotes. There was no significant difference in the frequency distribution in the diabetic population, which implies that this variant does not have any causative role in the disease etiology. The frequency distributions were found to be significantly different from the distributions in other ethnic populations such as Caucasians, Chinese, Japanese and Africans. But there was no significant difference when compared with the Gujarati Indians of Houston.Conclusion:The frequency distribution of this novel variant in South Indian population forms a framework for further gene disease association studies to establish the association of this variant with metformin response. Our study could not find any association of this variant with respect to the disease etiology.