title: Influence of SLC22A1 rs622342 genetic polymorphism on metformin response in South Indian type 2 diabetes mellitus patients.
abstract: 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.
authors.affiliation: Department of Pharmacology, ICMR Centre for Advanced Research in Pharmacogenomics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605006, India. umagenes@gmail.com.
authors.forename: Gurusamy
authors.initials: G
authors.lastname: Umamaheswaran
authors.affiliation: Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605006, India.
authors.forename: Ramakrishnan Geethakumari
authors.initials: RG
authors.lastname: Praveen
authors.affiliation: Department of Pharmacology, ICMR Centre for Advanced Research in Pharmacogenomics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605006, India.
authors.forename: Solai Elango
authors.initials: SE
authors.lastname: Damodaran
authors.affiliation: Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605006, India.|Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605006, India.
authors.forename: Ashok Kumar
authors.initials: AK
authors.lastname: Das
authors.affiliation: Department of Pharmacology, ICMR Centre for Advanced Research in Pharmacogenomics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605006, India.
authors.forename: Chandrasekaran
authors.initials: C
authors.lastname: Adithan
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D005260:Female; D060005:Genotyping Techniques; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007194:India; D008297:Male; D008687:Metformin / Q000008:administration & dosage*; D008875:Middle Aged; D027702:Organic Cation Transporter 1 / Q000235:genetics*; D011110:Polymorphism, Genetic; D060888:Real-Time Polymerase Chain Reaction; D016896:Treatment Outcome
chemical_list: D007004:Hypoglycemic Agents; D027702:Organic Cation Transporter 1; D008687:Metformin
keywords: Diabetes; Metformin; OCT1; Polymorphism; SLC22A1; South Indians