Analysis Of Genetic Polymorphisme In Type Il Diabetes Mellitus Among Malay: A Risk Factor And Pharmacogenetic Study
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Date
2017-01
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Universiti Sains Malaysia
Abstract
Type 2 diabetes mellitus (T2DM) is the most common type of diabetes disorder. T2DM arises from a combination of environmental and genetic factors. Genome wide association studies have found several single nucleotide polymorphisms in different genes such as SLC30A8, TCF7L2, FTO, KCNQ1, HHEX, and CDKN2A/2B associated with risk factors of T2DM. Although sitagliptin is known as an effective oral antidiabetic agent, some patients do not respond to it and fail to achieve a desirable glucose level. This study attempted to investigate the association of genetic polymorphisms in SLC30A8, TCF7L2, FTO, KCNQ1, HHEX, and CDKN2A/2B with type 2 diabetes mellitus (T2DM) and the response to sitagliptin among Malaysia’s Malay population. T2DM patients (n=180) aged 18 years and above as well as healthy subjects (n=180) were recruited following institutional ethical approval. All patients signed written informed consents. Out of 180 T2DM patients, 113 patients with uncontrolled glucose level were enrolled for 6 months to sitagliptin in addition to their previous medication (metformin and sulphonylureas). Lipid profiles, liver and renal function tests, fasting plasma glucose, and HbA1c at baseline and after 6 months of sitagliptin therapy were determined using commercially available kits. Response to sitagliptin was defined as HbA1c reduction of more than 0.5% from baseline following sitagliptin therapy. Genomic DNA was extracted from whole blood using a commercial kit. A total of 18 single nucleotide polymorphisms in SLC30A8, TCF7L2, FTO, KCNQ1, HHEX, and CDKN2A/2B were screened using the minisequencing method. The risk association of 18 single nucleotid
polymorphisms with T2DM and association of these SNPs with response to sitagliptin were analyzed using the logistic regression test. Significant differences in the frequencies of CT genotype of rs7901695, AC genotype of rs8050136, and GG genotype of rs7923837 between T2DM and control groups were observed. Findings from this study show that people with GG genotype of HHEX (rs7923837) showed 2.32 odds or chances to get type 2 diabetes compared to AA genotype (OR: 2.32 (95% CI 1.07–5.03), p=0.033). The other 17 single nucleotide polymorphisms were found to be not associated with T2DM risk in this population. Out of 113 T2DM patients, only 93 patients finished the sitagliptin therapy for 6 months. After 6 months of sitagliptin therapy, 47 (50.53%) of the patients achieved a reduction of HbA1c by more than 0.5% and were considered as responders. Type 2 diabetes mellitus patients with AG genotype of HHEX, rs1111875 and CT genotype of rs7903146 showed lower odds or chance to respond to sitagliptin compared to the reference genotype (OR=0.33 (95% CI 0.11–0.99), p=0.045) and (OR=0.15 (95% CI 0.03–0.72), p=0.018), respectively. In addition to that, the eGFR level was found to be significantly associated in response to sitagliptin (OR=0.93 (95% CI 0.89–0.98), p=0.012). In conclusion, this study supports the hypothesis that SNPs in HHEX (rs7923837) is associated with susceptibility of risk to T2DM among Malaysia’s Malay population. The eGFR level, SNPs rs1111875 (HHEX), and rs7903146 (TCF7L2) were found to be a predictive factor for response to sitagliptin.
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Keywords
Type 2 diabetes mellitus , most common type of diabetes disorder.