ADIPOQ,KCNJ11 and TCF7L2 polymorphisms in type 2 diabetes in Kyrgyz population: A case‐control study

Abstract The aim of this study was to ascertain the polymorphic markers profile of ADIPOQ,KCNJ11 and TCF7L2 genes in Kyrgyz population and to analyze the association of polymorphic markers and combinations of ADIPOQ gene's G276T locus, KCNJ11 gene's Glu23Lys locus and TCF7L2 gene's VS3C>T locus with type two diabetes (T2D) in Kyrgyz population. In this case‐control study, 114 T2D patients 109 non‐diabetic participants were genotyped using polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP). Two individual polymorphisms (ADIPOQ rs1501299, KCNJ11 rs5219) were found to be associated with T2D. We found two (Lys23Lys/CC and Glu23Lys/CT) of the overall nine combinations, which were more prevalent in T2D group compared to controls (χ2 = 4.21, P = 0.04). Lys23Lys/CC combination was associated with a 2.65‐fold increased likelihood of T2D (OR = 2.65, 95% CI 1.12‐6.28), whereas the Glu23Lys/CT combination also increased such likelihood (OR = 3.88, 95% CI 1.27‐11.91). This study demonstrated some association of 276T allele and ADIPOQ gene G276T heterozygous genotype as well as KCNJ11 gene 23Lys allele with T2D in ethnic Kyrgyz, but study results should be interpreted with caution because of the limited statistical power.


| INTRODUCTION
Diabetes mellitus type 2 (T2D) is one of the major threats to human health because of its high prevalence, persistently growing prevalence and the severity of its late vascular complications if unrecognized and untreated. 1 Up to 50% of T2D cases get diagnosis at years 5-7 of the disease, while specific macro-and micro-lesions already exist in 20%-30% patients at that time. 1 Genetic predisposition to T2D was studied widely during the last decades. [2][3][4] At present, around 50 candidate genes are considered to increase the likelihood of T2D, of which adiponectin gene (ADIPOQ), potassium channel, inwardly rectifying subfamily J, member 11 (KCNJ11) and transcription factor 7-like 2 (TCF7L2 [IVS3C>T]) may be associated with insulin resistance and β-cells dysfunction. [5][6][7][8][9][10][11][12][13] Carriage of various SNP combinations may explain clinical heterogeneity of this disease. Therefore, the analysis of cumulative SNP contribution in T2D is important.

| MATERIALS AND METHODS
This case-control study with the total sample size N = 223 of unre- DNA was extracted from blood using the standard method of phenol-chloroform extraction. We used PCR-RFLP method to genotype polymorphic loci. We used χ 2 with Yates correction to compare the frequency of alleles and genotypes in the polymorphic markers under study with T2D. The odds ratio (OR) was the measure of association of a given genotype with the outcome for the minor allele of each analysed locus with its corresponding 95% confidence interval (CI). The differences in P < 0.05 were considered statistically significant. We also tested the distribution of allele and genotype frequencies in the population under study using Hardy-Weinberg equilibrium.
When standardising genotyping data (z-clasterisation), we found no correlations between the polymorphic loci under study.
We found two-and three-locus gene-gene interactions of ADI-POQ, KCNJ11 and TCF7L2, which were significantly associated with T2D. Three of the total number of nine genotypes were associated with higher risk of T2D with varying effect ( Table 2).
Diabetes mellitus type 2 patients had a statistically significant higher prevalence of G276T/CC genotypes combination (42%) compared to controls (31%) ( protein, which results in suppressed insulin blood secretion as a result of increased ATP-dependent ionic channel activity, membrane potential change and intracellular calcium concentration decrease, which initiates insulin secretion. 2,[5][6][7] The association of ADIPOQ gene G276T polymorphic locus with T2D in our study was also previously confirmed in the Japanese and Taiwanese, 8,9 and such association may be explained with impaired tissue susceptibility to insulin. 2,8,9 TCF7L2 gene IVS3C/T polymorphic locus was not associated with T2D in the current analysis. Asian and Caucasian populations largely differ in the prevalence of IVS3-T allele of TCF7L2 gene IVS3C/T polymorphism. Asian population studies showed lower IVS3-T prevalence (5%-15%) as opposed to Caucasian ones (36%-46%), and even up to 50% in African populations. 10 IVS3-T allele prevalence (11%) in Kyrgyz population was somewhat similar to other Asian populations. 11 Literature data support the role of IVS3-T allele of TCF7L2 gene IVS3C/T polymorphic locus with T2D in the European populations. 10 In Asian populations, TCF7L2 gene IVS3C>T polymorphic locus is either not associated with T2D separately or has a weak association. [11][12][13] Studies of genetic background of T2D are vital to timely identify high-risk individuals and to implement a prevention plan in these individuals as well as in general population.

CONF LICT OF I NTEREST
The authors confirm that there are no conflicts of interest.