Nuclear Receptor Coactivator-2(NCOA2) Gene Polymorphism And Its Association With Type-2Diabetes Mellitus In The Chinese Han Population

Background InformationNuclear receptor coactivator-2(NCOA2, SRC-2) is a member of the p160steroidreceptor coactivator (SRCs) gene family. NCOA2is expressed in variety of hormoneresponsive tissue and is hence implicated in fertility, bone morphogenesis, cancer andother pathological conditions. Genetic ablation of the gene encoding NCOA2has inaddition, demonstrated its critical role in lipid metabolism and energy balance.Numerous mice knock out studies attested to the effects of SRC-2in energyhomeostasis and obesity.SRC-2null mice were protected against diet induced obesity.Moreover; SRC-2gene invalidation in those animal models revealed enhancedadaptive thermogenesis, lipolysis and increased energy expenditure rendering them aprotection against obesity and favoring insulin sensitivity. Brown adipose tissue ofmice lacking SRC-2expressed higher levels of uncoupling protein1, PGC-1, andacetyl coenzyme A oxidase, causing higher energy expenditure due to enhanced fattyacid oxidation and uncoupling of respiration. As a result, SRC-2null mice exhibithigher body temperature under cold conditions, less fat accumulation, lower levels offasting glycemia and triglyceride, and higher insulin sensitivityNCOA2gene is also observed to have a regulatory role on hepatic glucoserelease by controlling the expression G6Pase, the rate limiting enzyme that catalyzesglucose release during fasting. Mice lacking SRC-2exhibited a glycogen storagedisease mainly attributable to the deficit in G6Pase expression and attenuation of itscatalytic activity in the liver. Furthermore, liver hepatocytes ablation of SRC-2resulted in intestinal fat malabsorption and reduced entry of fat in to the circulationrevealing the role of the gene in positively regulating bile acid secretion in to the gutby monitoring the expression of Bile Salt Export Pump protein and mRNA levels. Moreover, NCOA2enhances adipogenesis by interacting with Peroxisomeproliferator-activated receptor gamma (PPARγ), a key regulator of adipogenesiswhich converts human preadipocyte into a mature fat cell. In white adipose cells,NCOA2predominates as the PPARγ coactivator stimulating fat uptake andadipogenesis in high fat feeding condition. One of the reasons rendering protection toNCOA2gene knockout mice from fat induced obesity is a decreased white adipocytedifferentiation. This partially explains the interplay between NCOA2and PPARγ inpromoting lipogenesis and contrarily, lack of NCOA2was ensued by a reducedadipocyte differentiation.As of late, common polymorphisms of different candidate genes have beenanalyzed for their contribution to prevalence and incidence of glucose intolerance andtype2diabetes mellitus. Numerous SNP association studies are identifying SNPalleles related to various complex disorders. Owing to large-scale genome-wideassociation studies (GWAS), as well as candidate gene studies, the total number ofconfirmed loci have increased staggeringly and the number of loci robustly implicatedin the development of T2D has consequently climbed. However, the polygenic natureof type-2diabetes mellitus necessitates analysis of multiple genes and their interactionwith environmental and lifestyle factors. There is no published association studyconducted on the nuclear receptor coactivator-2(NCOA2) gene and type-2diabetesmellitus, while gene knock out studies in animal models have evidenced its role inregulating energy homeostasis and lipid metabolism. Taking in to account thecomplexity and versatility of the gene, its wide expression in many organs and tissues,its crucial role in lipid and glucose metabolism-genetic association study in variants ofNCOA2gene with type-2diabetes mellitus is of paramount importance.Objective:To identify the association of NCOA2gene polymorphism with type2diabetes; toidnetify in patients with type2diabetes, the relationship between the NCOA2geneand lipid metabolism and complications of type2diabetes.Method:A total of383subjects were enrolled comprising;190type-2diabetes patientsand193normal healthy controls. All of the recruited subjects were Chinese Han Population who have attended the Petroleum Jilin Chemical General Hospital duringthe year2009-2010.Subjects were diagnosed for type-2diabetes mellitus based on theAmerican Diabetic association criteria (ADA,2007). The control group were unrelatedindividuals and with no clinically significant abnormal physical findings and othermetabolic disorders. Besides, case-only study was conducted to evaluate gene-environmental interactions. Whole blood DNA was extracted and genotyped usingMassArray system. Two tagging SNPs in the candidate gene namely: rs10504473A→C and rs41391448A→G were selected. Allelic and genotypic frequencies is bothcases and controls were computed and assessed for significant differences. In thecase-only study, biochemical parameters were analyzed for association with thedifferent genotypes. Pearson chi-square test, odds ratio and95%confidence intervalwas calculated using SPSS version16.Results:In SNP rs10504473A→C, the odds ratio (OR) for allelic frequency was1.305,at95%CI:0.970-1.755. Chi square(X2) for genotype distribution was3.038and P-value:0.219. The odds ratio and95%CI respectively in each of the four models ofinheritance showed the following results; recessive (1.295,0.805-2.0810), dominant(1.488,0.936-2.365) and codominant (1.139,0.747-1.737) and additive (P-value ofCA-X2:0.42).In SNP rs41391448A→G, the odds ratio (OR) for allelic frequency was0.829, at95%CI:0.503-1.366. Chi square (X2) for genotype distribution was0.620and P-value:0.733. The odds ratio and95%in each of the four genetic models were;recessive (1.092,0.217-5.493), dominant (1.253,0.722) and codominant (1.62,0.712-2.238) and additive (P-value of CA-X2:0.08).Haplotypes distribution between themarkers showed a Chi-square value of5.266(P=0.153).ConclusionFrom the results generated, conclusion could be drawn that both selected SNPs;rs rs10504473A→C and rs41391448A→G and their haplotypes are not significantlyassociated with a risk or protection to type-2diabetes mellitus in this population (P-value≥0.05and95%CI value which includes one in its range). In all of the fourmodels evaluated, the two loci were not positively and significantly associated withtype-2diabetes mellitus. In addition, the case-only study did not show a statistically significant association between the clinical parameters ((HDL, LDL, TG, and TC) andgenotypes of the two loci analyzed.