| BackgroundType2diabetes mellitus (T2DM) is a multifactorial disease whose causesinclude both genetic and environmental factors (mostly obesity) that affect pancreaticβ-cell function as well as insulin sensitivity of the main target peripheral tissues,namely: muscle, liver, adipose tissue and pancreas. Studies strongly indicate thatinsulin resistance occurs due to some obesity-induced interference in the normalinsulin signaling cascade. Emerging evidence from several studies in animal modelsshows that the nuclear receptor coactivator3(NCOA3)/steroid receptor coactivator3(SRC-3) gene plays a critical role in adipogenesis, obesity, insulin sensitivity as wellas glucose and lipid metabolism/energy homeostasis. However, there are no publishedhuman epidemiologic studies which have investigated whether single nucleotidepolymorphisms (SNPs) in the NCOA3gene are associated with T2DM. Hence, thisresearcher was prompted to investigate if NCOA3gene SNPs are associated withT2DM in the Chinese population.ObjectiveTo examine the association of SNPs within the NCOA3gene with T2DM in Chinesesubjects and to assess if there are any gene-environment interactions.Research design and methodsThis was an unmatched case-control genetic association study conducted onblood and genomic samples from subjects in Jilin city, North-East China. A total of383Chinese Han subjects (190cases and193controls) were included. Four tagSNPs(rs2425955G>T, rs6066394C>T, rs10485463C>G and rs6094753G>A) in NCOA3gene were selected from the HapMap website. Genomic DNA from subjects’ bloodsamples was extracted using standard protocol (phenol/chloroform extraction), andthe DNA was amplified and genotyped by using PCR methods and MALDI-TOF mass spectrometry, respectively, in the MassARRAY iPLEX System.ResultsOf the4SNPs typed, one of them (rs10485463) showed significant associationwith T2DM in all the genetic models tested except for the co-dominant model[dominant model: OR (95%CI)=0.240(0.003-0.177), P<0.001; recessive model: OR(95%CI)=0.502(0.302-0.835), P=0.008; co-dominant model: OR (95%CI)=0.783(0.495-1.239), P=0.296]. The other3SNPs were not significantly associated withT2DM (P>0.05). However, SNP rs10485463had deviated from the Hardy-Weinbergequilibrium in the controls (χ~2=34.320, df=2, P<0.000001). Haplotype analysisrevealed weak linkage disequilibrium (LD)[r~2<0.8] between the variants.Nevertheless, except for haplotypes formed by both rs2425955and rs6066394, therewere significant (P<0.05) differences in frequency distributions of all other inferredhaplotypes between cases and controls, suggesting association with T2DM-causinggenes. However, the extent of linkage of the inferred haplotypes to T2DM-causinggenes is unreliable (weak LD), and some of the genotypes (rs10485463) from whichthe significant haplotypes were inferred deviated from HWE. Hence, such observedassociation is most likely spurious and should thus be disregarded. Furthermore, case-only analysis showed non-significant gene-environment interactions for NCOA3andalcohol/smoking statuses.ConclusionAlthough there are some significant results in this study, this researcherconcludes that there is no statistical evidence supporting the association betweenT2DM and four SNPs at the NCOA3locus in the Chinese Han population. This isbecause SNP rs10485463genotypes (which showed significant association withT2DM) deviated from HWE in the controls. Furthermore, haplotypes which showedsignificance were reconstructed from one of the SNPs (rs10485463) whose genotypesdeviated from HWE in the controls, and there was weak LD between markers of allthe inferred haplotypes. In addition, there are no significant negative or positive gene-environment interactions for NCOA3and alcohol/smoking statuses. |
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