A Molecular Epidemiology Study On The Type2Diabetes Susceptibilty In Chinese Population

Type2diabetes is one of the major public problems which affect more than300million individuals worldwide, and its prevalence is continuously increasing in manycountries, especially in China. Both genetic and environmental factors contribute tothe pathogenesis of type2diabetes. It is considered to be a polygenic disorder inwhich each genetic variant confers a partial and additive effect. Given its publichealth importance and high heritability, the identifcation of the underlyingsusceptibility genes has been a high-priority mission of the scientifc research.With the development of genome-wide association study (GWAS), spectacularadvance has been made in identifying susceptibility genes involved in type2diabetes.Since the first GWAS conducted in French identified four new loci containingvariants that confered type2diabetes risk in2007, there had been about more than20GWAS that discovered at least40susceptibility loci harboring common variantsassociated with an increased risk of type2diabetes till now.Therefore, we hypothesized that the genetic variants on GWAS previouslyreported SNPs also play an important role in type2diabetes susceptibility inChinese population, and that the causal loci on those areas may predispose to thetype2diabetes.To test these hypotheses, a two-stage case-control study with large sample sizewas performed to detect the associations of common polymorphisms on35gene(regions) with type2diabetes risk in Chinese population. According to the resultsfrom GWAS,“fine mapping” and “candidate loci” approaches were conducted toselect single nucleotide polymorphisms (SNPs). The results of this study will be helpful for determining the genetic factors of type2diabetes in Chinese populationand elucidating the susceptibility mechanism in type2diabetes.Part I:“Fine Mapping” Type2Diabetes SusceptibilityRegion10q23.33in Chinese PopulationGenome-wide association studies (GWAS) in populations of European ancestryhave mapped a type2diabetes susceptibility region to chromosome10q23.33containing IDE, KIF11and HHEX genes (IDE-KIF11-HHEX), which has also beenreplicated in Chinese populations. Since the functional relevance for genetic variantsat this locus is still unclear, it is critical to systematically assess the relationship ofgenetic variants in this region with the risk of type2diabetes.To test this hypothesis, a two-stage case-control study was conducted in Hanethnic populations derived from Jiangsu, China. The first-stage, consisting of1,200cases and1,200controls, was to discover novel risk variants from19tagging SNPsselected according to linkage disequilibrium in Chinese population by using a finemapping approach, and these variants were then replicated in the second-stage,consisting of1,725cases and3,281controls. In addition, pairwise conditionalanalysis was used to detect the potential functional significance of the causal loci.The results showed seven tagging SNPs were consistently associated with type2diabetes in both stages (P<0.05) and all of them were still significant aftermultiple-test correction (P<0.0045) with combined odds ratios (ORs) ranging from1.14to1.33. The most significant locus was rs7923837[OR=1.33,95%confidenceinterval (CI):1.21-1.47] at the3’-flanking region of HHEX gene. SNP rs1111875wasfound to be another independent locus (OR=1.23,95%CI:1.13-1.35) in this regionthat was associated with type2diabetes risk. A cumulative effect of rs7923837andrs1111875was observed and individuals carrying1,2and3or4risk alleles having a1.27,1.44and1.73-fold increased risk, respectively, for type2diabetes (P for trend=4.1E-10). In summary, these findings suggest that genetic variants of theIDE-KIF11-HHEX region at10q23.33may contribute to type2diabetes susceptibilityand rs7923837and rs1111875may represent two strong signals related to type2diabetes risk in Chinese Han population.Part II: Identifying Type2Diabetes Susceptibilty Gene andPredicting Type2Diabetes Risk in Chinese Population onthe Basis of Genome-wide Association StudyWith the development of genome-wide association study (GWAS), spectacularadvance has been made in identifying susceptibility genes involved in type2diabetes.Since the first GWAS conducted in French identified four new loci containingvariants that confered type2diabetes risk in2007, there had been more than20GWASs that discovered at least40susceptibility gene regions harboring commonvariants associated with an increased risk of type2diabetes till now. These generegions included HHEX, SLC30A8, LOC387761, EXT2, CDKN2A/2B, IGF2BP2,CDKAL1, KCNJ11, PPARG, FTO, JAZF1, CDC123-CAMK1D, TSPAN8-LGR5,THADA, ADAMTS9, NOTCH2, KCNQ1, PEPD, PTPRD, SRR, SPRY2,C2CD4A-C2CD4B, RBMS1/ITGB6, IRS1, MTNR1B, BCL11A, ZBED3, KLF14,TP53INP1, CHCHD9, CENTD2, HMGA2, HNF1A, ZFAND6, PRC1, DUSP9,UBE2E2, ADCY5, PROX1, GCK, GCKR, DGKB/TMEM195. Therefore, wehypothesized that single nucleotide polymorphisms (SNPs) identified in these regionsin Caucasians were also important in the development of type2diabetes in Chinesepopulation.To test this hypothesis, we selected and genotyped48SNPs at35gene regionswith a “candidate loci” approach, in a two-stage case-control study consisited of2925type2diabetes cases and3281controls in Jiangsu Han ethnic population.Among the48SNPs, there were15SNPs from8gene regions showingsignificantly associated with type2diabetes risk. They were rs7756992(OR=1.29, 95%CI:1.19-1.40), rs6931514(OR=1.29,95%CI:1.19-1.39), rs4712524(OR=1.24,95%CI:1.15-1.35), rs4712523(OR=1.25,95%CI:1.15-1.35) from CDKAL1,rs9472138(OR=1.19,95%CI:1.05-1.34) from VEGFA, rs13266634(OR=1.19,95%CI:1.10-1.29) from SLC30A8, rs10811661(OR=1.30,95%CI:1.20-1.41) fromCDKN2A/2B, rs1111875(OR=1.23,95%CI:1.13-1.35), rs7923837(OR=1.33,95%CI:1.21-1.47), rs5015480(OR=1.25,95%CI:1.12-1.39) from HHEX, rs2237897(OR=1.41,95%CI:1.30-1.54), rs2237892(OR=1.35,95%CI:1.24-1.47), rs2237895(OR=1.22,95%CI:1.12-1.33) from KCNQ1, rs1552224(OR=1.28,95%CI:1.10-1.48)from CENTD2, rs8050136(OR=1.17,95%CI:1.03-1.32) from FTO. The KCNQ1rs2237897showed the strongest association to type2diabetes. After conditionalanalysis, a total of9SNPs from8gene regions (i.e. rs7756992from CDKAL1,rs9472138from VEGFA, rs13266634from SLC30A8, rs10811661from CDKN2A/2B,rs1111875and rs7923837from HHEX, rs2237897from KCNQ1, rs1552224fromCENTD2, rs8050136from FTO) showed independent effect on type2diabetes riskand were used to analyze the cumulative effects of gene-gene, gene-enviroment andpredict the type2diabetes risk. Individuals carrying12or more risk alleles of the9SNPs (6.80%of type2diabetes cases and3.64%of controls) had a nearly4-foldincreased risk for developing type2diabetes compared with the reference group of0-5risk alleles (6.76%of type2diabetes cases and12.99%of controls). When takingoverweight (obesity) into consideration, the top group (have more than13riskalleles/factors) had8.32-fold increased risk compared to the reference group (adjustedOR=8.32,95%CI:6.62-10.45). The AUC for the age-adjusted model was low (0.556)but improved significantly with the addition of the genetic risk score (0.602, χ2=34.11,P＜0.0001), and the relative risk for type2diabetes increased by13%per score. In amodel adjusted for age and family history of diabetes, the AUC was0.600andimproved significantly with the genetic risk score (0.652, χ2=27.11, P＜0.0001). In amodel adjusted for age, family history of diabetes and clinical risk factors, the AUCwas0.986without genetic risk score and0.987with the score (P=0.159).These results suggest that genetic variants in CENTD2, VEGFA, CDKAL1,SLC30A8, CDKN2A/2B, HHEX, KCNQ1, FTO genes be associated with type2 diabetes in Chinese Han Population, and genetic risk score based on the8genesprovide a better prediction of risk than knowledge of common risk factors alone.