| Type2diabetes （T2D） is a common, chronic and complicatedmetabolism disease characterized by insulin resistance and pancreaticβ-cell dysfunction. It is estimated that there are92.4million diabetics at theage≥20years in China alone. As the development of Genome-wideassociation study （GWAS）, more and more genetic loci was foundassociated with T2D, such as HHEX, WFS, SLC30A8, EXT2, FTO,TCF2/HNF1B, CDKN2A/B, IGF2BP2, CDKAL, PPARG, TCF7L2, KCNQ1and KCNJ11. However, the association between these genes and T2D isvaries in dfferent populations. Therefore, a Meta analysis is required.Cyclin-dependent kinase inhibitor-2A/B （CDKN2A/B） has beenreported as a candidate gene of T2D based on its chromosomal position andits important role in β-cell function and regeneration. However, studies todate have reported inconsistent findings regarding the association betweenT2D and CDKN2A/B. To clarify this inconsistence, we conducted ameta-analysis based on alleles and genotypes prevalence of rs10811661andrs564398in CDKN2A/B. The PubMed, EMBASE, and Medline databaseswere systematically reviewed for studies published between January,2006,and November,2010. A total of35reports were collected, among of themonly16studies （including24,407cases and33,937controls） match theinclusion criteria and were selected for the statistical test. In themeta-analysis of published data, our results suggest that the rs10811661Tallele (OR=1.28,95%CI=1.21-1.36, p=9×10-5) and TT genotype (OR=1.32,95%CI=1.22-1.43, p=9×10-5) of CDKN2A/B were associated with type2 diabetes respectively, but rs564398was not （for allele only: OR=0.96,95%CI=0.88-1.05, p=0.35）. The association between rs10811661T alleleand T2D was observed both in Asia (p=9×10-4) and Europe ethnicitygroups （p=0.002）. This meta-analysis yielded evidence that rs10811661ofCDKN2A/B confers risk for T2D. Larger studies with mixed ethnicitysubjects are required to validate our findings.To replicating the associations of T2D and six novel reported variantsin Han Chinese lean individuals of first episode T2D, a total of six high risksingle nucleotide polymorphisms （SNPs） from the BCL11A, DUSP9, IRS1,CENTD2, ADRA2A, and CDKAL1genes were examined. Candidate sixSNPs were genotyped in761T2D patients and433control subjects, andassociations between the six SNPs and Body Mass Index （BMI）, FastingPlasma Glucose （FPG） and Two Hours Oral Glucose Tolerance Test（2hOGTT） were also investigated. CDKAL1provided the strongestevidence for replication, where rs7754840was associated with T2D (oddsratio=1.54, per copy of the risk C allele, p=8.1×10-7). SNP rs5945326atDUSP9showed modest significance （odds ratio=0.81, per copy of theprotective G allele, p=0.02）. After adjusting the confounders of age, genderand BMI, the above results remain significant for both rs7754840(p<1.0×10-4) and rs5945326（p=0.043） respectively. After correcting formultiple testing, however, only the association between T2D andrs7754840at CDKAL1(p<1.0×10-4) remains significant. In addition, therisk C allele of CDKAL1rs7754840was significantly associated withincreased FPG levels (p=3.8×10-4). The association between genetic variantin CDKAL1gene was detected in the Han Chinese lean individuals. Thecorrelation between rs7754840-C allele and increased FPG levels isconsistent with the potential function of CDKAL1gene in pancreatic islets. |
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