Cross-Sectional and Longitudinal Replication Analyses of Genome-Wide Association Loci of Type 2 Diabetes in Han Chinese

<div><p>This study aimed to examine genomic loci of type 2 diabetes (T2D) initially identified by genome-wide association studies in populations of European ancestry for their associations with T2D and quantitative glycemic traits, as well as their effects on longitudinal change in fasting plasma glucose (FPG) and T2D development, in the Chinese population. Single nucleotide polymorphisms (SNP) from 25 loci were genotyped in a large case-control sample of 10,001 subjects (5,338 T2D cases and 4,663 controls) and a prospective cohort of 1,881 Chinese. In the case-control sample, 8 SNPs in or near <i>WFS1</i>, <i>CDKAL1</i>, <i>CDKN2A/2B</i>, <i>CDC123</i>, <i>HHEX</i>, <i>TCF7L2</i>, <i>KCNQ1</i>, and <i>MTNR1B</i> were significantly associated with T2D (<i>P</i><0.05). Thirteen SNPs were associated with quantitative glycemic traits. For example, the most significant SNP, rs10811661 near <i>CDKN2A</i>/<i>2B</i> (<i>P</i> = 1.11×10⁻⁸ for T2D), was also associated with 2-h glucose level of an oral glucose tolerance test (<i>P</i> = 9.11×10⁻³) and insulinogenic index (<i>P</i> = 2.71×10⁻²). In the cohort study, individuals carrying more risk alleles of the replicated SNPs had greater FPG increase and T2D incidence in a 7.5-year follow-up period, with each quartile increase in the number of risk alleles being associated with a 0.06 mmol/l greater increase in FPG (<i>P</i> = 0.03) and 19% higher odds of developing T2D (<i>P</i> = 0.058). Our study identified the associations of several established T2D-loci in Europeans with T2D and quantitative glycemic traits in the Chinese population. The prospective data also suggest their potential role in the risk prediction of T2D in the Chinese population.</p>