A genome-wide association study identifies GRK5 and RASGRP1 as type 2 diabetes loci in Chinese Hans

Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Graduate School of the Chinese Academy of Sciences, Shanghai, China.
Diabetes (Impact Factor: 8.1). 09/2012; 62(1). DOI: 10.2337/db12-0454
Source: PubMed


Substantial progress has been made in identification of type 2 diabetes (T2D) risk loci in the past few years, but our understanding of the genetic basis of T2D in ethnically diverse populations remains limited. We performed a genome-wide association study and a replication study in Chinese Hans comprising 8,569 T2D case subjects and 8,923 control subjects in total, from which 10 single nucleotide polymorphisms were selected for further follow-up in a de novo replication sample of 3,410 T2D case and 3,412 control subjects and an in silico replication sample of 6,952 T2D case and 11,865 control subjects. Besides confirming seven established T2D loci (CDKAL1, CDKN2A/B, KCNQ1, CDC123, GLIS3, HNF1B, and DUSP9) at genome-wide significance, we identified two novel T2D loci, including G-protein-coupled receptor kinase 5 (GRK5) (rs10886471: P = 7.1 × 10(-9)) and RASGRP1 (rs7403531: P = 3.9 × 10(-9)), of which the association signal at GRK5 seems to be specific to East Asians. In nondiabetic individuals, the T2D risk-increasing allele of RASGRP1-rs7403531 was also associated with higher HbA(1c) and lower homeostasis model assessment of β-cell function (P = 0.03 and 0.0209, respectively), whereas the T2D risk-increasing allele of GRK5-rs10886471 was also associated with higher fasting insulin (P = 0.0169) but not with fasting glucose. Our findings not only provide new insights into the pathophysiology of T2D, but may also shed light on the ethnic differences in T2D susceptibility.

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    • "ANK1, which encodes a member of the ankyrin family, is also reported to be associated with impaired insulin secretion and abnormal level of HbA1c [68, 78]. In addition, GWAS in Beijing and Shanghai populations added two new loci to the list, GRK5 and RASGRP1, and the association signal for GRK5 seems to be specific to East Asians [32]. GRK5 is regarded as a positive regulator of insulin sensitivity and this protein is a potential therapeutic target for the treatment of insulin resistance [79]. "
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    • "Genotyping and imputation of SNPs have been described in detail before [29]. In brief, all samples were genotyped using the Illumina Human660W-Quad BeadChip (Illumina, Inc., San Diego, CA) and sample call rates exceeded 97%. "
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    • "It has been reported that more than 50 genes are closely associated with T2DM by genome wide association study (GWAS) technology45. Cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like (CDKAL1) is one of the novel T2DM associated genes identified recently6. CDKAL1 gene, located in 6p22.3, "
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