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: 8.47). 09/2012; 62(1). DOI: 10.2337/db12-0454
Source: PubMed

ABSTRACT 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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Available from: Wei Bao, Aug 17, 2015
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    • "Table 3 | Meta-analysis of serine racemase rs391300 among Chinese Han populations Author Year n A allele frequency OR 95% CI Weight (%) References Case Control Case Control Zhang Current study 249 524 0.30 0.30 0.998 0.791 –1.260 12.09 Zhang Current study 4651 5029 0.29 0.29 1.014 0.953 –1.080 20.02 Li 2012 798 659 0.27 0.27 1.000 0.848 –1.178 19.31 9 Cui 2011 698 803 0.28 0.29 0.977 0.833 –1.145 15.39 2 Shu 2010 1019 1710 0.29 0.28 1.047 0.927 –1.182 15.66 3 Tsai 2010 2798 2367 0.31 0.37 0.765 0.705 –1.830 17.54 1 Pooled OR 0.956 0.845 –1.082 100 There was an extreme heterogeneity (P = 0.0008, I 2 = 85. "
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    ABSTRACT: A genome-wide association study in the Chinese Han population has identified several novel genetic variants of the serine racemase (SRR) gene in type 2 diabetes. Our purpose was to systematically evaluate the contribution of SRR variants in the Chinese Han population. rs391300 and rs4523957 in SRR were genotyped respectively in the two independent populations. A meta-analysis was used to estimate the effects of SRR in 21,305 Chinese Han individuals. Associations between single-nucleotide polymorphisms and diabetes-related phenotypes were analyzed among 2,615 newly diagnosed type 2 diabetes patients and 5,029 controls. Neither rs391300 nor rs4523957 were associated with type 2 diabetes in populations. Furthermore, meta-analysis did not confirm an association between type 2 diabetes and SRR. In the controls, rs391300-A and rs4523957-G were associated with higher 30-min plasma glucose in an oral glucose tolerance test. The present study did not confirm that SRR was associated with type 2 diabetes.
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