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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Available from: Wei Bao, Oct 05, 2015
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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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    ABSTRACT: With rapidly increasing prevalence, diabetes has become one of the major causes of mortality worldwide. According to the latest studies, genetic information makes substantial contributions towards the prediction of diabetes risk and individualized antidiabetic treatment. To date, approximately 70 susceptibility genes have been identified as being associated with type 2 diabetes (T2D) at a genome-wide significant level (P < 5 × 10(-8)). However, all the genetic loci identified so far account for only about 10% of the overall heritability of T2D. In addition, how these novel susceptibility loci correlate with the pathophysiology of the disease remains largely unknown. This review covers the major genetic studies on the risk of T2D based on ethnicity and briefly discusses the potential mechanisms and clinical utility of the genetic information underlying T2D.
    BioMed Research International 04/2014; 2014:926713. DOI:10.1155/2014/926713 · 3.17 Impact Factor
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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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    ABSTRACT: Recent large-scale genome-wide association studies have identified multiple loci robustly associated with BMI, predominantly in European ancestry (EA) populations. However, associations of these loci with obesity and related traits have not been well described in Chinese Hans. This study aimed to investigate whether BMI-associated loci are, individually and collectively, associated with adiposity-related traits and obesity in Chinese Hans and whether these associations are modified by physical activity (PA). We genotyped 28 BMI-associated single nucleotide polymorphisms (SNPs) in a population-based cohort including 2,894 unrelated Han Chinese. Genetic risk score (GRS), EA and East Asian ancestry (EAA) GRSs were calculated by adding BMI-increasing alleles based on all, EA and EAA identified SNPs, respectively. Interactions of GRS and PA were examined by including the interaction-term in the regression model. Individually, 26 of 28 SNPs showed directionally consistent effects on BMI, and associations of four loci (TMEM18, PCSK1, BDNF and MAP2K5) reached nominal significance (P<0.05). The GRS was associated with increased BMI, trunk fat and body fat percentages; and increased risk of obesity and overweight (all P<0.05). Effect sizes (0.11 vs. 0.17 kg/m2) and explained variance (0.90% vs. 1.45%) of GRS for BMI tended to be lower in Chinese Hans than in Europeans. The EA GRS and EAA GRS were associated with 0.11 and 0.13 kg/m2 higher BMI, respectively. In addition, we found that PA attenuated the effect of the GRS on BMI (Pinteraction = 0.022). Our observations suggest that the combined effect of obesity-susceptibility loci on BMI tended to be lower in Han Chinese than in EA. The overall, EA and EAA GRSs exert similar effects on adiposity traits. Genetic predisposition to increased BMI is attenuated by PA in this population of Han Chinese.
    PLoS ONE 03/2014; 9(3):e91442. DOI:10.1371/journal.pone.0091442 · 3.23 Impact Factor
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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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    ABSTRACT: The Cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like (CDKAL1) gene rs7756992 A/G polymorphism has been suggested to be associated with type 2 diabetes mellitus (T2DM), but the individual studies results are still controversial. To explore the association of CDKAL1 gene rs7756992 A/G polymorphism with T2DM, a meta-analysis involving 62,567 subjects from 21 separate studies was conducted. In the whole population, a significant association was found between CDKAL1 gene rs7756992 A/G polymorphism and T2DM under allelic (OR: 1.180, 95% CI: 1.130-1.230, P = 1.60 × 10(-14)), recessive (OR: 1.510, 95% CI: 1.380-1.660, P = 8.41 × 10(-18)), dominant (OR: 1.175, 95% CI: 1.109-1.246, P = 6.30 × 10(-8)), homozygous (OR: 1.400, 95% CI: 1.282-1.530, P = 8.02 × 10(-14)), and heterozygous genetic models (OR: 1.101, 95% CI: 1.040-1.166, P = 0.001). CDKAL1 gene rs7756992 A/G polymorphism was significantly associated with T2DM. The person with G allele of CDKAL1 gene rs7756992 A/G polymorphism might be predisposed to T2DM.
    Scientific Reports 11/2013; 3:3131. DOI:10.1038/srep03131 · 5.58 Impact Factor
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