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

Huaixing Li, Wei Gan, Ling Lu, Xiao Dong, Xueyao Han, Cheng Hu, Zhen Yang, Liang Sun, Wei Bao, Pengtao Li, Meian He, Liangdan Sun, Yiqin Wang, Jingwen Zhu, Qianqian Ning, Yong Tang, Rong Zhang, Jie Wen, Di Wang, Xilin ZhuKunquan Guo, Xianbo Zuo, Xiaohui Guo, Handong Yang, Xianghai Zhou, Xuejun Zhang, Lu Qi, Ruth J.F. Loos, Frank B. Hu, Tangchun Wu, Ying Liu, Liegang Liu, Ze Yang, Renming Hu, Weiping Jia, Linong Ji, Yixue Li, Xu Lin

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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 HbA1c 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.

Original languageEnglish (US)
Pages (from-to)291-298
Number of pages8
JournalDiabetes
Volume62
Issue number1
DOIs
StatePublished - Jan 1 2013
Externally publishedYes

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G-Protein-Coupled Receptor Kinase 5
Genome-Wide Association Study
Type 2 Diabetes Mellitus
Fasting
Alleles

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

A genome-wide association study identifies GRK5 and RASGRP1 as type 2 diabetes loci in Chinese Hans. / Li, Huaixing; Gan, Wei; Lu, Ling; Dong, Xiao; Han, Xueyao; Hu, Cheng; Yang, Zhen; Sun, Liang; Bao, Wei; Li, Pengtao; He, Meian; Sun, Liangdan; Wang, Yiqin; Zhu, Jingwen; Ning, Qianqian; Tang, Yong; Zhang, Rong; Wen, Jie; Wang, Di; Zhu, Xilin; Guo, Kunquan; Zuo, Xianbo; Guo, Xiaohui; Yang, Handong; Zhou, Xianghai; Zhang, Xuejun; Qi, Lu; Loos, Ruth J.F.; Hu, Frank B.; Wu, Tangchun; Liu, Ying; Liu, Liegang; Yang, Ze; Hu, Renming; Jia, Weiping; Ji, Linong; Li, Yixue; Lin, Xu.

In: Diabetes, Vol. 62, No. 1, 01.01.2013, p. 291-298.

Research output: Contribution to journalArticle

Li, H, Gan, W, Lu, L, Dong, X, Han, X, Hu, C, Yang, Z, Sun, L, Bao, W, Li, P, He, M, Sun, L, Wang, Y, Zhu, J, Ning, Q, Tang, Y, Zhang, R, Wen, J, Wang, D, Zhu, X, Guo, K, Zuo, X, Guo, X, Yang, H, Zhou, X, Zhang, X, Qi, L, Loos, RJF, Hu, FB, Wu, T, Liu, Y, Liu, L, Yang, Z, Hu, R, Jia, W, Ji, L, Li, Y & Lin, X 2013, 'A genome-wide association study identifies GRK5 and RASGRP1 as type 2 diabetes loci in Chinese Hans', Diabetes, vol. 62, no. 1, pp. 291-298. https://doi.org/10.2337/db12-0454
Li, Huaixing ; Gan, Wei ; Lu, Ling ; Dong, Xiao ; Han, Xueyao ; Hu, Cheng ; Yang, Zhen ; Sun, Liang ; Bao, Wei ; Li, Pengtao ; He, Meian ; Sun, Liangdan ; Wang, Yiqin ; Zhu, Jingwen ; Ning, Qianqian ; Tang, Yong ; Zhang, Rong ; Wen, Jie ; Wang, Di ; Zhu, Xilin ; Guo, Kunquan ; Zuo, Xianbo ; Guo, Xiaohui ; Yang, Handong ; Zhou, Xianghai ; Zhang, Xuejun ; Qi, Lu ; Loos, Ruth J.F. ; Hu, Frank B. ; Wu, Tangchun ; Liu, Ying ; Liu, Liegang ; Yang, Ze ; Hu, Renming ; Jia, Weiping ; Ji, Linong ; Li, Yixue ; Lin, Xu. / A genome-wide association study identifies GRK5 and RASGRP1 as type 2 diabetes loci in Chinese Hans. In: Diabetes. 2013 ; Vol. 62, No. 1. pp. 291-298.
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T1 - A genome-wide association study identifies GRK5 and RASGRP1 as type 2 diabetes loci in Chinese Hans

AU - Li, Huaixing

AU - Gan, Wei

AU - Lu, Ling

AU - Dong, Xiao

AU - Han, Xueyao

AU - Hu, Cheng

AU - Yang, Zhen

AU - Sun, Liang

AU - Bao, Wei

AU - Li, Pengtao

AU - He, Meian

AU - Sun, Liangdan

AU - Wang, Yiqin

AU - Zhu, Jingwen

AU - Ning, Qianqian

AU - Tang, Yong

AU - Zhang, Rong

AU - Wen, Jie

AU - Wang, Di

AU - Zhu, Xilin

AU - Guo, Kunquan

AU - Zuo, Xianbo

AU - Guo, Xiaohui

AU - Yang, Handong

AU - Zhou, Xianghai

AU - Zhang, Xuejun

AU - Qi, Lu

AU - Loos, Ruth J.F.

AU - Hu, Frank B.

AU - Wu, Tangchun

AU - Liu, Ying

AU - Liu, Liegang

AU - Yang, Ze

AU - Hu, Renming

AU - Jia, Weiping

AU - Ji, Linong

AU - Li, Yixue

AU - Lin, Xu

PY - 2013/1/1

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N2 - 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 HbA1c 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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