Dataset Information

Identification of type 2 diabetes loci in 433,540 East Asian individuals.

ABSTRACT: Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D)1,2; however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells3. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes-NKX6-3 and ANK1-in different tissues4-6. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways.

SUBMITTER: Spracklen CN

PROVIDER: S-EPMC7292783 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Identification of type 2 diabetes loci in 433,540 East Asian individuals.

Spracklen Cassandra N CN Horikoshi Momoko M Kim Young Jin YJ Lin Kuang K Bragg Fiona F Moon Sanghoon S Suzuki Ken K Tam Claudia H T CHT Tabara Yasuharu Y Kwak Soo-Heon SH Takeuchi Fumihiko F Long Jirong J Lim Victor J Y VJY Chai Jin-Fang JF Chen Chien-Hsiun CH Nakatochi Masahiro M Yao Jie J Choi Hyeok Sun HS Iyengar Apoorva K AK Perrin Hannah J HJ Brotman Sarah M SM van de Bunt Martijn M Gloyn Anna L AL Below Jennifer E JE Boehnke Michael M Bowden Donald W DW Chambers John C JC Mahajan Anubha A McCarthy Mark I MI Ng Maggie C Y MCY Petty Lauren E LE Zhang Weihua W Morris Andrew P AP Adair Linda S LS Akiyama Masato M Bian Zheng Z Chan Juliana C N JCN Chang Li-Ching LC Chee Miao-Li ML Chen Yii-Der Ida YI Chen Yuan-Tsong YT Chen Zhengming Z Chuang Lee-Ming LM Du Shufa S Gordon-Larsen Penny P Gross Myron M Guo Xiuqing X Guo Yu Y Han Sohee S Howard Annie-Green AG Huang Wei W Hung Yi-Jen YJ Hwang Mi Yeong MY Hwu Chii-Min CM Ichihara Sahoko S Isono Masato M Jang Hye-Mi HM Jiang Guozhi G Jonas Jost B JB Kamatani Yoichiro Y Katsuya Tomohiro T Kawaguchi Takahisa T Khor Chiea-Chuen CC Kohara Katsuhiko K Lee Myung-Shik MS Lee Nanette R NR Li Liming L Liu Jianjun J Luk Andrea O AO Lv Jun J Okada Yukinori Y Pereira Mark A MA Sabanayagam Charumathi C Shi Jinxiu J Shin Dong Mun DM So Wing Yee WY Takahashi Atsushi A Tomlinson Brian B Tsai Fuu-Jen FJ van Dam Rob M RM Xiang Yong-Bing YB Yamamoto Ken K Yamauchi Toshimasa T Yoon Kyungheon K Yu Canqing C Yuan Jian-Min JM Zhang Liang L Zheng Wei W Igase Michiya M Cho Yoon Shin YS Rotter Jerome I JI Wang Ya-Xing YX Sheu Wayne H H WHH Yokota Mitsuhiro M Wu Jer-Yuarn JY Cheng Ching-Yu CY Wong Tien-Yin TY Shu Xiao-Ou XO Kato Norihiro N Park Kyong-Soo KS Tai E-Shyong ES Matsuda Fumihiko F Koh Woon-Puay WP Ma Ronald C W RCW Maeda Shiro S Millwood Iona Y IY Lee Juyoung J Kadowaki Takashi T Walters Robin G RG Kim Bong-Jo BJ Mohlke Karen L KL Sim Xueling X

Nature 20200506 7811

Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D)<sup>1,2</sup>; however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 ...[more]

PMID: 32499647

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Project description:Type 2 diabetes in East Asians is characterized primarily by β-cell dysfunction, and with less adiposity and less insulin resistance compared with that in Caucasians. Such pathophysiological differences can determine the appropriate therapeutics for the disease. Incretins, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, are secreted in response to meal ingestion, and enhance insulin secretion glucose-dependently. Incretin-based drugs, dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists, that ameliorate β-cell dysfunction with limited hypoglycemia risk are now widely used in type 2 diabetes management. Recent meta-analyses of clinical trials on DPP-4i and glucagon-like peptide-1 receptor agonists found that the drugs were more effective in Asians, most likely because of amelioration of β-cell dysfunction. In addition, we found increased glycated hemoglobin-lowering effects of DPP-4i to be associated with intake of fish in type 2 diabetes, which suggests that dietary customs of East Asians might also underlie the greater efficacy of DPP-4i. Despite the limited risk, cases of severe hypoglycemia were reported for DPP-4i/sulfonylureas combinations. Importantly, hypoglycemia was more frequent in patients also receiving glibenclamide or glimepiride, which activate exchange protein directly activated by cyclic adenosine monophosphate 2, a critical mediator of incretin signaling, and was less frequent in patients receiving gliclazide, which does not activate exchange protein directly activated by cyclic adenosine monophosphate 2. Prevention of insulin-associated hypoglycemia by DPP-4i has gained attention with regard to the enhancement of hypoglycemia-induced glucagon secretion by insulinotropic polypeptide, but remains to be investigated in East Asians. Despite the safety issues, which are paramount and must be carefully monitored, the incretin-based drugs could have potential as a first choice therapy in East Asian type 2 diabetes patients.

Dataset Information

Identification of type 2 diabetes loci in 433,540 East Asian individuals.

Publications

Identification of type 2 diabetes loci in 433,540 East Asian individuals.

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