Type 2 diabetes pathway-specific polygenic risk scores elucidate heterogeneity in clinical presentation, disease progression and diabetic complications in 18,217 Chinese individuals with type 2 diabetes

作者：Gechang Yu, Claudia H.T. Tam, Cadmon K.P. Lim, Mai Shi, Eric S. H. Lau, Risa Ozaki, Heung Man Lee, Alex C.W. Ng, Yong Hou, Baoqi Fan, Chuiguo Huang, Hongjiang Wu, Aimin Yang, Hoi Man Cheung, Ka Fai Lee, Shing Chung Siu, Grace Hui, Chiu Chi Tsang, Kam Piu Lau, Jenny Leung, Elaine Yun Ning Cheung, Man Wo Tsang, Grace Kam, Ip Tim Lau, June K.Y. Li, Ming Wai Yeung, Emmy Lau, Stanley Lo, Samuel Fung, Yuk Lun Cheng, Cheuk‐Chun Szeto, The Hong Kong Diabetes Biobank Study Group, Elaine Chow, Alice P.S. Kong, Wing Hung Tam, Andrea O. Y. Luk, Michael N. Weedon, Wing‐Yee So, Juliana C.N. Chan, Richard A. Oram, Ronald C.W. · 发表于：Diabetologia · 年份：2024 · DOI：10.1007/s00125-024-06309-y · 被引用次数：19 · 研究领域：Genetic Associations and Epidemiology、Adipokines, Inflammation, and Metabolic Diseases、Diabetes, Cardiovascular Risks, and Lipoproteins

Abstract Aims/hypothesis Type 2 diabetes is a complex and heterogeneous disease and the aetiological components underlying the heterogeneity remain unclear in the Chinese and East Asian population. Therefore, we aimed to investigate whether specific pathophysiological pathways drive the clinical heterogeneity in type 2 diabetes. Methods We employed newly developed type 2 diabetes hard-clustering and soft-clustering pathway-specific polygenic risk scores (psPRSs) to characterise individual genetic susceptibility to pathophysiological pathways implicated in type 2 diabetes in 18,217 Chinese patients from Hong Kong. The ‘total’ type 2 diabetes polygenic risk score (PRS) was summed by genome-wide significant type 2 diabetes signals ( n =1289). We examined the associations between psPRSs and cardiometabolic profile, age of onset, two glycaemic deterioration outcomes (clinical requirement of insulin treatment, defined by two consecutive HbA 1c values ≥69 mmol/mol [8.5%] more than 3 months apart during treatment with two or more oral glucose-lowering drugs, and insulin initiation), three renal (albuminuria, end-stage renal disease and chronic kidney disease) outcomes and five cardiovascular outcomes. Results Although most psPRSs and total type 2 diabetes PRS were associated with an earlier and younger onset of type 2 diabetes, the psPRSs showed distinct associations with clinical outcomes. In particular, individuals with normal weight showed higher psPRSs for beta cell dysfunction a...