A polygenic risk score derived from common variants of monogenic diabetes genes is associated with young-onset type 2 diabetes and cardiovascular–kidney complications

作者：O Chun-Kwan, Baoqi Fan, Sandra T.F. Tsoi, Claudia H.T. Tam, Raymond Wan, Eric S. H. Lau, Mai Shi, Cadmon K.P. Lim, Gechang Yu, Jane P. Y. Ho, Elaine Chow, Alice P.S. Kong, Risa Ozaki, Wing Yee So, Ronald C.W., Andrea O. Y. Luk, Juliana C.N. Chan · 发表于：Diabetologia · 年份：2024 · DOI：10.1007/s00125-024-06320-3 · 被引用次数：7 · 研究领域：Pancreatic function and diabetes、Genetic Associations and Epidemiology、Diabetes and associated disorders

AIMS/HYPOTHESIS: Monogenic diabetes is caused by rare mutations in genes usually implicated in beta cell biology. Common variants of monogenic diabetes genes (MDG) may jointly influence the risk of young-onset type 2 diabetes (YOD, diagnosed before the age of 40 years) and cardiovascular and kidney events. METHODS: >0.2 for linkage disequilibrium in a discovery case-control cohort of 453 adults with YOD (median [IQR] age 39.7 [34.9-46.9] years) and 405 without YOD (median [IQR] age 56.7 [50.3-61.0] years), followed by validation in an independent cross-sectional cohort with array-based genotyping for YOD and a prospective cohort of individuals with type 2 diabetes for cardiovascular and kidney events. RESULTS: In the discovery cohort, the OR of the 135 common variants for YOD ranged from 1.00 to 2.61. In the validation cohort (920 YOD and 4910 non-YOD), top-10%-wPRS was associated with an OR of 1.42 (95% CI 1.03, 1.95, p=0.033) for YOD compared with bottom-10%-wPRS. In 2313 individuals with type 2 diabetes (median [IQR]: age 53.4 [45.4-61.7] years; disease duration 4.0 [1.0-9.0] years) observed for a median (IQR) of 17.5 (14.4-21.8) years, standardised wPRS was associated with increased HR for incident cardiovascular events (1.16 [95% CI 1.06, 1.27], p=0.001), kidney events (1.09 [95% CI 1.02, 1.16], p=0.013) and cardiovascular-kidney events (1.10 [95% CI 1.03, 1.16], p=0.003). Using the 'bottom-20%-wPRS plus baseline disease duration <5 years' group as referent, the 'top-20%...