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
Authors: Yu Gechang , Tam Claudia H. T. , Lim Cadmon K. P. , Shi Mai , Lau Eric S. H. , Ozaki Risa , Lee Heung-man , Ng Alex C. W. , Hou Yong , Fan Baoqi , Huang Chuiguo , Wu Hongjiang , Yang Aimin , Cheung Hoi Man , Lee Ka Fai , Siu Shing Chung , Hui Grace , Tsang Chiu Chi , Lau Kam Piu , Leung Jenny Y. Y. , Cheung Elaine Y. N. , Tsang Man Wo , Kam Grace , Lau Ip Tim , Li June K. Y. , Yeung Vincent T. F. , Lau Emmy , Lo Stanley , Fung Samuel , Cheng Yuk Lun , Szeto Cheuk Chun ,   The Hong Kong Diabetes Biobank Study Group, Chow Elaine , Kong Alice P. S. , Tam Wing Hung , Luk Andrea O. Y. , Weedon Michael N. , So Wing-yee , Chan Juliana C. N. , Oram Richard A. , Ma Ronald C. W. ,   for the TRANSCEND Consortium
Published: November 2024

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 HbA1c 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 and lipodystrophy than those who were overweight. The psPRSs for obesity were associated with faster progression to clinical requirement of insulin treatment (adjusted HR [95% CI] 1.09 [1.05, 1.13], p<0.0001), end-stage renal disease (1.10 [1.04, 1.16], p=0.0007) and CVD (1.10 [1.05, 1.16], p<0.0001) while the psPRSs for beta cell dysfunction were associated with reduced incident end-stage renal disease (0.90 [0.85, 0.95], p=0.0001) and heart failure (0.83 [0.73, 0.93], p=0.0011). Major findings remained significant after adjusting for a set of clinical variables.

Conclusions/interpretation
Beta cell dysfunction and lipodystrophy could be the driving pathological pathways in type 2 diabetes in individuals with normal weight. Genetic risks of beta cell dysfunction and obesity represent two major genetic drivers of type 2 diabetes heterogeneity in disease progression and diabetic complications, which are shared across ancestry groups. Type 2 diabetes psPRSs may help inform patient stratification according to aetiology and guide precision diabetes care.

Graphical Abstract