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

IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM
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 Y. Y. Leung, Elaine Y. N. Cheung, Man Wo Tsang, Grace Kam, Ip Tim Lau, June K. Y. Li, Vincent T. F. Yeung, Emmy Lau, Stanley Lo, Samuel Fung, Yuk Lun Cheng, Cheuk Chun Szeto, 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. Ma
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引用次数: 0

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

2型糖尿病路径特异性多基因风险评分阐明了18 217名中国2型糖尿病患者在临床表现、疾病进展和糖尿病并发症方面的异质性
目的/假设2型糖尿病是一种复杂的异质性疾病,在中国和东亚人群中,异质性的病因尚不清楚。方法我们采用新开发的2型糖尿病硬聚类和软聚类途径特异性多基因风险评分(psPRSs),对18217名香港华裔患者的2型糖尿病病理生理途径的个体遗传易感性进行表征。2型糖尿病多基因风险 "总分"(PRS)由全基因组显著的2型糖尿病信号(n=1289)相加得出。我们研究了 psPRSs 与心血管代谢概况、发病年龄、两种血糖恶化结果(临床需要胰岛素治疗,定义为连续两次 HbA1c 值≥69 mmol/mol [8.结果虽然大多数 psPRSs 和 2 型糖尿病总 PRS 与 2 型糖尿病发病较早和较年轻有关,但 psPRSs 与临床结果有明显的关联。特别是,体重正常者的β细胞功能障碍和脂肪营养不良的psPRS高于超重者。肥胖的 psPRSs 与临床需要胰岛素治疗(调整 HR [95% CI] 1.09 [1.05, 1.13],p<0.0001)、终末期肾病(1.10 [1.04, 1.16],p=0.0007)和心血管疾病(1.10[1.05,1.16],p<0.0001),而β细胞功能障碍的psPRSs与终末期肾病(0.90[0.85,0.95],p=0.0001)和心力衰竭(0.83[0.73,0.93],p=0.0011)的发生率降低相关。结论/解释β细胞功能障碍和脂肪营养不良可能是体重正常者患 2 型糖尿病的驱动病理途径。β细胞功能障碍和肥胖的遗传风险是导致2型糖尿病在疾病进展和糖尿病并发症方面异质性的两个主要遗传因素,而这两个因素在不同的祖先群体中是共享的。2型糖尿病的PsPRS有助于根据病因对患者进行分层,并指导糖尿病的精准治疗。
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来源期刊
Diabetologia
Diabetologia 医学-内分泌学与代谢
CiteScore
18.10
自引率
2.40%
发文量
193
审稿时长
1 months
期刊介绍: Diabetologia, the authoritative journal dedicated to diabetes research, holds high visibility through society membership, libraries, and social media. As the official journal of the European Association for the Study of Diabetes, it is ranked in the top quartile of the 2019 JCR Impact Factors in the Endocrinology & Metabolism category. The journal boasts dedicated and expert editorial teams committed to supporting authors throughout the peer review process.
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