Pathway-Specific Polygenic Risk Scores and Cardiorenal Complications in Asians With Type 2 Diabetes.

Area of Science:

• Genetics
• Endocrinology
• Nephrology
• Cardiology

Background:

• Cardiorenal complications pose a significant risk for patients with type 2 diabetes (T2D).
• Pathway-specific polygenic risk scores (psPRS) for T2D have shown utility in European populations but require validation in diverse ethnic groups.
• The relevance of T2D-derived psPRS in multi-ethnic Asian populations for cardiorenal outcomes is not well understood.

Purpose of the Study:

• To investigate the associations between T2D-derived psPRS and cardiorenal outcomes in a multi-ethnic Asian cohort.
• To explore the relationship between these psPRS and circulating proteins implicated in cardiorenal complications.

Main Methods:

• Utilized data from 2057 multi-ethnic individuals with T2D in the prospective SMART2D cohort.
• Constructed eight T2D pathway-related psPRS using East Asian-specific effect sizes.
• Employed Cox regression, logistic regression, and linear regression to assess associations with end-stage kidney disease (ESKD), heart failure (HF), rapid decline in kidney function (RDKF), and circulating proteins.

Main Results:

• The Beta-cell -Proinsulin (PI) psPRS was inversely associated with ESKD, RDKF, and HF.
• The lipodystrophy psPRS was associated with increased odds of RDKF.
• The Beta-cell -PI psPRS demonstrated associations with circulating levels of LILRA5, EDA2R, and FABP4.

Conclusions:

• Pathway-specific genetic susceptibility in a multi-ethnic Asian population is differentially associated with cardiorenal outcomes and related circulating proteins.
• These findings highlight the potential utility of biologically informed genetic pathways in diverse populations.
• Further validation in independent cohorts is warranted to confirm these associations.