Proteomic Profile of the ICAM1 p.K56M HFpEF Risk Variant.

Area of Science:

• Genetics
• Cardiovascular Disease
• Proteomics

Background:

• A common missense variant in ICAM1 (rs5491; pK56M) is associated with heart failure with preserved ejection fraction (HFpEF) risk in African Americans.
• The specific biological pathways linking this variant to HFpEF remain unclear.

Purpose of the Study:

• To investigate the circulating proteomic networks associated with the ICAM1 rs5491 variant.
• To identify inflammatory pathways potentially driving HFpEF in African Americans carrying the rs5491 variant.

Main Methods:

• Analysis of 92 circulating proteins and their networks in over 600 African American individuals.
• Weighted gene co-expression network analysis to identify protein networks associated with rs5491.
• Validation of the inflammatory proteomic profile in a separate cohort.

Main Results:

• Seven circulating inflammatory proteins were associated with the rs5491 variant.
• One protein network, enriched with tumor necrosis receptor superfamily members, was significantly associated with rs5491.
• The rs5491 variant showed a consistent inflammatory proteomic profile across cohorts.

Conclusions:

• Inflammatory pathways, particularly those involving the tumor necrosis receptor superfamily, are implicated in HFpEF pathogenesis in African Americans with the ICAM1 rs5491 variant.
• This research provides insight into the molecular mechanisms underlying genetic risk for HFpEF.