Abstract 12132: The Intercellular Adhesion Molecule-1 Missense Variant rs5491, High-Sensitivity C-reactive Protein, and Heart Failure With Preserved Ejection Fraction Risk

Introduction: Intercellular adhesion molecule-1 (ICAM-1) is a cell surface protein involved in leukocyte transmigration, thereby promoting inflammation. A missense genetic variant in ICAM1 , rs5491, is common among Black individuals but rare in other race/ethnic groups, and has been associated with increased risk of heart failure with preserved ejection fraction (HFpEF). The pathways by which rs5491 may lead to HFpEF, however, are not known.

Hypothesis: We hypothesized that rs5491 is associated with systemic inflammation as measured by high-sensitivity C-reactive protein (hsCRP) and that the association between rs5491 and HFpEF is mediated by higher hsCRP.

Methods: Among Black individuals within the Multi-Ethnic Study of Atherosclerosis, we evaluated the association of rs5491 with hsCRP at Exam 1 and performed a formal mediation analysis of hsCRP on the association between rs5491 and incident HFpEF.

Results: Among 1558 Black participants (mean age 62±10 y, 47% female), individuals with at least one copy of rs5491 (N=580) had higher hsCRP in unadjusted analysis (2.78 mg/L [IQR: 1.11-6.25] vs 2.25 mg/L [IQR: 0.99-4.82], P=0.009). After covariate adjustment, each additional rs5491 allele was significantly associated with higher hsCRP (β: 0.15, SE: 0.07, P=0.02; Figure ). Each additional rs5491 allele remained significantly associated with incident HFpEF after adjustment for hsCRP in addition to clinical covariates and principal components of ancestry 1-10 (HR 1.86, 95% CI: 1.15-3.01, P=0.01). On mediation analysis, hsCRP did not significantly mediate the association between rs5491 and HFpEF (percent mediated: 0%, 95% CI: 0-31%, P= 0.08).

Conclusions: In Black individuals, the ICAM1 missense variant rs5491 is associated with incident HFpEF and systemic inflammation, as measured by hsCRP. The relationship between rs5491 and HFpEF is not mediated by hsCRP, suggesting that other inflammatory pathways may drive HFpEF risk among individuals with this variant.