Research Article|Articles in Press

Missense Genetic Variation of ICAM1 and Incident Heart Failure


      • Of 3 identified missense genetic variants in ICAM1, rs5491 was common in individuals of Black race/ethnicity and rare in other race/ethnic groups.
      • Among Black individuals, rs5491 was associated with higher circulating ICAM-1 levels.
      • In Black individuals, the presence of rs5491 was associated with an increased risk of incident heart failure with preserved ejection fraction in our primary cohort and with overall heart failure in a separate cohort. These findings suggest that a common missense variant of ICAM1 in individuals of Black race/ethnicity is associated with risk of heart failure.



      Intercellular adhesion molecule-1 (ICAM-1) is a cell surface protein that participates in endothelial activation and is hypothesized to play a central role in heart failure (HF). We evaluated associations of ICAM1 missense genetic variants with circulating ICAM-1 levels and with incident HF.

      Methods and Results

      We identified 3 missense variants within ICAM1 (rs5491, rs5498 and rs1799969) and evaluated their associations with ICAM-1 levels in the Coronary Artery Risk Development in Young Adults Study and the Multi-Ethnic Study of Atherosclerosis (MESA). We determined the association among these 3 variants and incident HF in MESA. We separately evaluated significant associations in the Atherosclerosis Risk in Communities (ARIC) study. Of the 3 missense variants, rs5491 was common in Black participants (minor allele frequency [MAF] > 20%) and rare in other race/ethnic groups (MAF < 5%). In Black participants, the presence of rs5491 was associated with higher levels of circulating ICAM-1 at 2 timepoints separated by 8 years. Among Black participants in MESA (n = 1600), the presence of rs5491 was associated with an increased risk of incident HF with preserved ejection fraction (HFpEF; HR = 2.30; [95% CI 1.25–4.21; P = 0.007]). The other ICAM1 missense variants (rs5498 and rs1799969) were associated with ICAM-1 levels, but there were no associations with HF. In ARIC, rs5491 was significantly associated with incident HF (HR = 1.24 [95% CI 1.02 – 1.51]; P = 0.03), with a similar direction of effect for HFpEF that was not statistically significant.


      A common ICAM1 missense variant among Black individuals may be associated with increased risk of HF, which may be HFpEF-specific.

      Graphical Abstract

      Key Words

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