- •Of 3 identified missense genetic variants in ICAM1, rs5491 was common among 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 a common missense variant of ICAM1 among 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 between 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 (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]). While the other ICAM1 missense variants (rs5498 and rs1799969) were associated with ICAM-1 levels, 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.
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- A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation.J Am Coll Cardiol. 2013; 62: 263-271
- Reappraising the role of inflammation in heart failure.Nat Rev Cardiol. 2020; 17: 269-285
- Phenotype-Specific Treatment of Heart Failure With Preserved Ejection Fraction: A Multiorgan Roadmap.Circulation. 2016; 134: 73-90
- Myocardial Microvascular Inflammatory Endothelial Activation in Heart Failure With Preserved Ejection Fraction.JACC Heart Fail. 2016; 4: 312-324
- Gene expression and gene associations during the development of heart failure with preserved ejection fraction in the Dahl salt sensitive model of hypertension.Clin Exp Hypertens. 2018; 40: 155-166
- Cellular Adhesion Molecules in Young Adulthood and Cardiac Function in Later Life.J Am Coll Cardiol. 2020; 75: 2156-2165
- Intercellular Adhesion Molecule 1 Regulates Left Ventricular Leukocyte Infiltration, Cardiac Remodeling, and Function in Pressure Overload-Induced Heart Failure.J Am Heart Assoc. 2016; 5e003126
- Genome-Wide Analysis of Left Ventricular Image-Derived Phenotypes Identifies Fourteen Loci Associated With Cardiac Morphogenesis and Heart Failure Development.Circulation. 2019; 140: 1318-1330
- Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.Nat Commun. 2020; 11: 163
- Multi-Ethnic Study of Atherosclerosis: objectives and design.Am J Epidemiol. 2002; 156: 871-881
- PLINK: a tool set for whole-genome association and population-based linkage analyses.Am J Hum Genet. 2007; 81: 559-575
- Genome-wide association study of a heart failure related metabolomic profile among African Americans in the Atherosclerosis Risk in Communities (ARIC) study.Genet Epidemiol. 2013; 37: 840-845
- The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019.Nucleic Acids Res. 2019; 47: D1005-D1012
- Measuring soluble ICAM-1 in African populations.PLoS One. 2014; 9e108956
- Polymorphisms in the ICAM1 gene predict circulating soluble intercellular adhesion molecule-1(sICAM-1).Atherosclerosis. 2011; 216: 390-394
- Prognostic Importance of Impaired Systolic Function in Heart Failure With Preserved Ejection Fraction and the Impact of Spironolactone.Circulation. 2015; 132: 402-414
- A high frequency African coding polymorphism in the N-terminal domain of ICAM-1 predisposing to cerebral malaria in Kenya.Hum Mol Genet. 1997; 6: 1357-1360
- Framingham Heart Study 100K project: genome-wide associations for cardiovascular disease outcomes.BMC Med Genet. 2007; 8 (Suppl): S5
- A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathy.Eur Heart J. 2011; 32: 1065-1076
- Association of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry: a prospective meta-analysis from the cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium.Circ Cardiovasc Genet. 2010; 3: 256-266
- Phenotype-Specific Association of Single-Nucleotide Polymorphisms with Heart Failure and Preserved Ejection Fraction: a Genome-Wide Association Analysis of the Cardiovascular Health Study.J Cardiovasc Transl Res. 2017; 10: 285-294
- Limitations of Administrative Data for Studying Patients Hospitalized With Heart Failure.Ann Intern Med. 2017; 166: 916-917
- Genetic and phenotypic profiling of supranormal ejection fraction reveals decreased survival and underdiagnosed heart failure.Eur J Heart Fail. 2022;
- A functional analysis of a natural variant of intercellular adhesion molecule-1 (ICAM-1Kilifi).Hum Mol Genet. 2000; 9: 525-530
- A polymorphism of intercellular adhesion molecule-1 is associated with a reduced incidence of nonmalarial febrile illness in Kenyan children.Clin Infect Dis. 2005; 41: 1817-1819
Accepted: February 10, 2023
Received in revised form: February 9, 2023
Received: February 2, 2023
Publication stageIn Press Journal Pre-Proof
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