The ICAM1 p.K56M variant and risk of heart failure in chronic kidney disease: the Chronic Renal Insufficiency Cohort study

Kasen Culler; Leila R. Zelnick; Rupal C Mehta; Giselle R. De Sosa; Mayank Kansal; Panduranga S. Rao; Zeenat Bhat; Jonathan Taliercio; Edward Horwitz; Jing Chen; Jiang He; Sanjiv J Shah; Tamara Isakova; Ravi B Patel

doi:10.1136/heartjnl-2024-325205

The ICAM1 p.K56M variant and risk of heart failure in chronic kidney disease: the Chronic Renal Insufficiency Cohort study

Kasen Culler, Leila R. Zelnick, Rupal C Mehta, Giselle R. De Sosa, Mayank Kansal, Panduranga S. Rao, Zeenat Bhat, Jonathan Taliercio, Edward Horwitz, Jing Chen, Jiang He, Sanjiv J Shah, Tamara Isakova, Ravi B Patel^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Background: Intercellular adhesion molecule-1 (ICAM-1) is a cell-surface protein that facilitates inflammation through leucocyte adhesion. Approximately 35% of Black individuals carry at least one copy of an ICAM1 missense variant (rs5491; p.K56M), which has been associated with increased risk of heart failure (HF) with preserved ejection fraction (HFpEF). Whether the risk of HFpEF conferred by rs5491 extends to individuals with chronic kidney disease (CKD), a cohort at high risk for HF, is unknown. Aims: We investigated the association between rs5491 and the incidence of HF in CKD. Methods: We estimated associations of rs5491 with incident HF and HF subtypes among Black individuals who were free from HF at baseline in the Chronic Renal Insufficiency Cohort (CRIC). The CRIC study recruited individuals who were 21-74 years old with estimated glomerular filtration rate (eGFR) of 20-70 mL/min/1.73 m² at baseline. Results: Among 1267 Black participants (mean age 57±11 years, 51% female, mean eGFR 45±15 mL/min/1.73 m²), 464 (37%) had at least one copy of rs5491. During a median follow-up of 10.3 years (IQR: 4.7-15.0 years), there were 309 incident overall HF hospitalisations (160 HFpEF, 111 HF with reduced ejection fraction (HFrEF) and 38 HF with unknown ejection fraction). Each additional rs5491 allele was significantly associated with incident HFpEF (HR 1.35, 95% CI 1.03 to 1.76, p=0.029). The rs5491 variant was not associated with incident overall HF (HR 1.14, 95% CI 0.93 to 1.39, p=0.20) or incident HFrEF (HR 0.76, 95% CI 0.53 to 1.10, p=0.15). Conclusion: The ICAM1 p.K56M variant is specifically associated with increased risk of incident HFpEF among individuals with CKD.

Original language	English (US)
Article number	325205
Journal	Heart
DOIs	https://doi.org/10.1136/heartjnl-2024-325205
State	Accepted/In press - 2025

Funding

'RP is supported by grant R01HL167986 from the National Institutes of Health. Funding for the CRIC study was obtained under a cooperative agreement from the National Institute of Diabetes and Digestive and Kidney Diseases (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902, U24DK060990). In addition, this work was supported in part by the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award NIH/NCATS UL1TR000003, Johns Hopkins University UL1TR-000424, University of Maryland GCRC M01 RR-16500, Clinical and Translational Science Collaborative of Cleveland, UL1TR000439 from the National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health and NIH Roadmap for Medical Research, Michigan Institute for Clinical and Health Research (MICHR) UL1TR000433, University of Illinois at Chicago CTSA UL1RR029879, Tulane COBRE for Clinical and Translational Research in Cardiometabolic Diseases P20 GM109036, Kaiser Permanente NIH/NCRR UCSF-CTSI UL1RR-024131, Department of Internal Medicine, University of New Mexico School of Medicine Albuquerque, NM R01DK119199.'

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

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10.1136/heartjnl-2024-325205

Cite this

Culler, K., Zelnick, L. R., Mehta, R. C., De Sosa, G. R., Kansal, M., Rao, P. S., Bhat, Z., Taliercio, J., Horwitz, E., Chen, J., He, J., Shah, S. J., Isakova, T., & Patel, R. B. (Accepted/In press). The ICAM1 p.K56M variant and risk of heart failure in chronic kidney disease: the Chronic Renal Insufficiency Cohort study. Heart, Article 325205. https://doi.org/10.1136/heartjnl-2024-325205

@article{06effcd5c5fd4eabbd5f8f7b667d352d,

title = "The ICAM1 p.K56M variant and risk of heart failure in chronic kidney disease: the Chronic Renal Insufficiency Cohort study",

abstract = "Background: Intercellular adhesion molecule-1 (ICAM-1) is a cell-surface protein that facilitates inflammation through leucocyte adhesion. Approximately 35% of Black individuals carry at least one copy of an ICAM1 missense variant (rs5491; p.K56M), which has been associated with increased risk of heart failure (HF) with preserved ejection fraction (HFpEF). Whether the risk of HFpEF conferred by rs5491 extends to individuals with chronic kidney disease (CKD), a cohort at high risk for HF, is unknown. Aims: We investigated the association between rs5491 and the incidence of HF in CKD. Methods: We estimated associations of rs5491 with incident HF and HF subtypes among Black individuals who were free from HF at baseline in the Chronic Renal Insufficiency Cohort (CRIC). The CRIC study recruited individuals who were 21-74 years old with estimated glomerular filtration rate (eGFR) of 20-70 mL/min/1.73 m2 at baseline. Results: Among 1267 Black participants (mean age 57±11 years, 51% female, mean eGFR 45±15 mL/min/1.73 m2), 464 (37%) had at least one copy of rs5491. During a median follow-up of 10.3 years (IQR: 4.7-15.0 years), there were 309 incident overall HF hospitalisations (160 HFpEF, 111 HF with reduced ejection fraction (HFrEF) and 38 HF with unknown ejection fraction). Each additional rs5491 allele was significantly associated with incident HFpEF (HR 1.35, 95% CI 1.03 to 1.76, p=0.029). The rs5491 variant was not associated with incident overall HF (HR 1.14, 95% CI 0.93 to 1.39, p=0.20) or incident HFrEF (HR 0.76, 95% CI 0.53 to 1.10, p=0.15). Conclusion: The ICAM1 p.K56M variant is specifically associated with increased risk of incident HFpEF among individuals with CKD.",

author = "Kasen Culler and Zelnick, {Leila R.} and Mehta, {Rupal C} and {De Sosa}, {Giselle R.} and Mayank Kansal and Rao, {Panduranga S.} and Zeenat Bhat and Jonathan Taliercio and Edward Horwitz and Jing Chen and Jiang He and Shah, {Sanjiv J} and Tamara Isakova and Patel, {Ravi B}",

note = "Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2025.",

year = "2025",

doi = "10.1136/heartjnl-2024-325205",

language = "English (US)",

journal = "Heart",

issn = "1355-6037",

publisher = "BMJ Publishing Group",

}

TY - JOUR

T1 - The ICAM1 p.K56M variant and risk of heart failure in chronic kidney disease

T2 - the Chronic Renal Insufficiency Cohort study

AU - Culler, Kasen

AU - Zelnick, Leila R.

AU - Mehta, Rupal C

AU - De Sosa, Giselle R.

AU - Kansal, Mayank

AU - Rao, Panduranga S.

AU - Bhat, Zeenat

AU - Taliercio, Jonathan

AU - Horwitz, Edward

AU - Chen, Jing

AU - He, Jiang

AU - Shah, Sanjiv J

AU - Isakova, Tamara

AU - Patel, Ravi B

PY - 2025

Y1 - 2025

N2 - Background: Intercellular adhesion molecule-1 (ICAM-1) is a cell-surface protein that facilitates inflammation through leucocyte adhesion. Approximately 35% of Black individuals carry at least one copy of an ICAM1 missense variant (rs5491; p.K56M), which has been associated with increased risk of heart failure (HF) with preserved ejection fraction (HFpEF). Whether the risk of HFpEF conferred by rs5491 extends to individuals with chronic kidney disease (CKD), a cohort at high risk for HF, is unknown. Aims: We investigated the association between rs5491 and the incidence of HF in CKD. Methods: We estimated associations of rs5491 with incident HF and HF subtypes among Black individuals who were free from HF at baseline in the Chronic Renal Insufficiency Cohort (CRIC). The CRIC study recruited individuals who were 21-74 years old with estimated glomerular filtration rate (eGFR) of 20-70 mL/min/1.73 m2 at baseline. Results: Among 1267 Black participants (mean age 57±11 years, 51% female, mean eGFR 45±15 mL/min/1.73 m2), 464 (37%) had at least one copy of rs5491. During a median follow-up of 10.3 years (IQR: 4.7-15.0 years), there were 309 incident overall HF hospitalisations (160 HFpEF, 111 HF with reduced ejection fraction (HFrEF) and 38 HF with unknown ejection fraction). Each additional rs5491 allele was significantly associated with incident HFpEF (HR 1.35, 95% CI 1.03 to 1.76, p=0.029). The rs5491 variant was not associated with incident overall HF (HR 1.14, 95% CI 0.93 to 1.39, p=0.20) or incident HFrEF (HR 0.76, 95% CI 0.53 to 1.10, p=0.15). Conclusion: The ICAM1 p.K56M variant is specifically associated with increased risk of incident HFpEF among individuals with CKD.

AB - Background: Intercellular adhesion molecule-1 (ICAM-1) is a cell-surface protein that facilitates inflammation through leucocyte adhesion. Approximately 35% of Black individuals carry at least one copy of an ICAM1 missense variant (rs5491; p.K56M), which has been associated with increased risk of heart failure (HF) with preserved ejection fraction (HFpEF). Whether the risk of HFpEF conferred by rs5491 extends to individuals with chronic kidney disease (CKD), a cohort at high risk for HF, is unknown. Aims: We investigated the association between rs5491 and the incidence of HF in CKD. Methods: We estimated associations of rs5491 with incident HF and HF subtypes among Black individuals who were free from HF at baseline in the Chronic Renal Insufficiency Cohort (CRIC). The CRIC study recruited individuals who were 21-74 years old with estimated glomerular filtration rate (eGFR) of 20-70 mL/min/1.73 m2 at baseline. Results: Among 1267 Black participants (mean age 57±11 years, 51% female, mean eGFR 45±15 mL/min/1.73 m2), 464 (37%) had at least one copy of rs5491. During a median follow-up of 10.3 years (IQR: 4.7-15.0 years), there were 309 incident overall HF hospitalisations (160 HFpEF, 111 HF with reduced ejection fraction (HFrEF) and 38 HF with unknown ejection fraction). Each additional rs5491 allele was significantly associated with incident HFpEF (HR 1.35, 95% CI 1.03 to 1.76, p=0.029). The rs5491 variant was not associated with incident overall HF (HR 1.14, 95% CI 0.93 to 1.39, p=0.20) or incident HFrEF (HR 0.76, 95% CI 0.53 to 1.10, p=0.15). Conclusion: The ICAM1 p.K56M variant is specifically associated with increased risk of incident HFpEF among individuals with CKD.

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JF - Heart

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ER -

The ICAM1 p.K56M variant and risk of heart failure in chronic kidney disease: the Chronic Renal Insufficiency Cohort study

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