Large multiethnic Candidate Gene Study for C-reactive protein levels: Identification of a novel association at CD36 in African Americans

Jaclyn Ellis, Ethan M. Lange, Jin Li, Josee Dupuis, Jens Baumert, Jeremy D. Walston, Brendan J. Keating, Peter Durda, Ervin R. Fox, Cameron D. Palmer, Yan A. Meng, Taylor Young, Deborah N. Farlow, Renate B. Schnabel, Carola S. Marzi, Emma Larkin, Lisa W. Martin, Joshua C. Bis, Paul Auer, Vasan S. RamachandranStacey B. Gabriel, Monte S. Willis, James S. Pankow, George J. Papanicolaou, Jerome I. Rotter, Christie M. Ballantyne, Myron D. Gross, Guillaume Lettre, James G. Wilson, Ulrike Peters, Wolfgang Koenig, Russell P. Tracy, Susan Redline, Alex P. Reiner, Emelia J. Benjamin, Leslie A. Lange

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


C-reactive protein (CRP) is a heritable biomarker of systemic inflammation and a predictor of cardiovascular disease (CVD). Large-scale genetic association studies for CRP have largely focused on individuals of European descent. We sought to uncover novel genetic variants for CRP in a multiethnic sample using the ITMAT Broad-CARe (IBC) array, a custom 50,000 SNP gene-centric array having dense coverage of over 2,000 candidate CVD genes. We performed analyses on 7,570 African Americans (AA) from the Candidate gene Association Resource (CARe) study and race-combined meta-analyses that included 29,939 additional individuals of European descent from CARe, the Women's Health Initiative (WHI) and KORA studies. We observed array-wide significance (p < 2.2 × 10-6) for four loci in AA, three of which have been reported previously in individuals of European descent (IL6R, p = 2.0 × 10 -6; CRP, p = 4.2 × 10-71; APOE, p = 1.6 × 10-6). The fourth significant locus, CD36 (p = 1.6 × 10 -6), was observed at a functional variant (rs3211938) that is extremely rare in individuals of European descent. We replicated the CD36 finding (p = 1.8 × 10-5) in an independent sample of 8,041 AA women from WHI; a meta-analysis combining the CARe and WHI AA results at rs3211938 reached genome-wide significance (p = 1.5 × 10-10). In the race-combined meta-analyses, 13 loci reached significance, including ten (CRP, TOMM40/APOE/APOC1, HNF1A, LEPR, GCKR, IL6R, IL1RN, NLRP3, HNF4A and BAZ1B/BCL7B) previously associated with CRP, and one (ARNTL) previously reported to be nominally associated with CRP. Two novel loci were also detected (RPS6KB1, p = 2.0 × 10-6; CD36, p = 1.4 × 10 -6). These results highlight both shared and unique genetic risk factors for CRP in AA compared to populations of European descent.

Original languageEnglish (US)
Pages (from-to)985-995
Number of pages11
JournalHuman Genetics
Issue number8
StatePublished - Aug 2014

Bibliographical note

Funding Information:
Acknowledgments Care is supported by contract number HHsn268200625226C from the national Institutes of Health (nIH)/national Heart lung and Blood Institute (nHlBI). sources of funding for individual Care cohorts: atherosclerosis risk in Communities (arIC): nHlBI (n01 HC-55015, n01 HC-55016, n01HC-55017, n01 HC-55018, n01 HC-55019, n01 HC-55020, n01 HC-55021); Cardiovascular Health study (CHs): nHlBI (n01-HC-85239, n01-HC-85079 through n01-HC-85086, n01-HC-35129, n01 HC-15103, n01 HC-55222, n01-HC-75150, n01-HC-45133, grant Hl080295 and contract HHsn268201200036C), with additional support from nInDs and from nIa (aG-023629, aG-15928, aG-20098, and aG-027058); Coronary artery risk Development in Young adults (CarDIa): nHlBI (n01-HC95095 & n01-HC48047, n01-HC48048, n01-HC48049, and n01-HC48050); Framingham Heart study (FHs): nHlBI (n01-HC-25195 and grant r01 ns17950) with additional support from nIa (aG08122 and aG033193); Jackson Heart study (JHs): nHlBI and the national Institute on Minority Health and Health Disparities (n01 HC-95170, n01 HC-95171 and n01 HC-95172); Multiethnic study of atherosclerosis (Mesa): n01 HC-95159, n01-HC-95160, n01-HC-95161, n01-HC-95162, n01-HC-95163, n01-HC-95164, n01-HC-95165, n01-HC-95166, n01-HC-95167, n01-HC-95168, n01-HC-95169 and rr-024156. Funding for Care genotyping was provided by nHlBI Contract n01-HC-65226. additional financial support was provided by nHlBI grant r01 Hl071862. the MOnICa/KOra augsburg studies were financed by the Helmholtz Zentrum München, German research Center for environmental Health, neuherberg, Germany and supported by grants from the German Federal Ministry of education and research. Part of this work was financed by the German national Genome research network (project number 01Gs0834), by the German research Foundation (tH-784/2-1 and tH-784/2-2), by the european Foundation for the study of Diabetes and through additional funds from the Helmholtz Zentrum München, the German Diabetes Center and the University of Ulm. Furthermore, the research was supported within the Munich Center of Health sciences as part of the ludwig Maximilians University innovative. the authors wish to thank the national Heart, lung, and Blood Institute (nHlBI) exome sequencing Project for providing a reference panel for CD36 rs3211938 imputation. Funding for GO esP was provided by nHlBI grants rC2 Hl-103010 (HeartGO), rC2 Hl-102923


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