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

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Abstract

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.

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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 (LungGO) and RC2 HL-102924 (WHISP). The exome sequencing was performed through NHLBI grants RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO).

Conflict of interest

The authors have no conflicts of interest to disclose.

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Authors and Affiliations

  1. Department of Genetics, University of North Carolina, 5112 Genetic Medicine Bldg., Chapel Hill, NC, 27599-7264, USA

    Jaclyn Ellis, Ethan M. Lange, Jin Li & Leslie A. Lange

  2. Department of Biostatistics, University of North Carolina, Chapel Hill, NC, 27599, USA

    Ethan M. Lange

  3. National Heart, Lung, and Blood Institute’s and Boston University’s Framingham Heart Study, Framingham, MA, 01702, USA

    Josee Dupuis & Emelia J. Benjamin

  4. Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA

    Josee Dupuis

  5. Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, 23538, Neuherberg, Germany

    Jens Baumert & Carola S. Marzi

  6. Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Jeremy D. Walston

  7. Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA

    Brendan J. Keating

  8. Departments of Pathology and Biochemistry, University of Vermont College of Medicine, Burlington, VT, 05405, USA

    Peter Durda & Russell P. Tracy

  9. Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, 39216, USA

    Ervin R. Fox & James G. Wilson

  10. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, 02142, USA

    Cameron D. Palmer, Yan A. Meng, Taylor Young, Deborah N. Farlow & Stacey B. Gabriel

  11. Divisions of Genetics and Endocrinology and Program in Genomics, Children’s Hospital Boston, Boston, MA, 02115, USA

    Cameron D. Palmer

  12. Department of General and Interventional Cardiology, University Heart Center Hamburg, 21046, Hamburg, Germany

    Renate B. Schnabel

  13. Division of Allergy, Pulmonary and Critical Care, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

    Emma Larkin

  14. Division of Cardiology, George Washington School of Medicine, Washington, DC, 20037, USA

    Lisa W. Martin

  15. Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, WA, 98101, USA

    Joshua C. Bis

  16. School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, 53206, USA

    Paul Auer

  17. Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA

    Vasan S. Ramachandran

  18. Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA

    Monte S. Willis

  19. Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN, 55455, USA

    James S. Pankow

  20. Division of Cardiovascular Sciences, National Heart, Lung and Blood Institute, Bethesda, MD, 20892, USA

    George J. Papanicolaou

  21. Departments of Pediatrics, Medicine, and Human Genetics, University of California, Los Angeles, CA, 90095, USA

    Jerome I. Rotter

  22. Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Los Angeles, CA, USA

    Jerome I. Rotter

  23. Division of Genomic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Los Angeles, CA, USA

    Jerome I. Rotter

  24. Section of Cardiovascular Research, Baylor College of Medicine, Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart Center, Houston, TX, 77030, USA

    Christie M. Ballantyne

  25. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA

    Myron D. Gross

  26. Montréal Heart Institute, Montréal, H3A 2T5, Canada

    Guillaume Lettre

  27. Département de Médecine, Université de Montréal, Montréal, H3A 2T5, Canada

    Guillaume Lettre

  28. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA

    Ulrike Peters

  29. Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, 07304, Ulm, Germany

    Wolfgang Koenig

  30. Department of Medicine, Brigham and Women’s Hospital and Beth Israel Deaconess Medical Center, Boston, MA, USA

    Susan Redline

  31. Department of Epidemiology, University of Washington, Seattle, WA, 98195, USA

    Alex P. Reiner

  32. Department of Epidemiology, Boston University School of Public Health, Boston, MA, 02118, USA

    Emelia J. Benjamin

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  1. Jaclyn Ellis
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  2. Ethan M. Lange
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  3. Jin Li
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  4. Josee Dupuis
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  8. Peter Durda
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  9. Ervin R. Fox
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  10. Cameron D. Palmer
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  11. Yan A. Meng
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  12. Taylor Young
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  13. Deborah N. Farlow
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  14. Renate B. Schnabel
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  15. Carola S. Marzi
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  16. Emma Larkin
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  17. Lisa W. Martin
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  18. Joshua C. Bis
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  19. Paul Auer
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  20. Vasan S. Ramachandran
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  21. Stacey B. Gabriel
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  22. Monte S. Willis
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  23. James S. Pankow
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  24. George J. Papanicolaou
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  25. Jerome I. Rotter
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  26. Christie M. Ballantyne
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  27. Myron D. Gross
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  28. Guillaume Lettre
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  29. James G. Wilson
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  30. Ulrike Peters
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  31. Wolfgang Koenig
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  32. Russell P. Tracy
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  33. Susan Redline
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  34. Alex P. Reiner
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  35. Emelia J. Benjamin
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  36. Leslie A. Lange
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Correspondence to Leslie A. Lange.

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Ellis, J., Lange, E.M., Li, J. et al. Large multiethnic Candidate Gene Study for C-reactive protein levels: identification of a novel association at CD36 in African Americans. Hum Genet 133, 985–995 (2014). https://doi.org/10.1007/s00439-014-1439-z

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