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 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 journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)985-995
Number of pages11
JournalHuman Genetics
Volume133
Issue number8
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

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African Americans
C-Reactive Protein
Genes
Women's Health
Meta-Analysis
Genetic Association Studies
Cardiovascular Diseases
Apolipoproteins E
Single Nucleotide Polymorphism
Biomarkers
Genome
Inflammation
Population

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Large multiethnic Candidate Gene Study for C-reactive protein levels : Identification of a novel association at CD36 in African Americans. / Ellis, Jaclyn; Lange, Ethan M.; Li, Jin; Dupuis, Josee; Baumert, Jens; Walston, Jeremy D.; Keating, Brendan J.; Durda, Peter; Fox, Ervin R.; Palmer, Cameron D.; Meng, Yan A.; Young, Taylor; Farlow, Deborah N.; Schnabel, Renate B.; Marzi, Carola S.; Larkin, Emma; Martin, Lisa W.; Bis, Joshua C.; Auer, Paul; Ramachandran, Vasan S.; Gabriel, Stacey B.; Willis, Monte; Pankow, James S.; Papanicolaou, George J.; Rotter, Jerome I.; Ballantyne, Christie M.; Gross, Myron D.; Lettre, Guillaume; Wilson, James G.; Peters, Ulrike; Koenig, Wolfgang; Tracy, Russell P.; Redline, Susan; Reiner, Alex P.; Benjamin, Emelia J.; Lange, Leslie A.

In: Human Genetics, Vol. 133, No. 8, 01.01.2014, p. 985-995.

Research output: Contribution to journalArticle

Ellis, J, Lange, EM, Li, J, Dupuis, J, Baumert, J, Walston, JD, Keating, BJ, Durda, P, Fox, ER, Palmer, CD, Meng, YA, Young, T, Farlow, DN, Schnabel, RB, Marzi, CS, Larkin, E, Martin, LW, Bis, JC, Auer, P, Ramachandran, VS, Gabriel, SB, Willis, M, Pankow, JS, Papanicolaou, GJ, Rotter, JI, Ballantyne, CM, Gross, MD, Lettre, G, Wilson, JG, Peters, U, Koenig, W, Tracy, RP, Redline, S, Reiner, AP, Benjamin, EJ & Lange, LA 2014, 'Large multiethnic Candidate Gene Study for C-reactive protein levels: Identification of a novel association at CD36 in African Americans', Human Genetics, vol. 133, no. 8, pp. 985-995. https://doi.org/10.1007/s00439-014-1439-z
Ellis, Jaclyn ; Lange, Ethan M. ; Li, Jin ; Dupuis, Josee ; Baumert, Jens ; Walston, Jeremy D. ; Keating, Brendan J. ; Durda, Peter ; Fox, Ervin R. ; Palmer, Cameron D. ; Meng, Yan A. ; Young, Taylor ; Farlow, Deborah N. ; Schnabel, Renate B. ; Marzi, Carola S. ; Larkin, Emma ; Martin, Lisa W. ; Bis, Joshua C. ; Auer, Paul ; Ramachandran, Vasan S. ; Gabriel, Stacey B. ; Willis, Monte ; Pankow, James S. ; Papanicolaou, George J. ; Rotter, Jerome I. ; Ballantyne, Christie M. ; Gross, Myron D. ; Lettre, Guillaume ; Wilson, James G. ; Peters, Ulrike ; Koenig, Wolfgang ; Tracy, Russell P. ; Redline, Susan ; Reiner, Alex P. ; Benjamin, Emelia J. ; Lange, Leslie A. / Large multiethnic Candidate Gene Study for C-reactive protein levels : Identification of a novel association at CD36 in African Americans. In: Human Genetics. 2014 ; Vol. 133, No. 8. pp. 985-995.
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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.",
author = "Jaclyn Ellis and Lange, {Ethan M.} and Jin Li and Josee Dupuis and Jens Baumert and Walston, {Jeremy D.} and Keating, {Brendan J.} and Peter Durda and Fox, {Ervin R.} and Palmer, {Cameron D.} and Meng, {Yan A.} and Taylor Young and Farlow, {Deborah N.} and Schnabel, {Renate B.} and Marzi, {Carola S.} and Emma Larkin and Martin, {Lisa W.} and Bis, {Joshua C.} and Paul Auer and Ramachandran, {Vasan S.} and Gabriel, {Stacey B.} and Monte Willis and Pankow, {James S.} and Papanicolaou, {George J.} and Rotter, {Jerome I.} and Ballantyne, {Christie M.} and Gross, {Myron D.} and Guillaume Lettre and Wilson, {James G.} and Ulrike Peters and Wolfgang Koenig and Tracy, {Russell P.} and Susan Redline and Reiner, {Alex P.} and Benjamin, {Emelia J.} and Lange, {Leslie A.}",
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TY - JOUR

T1 - Large multiethnic Candidate Gene Study for C-reactive protein levels

T2 - Identification of a novel association at CD36 in African Americans

AU - Ellis, Jaclyn

AU - Lange, Ethan M.

AU - Li, Jin

AU - Dupuis, Josee

AU - Baumert, Jens

AU - Walston, Jeremy D.

AU - Keating, Brendan J.

AU - Durda, Peter

AU - Fox, Ervin R.

AU - Palmer, Cameron D.

AU - Meng, Yan A.

AU - Young, Taylor

AU - Farlow, Deborah N.

AU - Schnabel, Renate B.

AU - Marzi, Carola S.

AU - Larkin, Emma

AU - Martin, Lisa W.

AU - Bis, Joshua C.

AU - Auer, Paul

AU - Ramachandran, Vasan S.

AU - Gabriel, Stacey B.

AU - Willis, Monte

AU - Pankow, James S.

AU - Papanicolaou, George J.

AU - Rotter, Jerome I.

AU - Ballantyne, Christie M.

AU - Gross, Myron D.

AU - Lettre, Guillaume

AU - Wilson, James G.

AU - Peters, Ulrike

AU - Koenig, Wolfgang

AU - Tracy, Russell P.

AU - Redline, Susan

AU - Reiner, Alex P.

AU - Benjamin, Emelia J.

AU - Lange, Leslie A.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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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