title: Large multiethnic Candidate Gene Study for C-reactive protein levels: identification of a novel association at CD36 in African Americans.
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.
authors.affiliation: Department of Genetics, University of North Carolina, 5112 Genetic Medicine Bldg., Chapel Hill, NC, 27599-7264, USA.
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Ellis
authors.forename: Ethan M
authors.initials: EM
authors.lastname: Lange
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.forename: Josee
authors.initials: J
authors.lastname: Dupuis
authors.forename: Jens
authors.initials: J
authors.lastname: Baumert
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Walston
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Keating
authors.forename: Peter
authors.initials: P
authors.lastname: Durda
authors.forename: Ervin R
authors.initials: ER
authors.lastname: Fox
authors.forename: Cameron D
authors.initials: CD
authors.lastname: Palmer
authors.forename: Yan A
authors.initials: YA
authors.lastname: Meng
authors.forename: Taylor
authors.initials: T
authors.lastname: Young
authors.forename: Deborah N
authors.initials: DN
authors.lastname: Farlow
authors.forename: Renate B
authors.initials: RB
authors.lastname: Schnabel
authors.forename: Carola S
authors.initials: CS
authors.lastname: Marzi
authors.forename: Emma
authors.initials: E
authors.lastname: Larkin
authors.forename: Lisa W
authors.initials: LW
authors.lastname: Martin
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Bis
authors.forename: Paul
authors.initials: P
authors.lastname: Auer
authors.forename: Vasan S
authors.initials: VS
authors.lastname: Ramachandran
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.forename: Monte S
authors.initials: MS
authors.lastname: Willis
authors.forename: James S
authors.initials: JS
authors.lastname: Pankow
authors.forename: George J
authors.initials: GJ
authors.lastname: Papanicolaou
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Christie M
authors.initials: CM
authors.lastname: Ballantyne
authors.forename: Myron D
authors.initials: MD
authors.lastname: Gross
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lettre
authors.forename: James G
authors.initials: JG
authors.lastname: Wilson
authors.forename: Ulrike
authors.initials: U
authors.lastname: Peters
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Koenig
authors.forename: Russell P
authors.initials: RP
authors.lastname: Tracy
authors.forename: Susan
authors.initials: S
authors.lastname: Redline
authors.forename: Alex P
authors.initials: AP
authors.lastname: Reiner
authors.forename: Emelia J
authors.initials: EJ
authors.lastname: Benjamin
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Lange
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D015415:Biomarkers / Q000032:analysis*; D002097:C-Reactive Protein / Q000378:metabolism*; D018955:CD36 Antigens / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000209:etiology*; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D006801:Humans; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D018955:CD36 Antigens; D002097:C-Reactive Protein