Large multiethnic Candidate Gene Study for C-reactive protein levels: Identification of a novel association at CD36 in African Americans
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. © 2014 Springer-Verlag.
Ellis, J., Lange, E., Li, J., Dupuis, J., Baumert, J., Walston, J., Keating, B., Durda, P., Fox, E., Palmer, C., Meng, Y., Young, T., Farlow, D., Schnabel, R., Marzi, C., Larkin, E., Martin, L., Bis, J., Auer, P., Ramachandran, V., Gabriel, S., Willis, M., Pankow, J., Papanicolaou, G., Rotter, J., Ballantyne, C., Gross, M., Lettre, G., Wilson, J., Peters, U., Koenig, W., & Tracy, R. (2014). Large multiethnic Candidate Gene Study for C-reactive protein levels: Identification of a novel association at CD36 in African Americans. Human Genetics, 133 (8). http://dx.doi.org/10.1007/s00439-014-1439-z