Background Increased serum levels of C-reactive protein (CRP), an important component of the innate immune response, are associated with increased risk of cardiovascular disease (CVD). Multiple single nucleotide polymorphisms (SNP) have been identified which are associated with CRP levels, and Mendelian randomization studies have shown a positive association between SNPs increasing CRP expression and risk of colon cancer (but thus far not CVD). The effects of individual genetic variants often interact with the genetic background of a population and hence we sought to resolve the genetic determinants of serum CRP in a number of American Indian populations. Methods The Strong Heart Family Study (SHFS) has serum CRP measurements from 2428 tribal members, recruited as large families from three regions of the United States. Microsatellite markers and MetaboChip defined SNP genotypes were incorporated into variance components, decomposition-based linkage and association analyses. Results CRP levels exhibited significant heritability (h2 = 0.33 ± 0.05, p<1.3 X 10−20). A locus on chromosome (chr) 6, near marker D6S281 (approximately at 169.6 Mb, GRCh38/hg38) showed suggestive linkage (LOD = 1.9) to CRP levels. No individual SNPs were found associated with CRP levels after Bonferroni adjustment for multiple testing (threshold <7.77 x 10−7), however, we found nominal associations, many of which replicate previous findings at the CRP, HNF1A and 7 other loci. In addition, we report association of 46 SNPs located at 7 novel loci on chromosomes 2, 5, 6(2 loci), 9, 10 and 17, with an average of 15.3 Kb between SNPs and all with p-values less than 7.2 X 10−4. Conclusion In agreement with evidence from other populations, these data show CRP serum levels are under considerable genetic influence; and include loci, such as near CRP and other genes, that replicate results from other ethnic groups. These findings also suggest possible novel loci on chr 6 and other chromosomes that warrant further investigation.
Bibliographical noteFunding Information:
This work received support from National Institute of Environmental Health Sciences ES021367 to Dr Poojitha Balakrishnan, Dr Nora Franceschini, and Dr Ana Navas-Acien; the National Heart, Lung, and Blood Institute HL109301 to Dr Shelley A Cole and Dr Karin Haack; National Institute of Diabetes and Digestive and Kidney Diseases DK092238 to Dr. V. Saroja Voruganti; National Heart, Lung, and Blood Institute HL109315 to Dr. Lyle G. Best and Joseph M Yracheta; National Heart, Lung, and Blood Institute HL109284 to Dr. Elisa T Lee; and National Heart, Lung, and Blood Institute HL109319 to Dr Barbara V Howard and Dr. Jason G Umans. Missouri Breaks Industries Research Inc, (MBIRI) provided support in the form of salaries for an author, Mr. Yracheta and compensation as an independent consultant to Dr. Lyle Best, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the?author contributions? section. We thank the study participants, Indian Health Service facilities, and participating tribal communities for their extraordinary cooperation and involvement, which has been critical to the success of the Strong Heart Family Study. The views expressed in this paper are those of the authors and do not necessarily reflect those of the Indian Health Service or NIH.