Fine-mapping the genetic basis of CRP regulation in African Americans: a Bayesian approach

• Published in: Human genetics 2008-07, Vol.123 (6), p.633-642
• Main Authors: Rhodes, Benjamin, Morris, David L., Subrahmanyan, Lakshman, Aubin, Cristin, de Leon, Carlos F. Mendes, Kelly, Jeremiah F., Evans, Dennis A., Whittaker, John C., Oksenberg, Jorge R., De Jager, Philip L., Vyse, Tim J.
• Format: Article
• Language: English
• Subjects: African Americans; African Americans - genetics; Aged; Aged, 80 and over; Alzheimer's disease; Analysis; Atherosclerosis; Base Sequence; Bayes Theorem; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; C-reactive protein; C-Reactive Protein - genetics; Cardiovascular Diseases - genetics; Chromosome Mapping; Classical genetics, quantitative genetics, hybrids; Cohort Studies; Cytokines; Disease; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - genetics; Gene Function; Gene loci; Genetic aspects; Genetic research; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genomes; Genotype; Haplotypes; Human; Human Genetics; Humans; Internal medicine; Linkage Disequilibrium; Male; Medicine; Metabolic Diseases; Methods, theories and miscellaneous; Molecular Medicine; Molecular Sequence Data; Original Investigation; Phylogeny; Polymorphism, Single Nucleotide; Single nucleotide polymorphisms; Twin studies; Twins
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-008-0517-5

Basal levels of C-reactive protein (CRP) have been associated with disease, particularly future cardiovascular events. Twin studies estimate 50% CRP heritability, so the identification of genetic variants influencing CRP expression is important. Existing studies in populations of European ancestry have identified numerous cis -acting variants but leave significant ambiguity over the identity of the key functional polymorphisms. We addressed this issue by typing a dense map of CRP single-nucleotide polymorphisms (SNPs), and quantifying serum CRP in 594 unrelated African Americans. We used Bayesian model choice analysis to select the combination of SNPs best explaining basal CRP and found strong support for triallelic rs3091244 alone, with the T allele acting in an additive manner (Bayes factor > 100 vs. null model), with additional support for a model incorporating both rs3091244 and rs12728740. Admixture analysis suggested SNP rs12728740 segregated with haplotypes predicted to be of recent European origin. Using a cladistic approach we confirmed the importance of rs3091244(T) by demonstrating a significant partition of haplotype effect based on the rs3091244(C/T) mutation ( F  = 8.91, P  = 0.006). We argue that weaker linkage disequilibrium across the African American CRP locus compared with Europeans has allowed us to establish an unambiguous functional role for rs3091244(T), while also recognising the potential for additional functional mutations present in the European genome.