Published Online
on March 13, 2006

A more recent version of this article appeared on March 21, 2006

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Submitted on September 26, 2005
Revised on December 11, 2005
Accepted on January 9, 2006

Contribution of Clinical Correlates and 13 C-Reactive Protein Gene Polymorphisms to Interindividual Variability in Serum C-Reactive Protein Level

Sekar Kathiresan MD, Martin G. Larson ScD, Ramachandran S. Vasan MD, Chao-Yu Guo PhD, Philimon Gona PhD, John F. Keaney Jr MD, Peter W.F. Wilson MD, Christopher Newton-Cheh MD, MPH, Stacy L. Musone BA, Amy L. Camargo BA, Jared A. Drake BA, Daniel Levy MD, Christopher J. O’Donnell MD, MPH, Joel N. Hirschhorn MD, PhD, and Emelia J. Benjamin MD, ScM^*

From the Framingham Heart Study (S.K., M.G.L., R.S.V., C.-Y.G., P.G., C.N.-C., D.L., C.J.O., E.J.B.), Framingham, Mass; Department of Mathematics and Statistics (M.G.L., C.-Y.G., P.G.), Evans Department of Medicine (R.S.V., J.F.K., E.J.B.), Whitaker Cardiovascular Institute (R.S.V., J.F.K., E.J.B.), Boston University, Boston, Mass; Department of Endocrinology (P.W.F.W.), Diabetes and Medical Genetics, Medical University of South Carolina, Charleston, SC; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard University (S.K., C.N.-C., S.L.M., A.L.C., J.A.D., C.J.O., J.N.H.), Cambridge, Mass; Cardiology Division (S.K., C.N.-C., C.J.O.), Massachusetts General Hospital, Divisions of Genetics and Endocrinology, Children’s Hospital (J.A.D., J.N.H.), and Department of Genetics (J.N.H.), Harvard Medical School, Boston, Mass.

^* To whom correspondence should be addressed. E-mail: emelia{at}bu.edu.

Background--Serum C-reactive protein (CRP) level is a heritable complex trait that predicts incident cardiovascular disease. We investigated the clinical and genetic sources of interindividual variability in serum CRP.

Methods and Results--We studied serum CRP in 3301 Framingham Heart Study (FHS) participants (mean age 61 years, 53% women). Twelve clinical covariates explained 26% of the variability in CRP level, with body mass index alone explaining 15% (P<0.0001) of the variance. To investigate the influence of genetic variation at the CRP gene on CRP levels, we first constructed a dense linkage disequilibrium map for common single-nucleotide polymorphisms (SNPs) spanning the CRP locus (1 SNP every 850 bases, 26 kilobase [kb] genomic region). Thirteen CRP SNPs were genotyped in 1640 unrelated FHS participants with measured CRP levels. After adjustment for clinical covariates, 9 of 13 SNPs were associated with CRP level (P<0.05). To account for correlation among SNPs, we conducted forward stepwise selection among all 13 SNPs; a triallelic SNP (rs3091244) remained associated with CRP level (stepwise P<0.0001). The triallelic SNP (CTA; allele frequencies 62%, 31%, and 7%), located in the promoter sequence, explained 1.4% of total serum CRP variation; haplotypes harboring the minor T and A alleles of this SNP were associated with higher CRP level (haplotype P=0.0002 and 0.004).

Conclusions--In our community-based sample, clinical variables explained 26% of the interindividual variation in CRP, whereas a common triallelic CRP SNP contributed modestly. Studies of larger samples are warranted to assess the association of genetic variation in CRP and risk of cardiovascular disease.

Key words: epidemiology • inflammation • genetics • C-reactive protein • risk factors

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