Published Online
on November 13, 2006

A more recent version of this article appeared on December 5, 2006

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Submitted on January 25, 2006
Revised on August 30, 2006
Accepted on October 5, 2006

Genetic Variation Is Associated With C-Reactive Protein Levels in the Third National Health and Nutrition Examination Survey

Dana C. Crawford PhD^*, Christopher L. Sanders MS, Xiaoting Qin PhD, Joshua D. Smith BS, Cynthia Shephard BS, Michelle Wong BS, Laura Witrak BA, Mark J. Rieder PhD, and Deborah A. Nickerson PhD

From the Department of Genome Sciences, University of Washington, Seattle (D.C.C., J.D.S., C.S., M.W., L.W., M.J.R., D.A.N.), and Harris Corporation/National Center for Health Statistics, CDC, Hyattsville, Md (C.L.S., X.Q.). Dr Qin is now with Business Computer Applications, Inc, Survey Operation Section/National Center for Chronic Disease Prevention and Health Promotion, Division of Adult and Community Health, Behavioral Surveillance Branch, Atlanta, Ga. Dr Crawford is now at Vanderbilt University, Center for Human Genetics Research, Nashville, Tenn.

^* To whom correspondence should be addressed. E-mail: crawford{at}chgr.mc.vanderbilt.edu.

Background--Increased serum C-reactive protein (CRP) is an independent risk factor for cardiovascular disease. Previous studies have suggested that genetic variation within the CRP gene is associated with serum CRP.

Methods and Results--We genotyped CRP genetic variants in 7159 individuals from the Third National Health and Nutrition Examination Survey (NHANES III). NHANES III is American population-based sample linked to hundreds of phenotypes, including CRP; however, the CRP assay used in this survey is not a high-sensitivity CRP assay, and 65% of participants (n=4679) had CRP measurements at or below the level of detection. Despite these limitations, we identified specific CRP single-nucleotide polymorphisms (SNPs) and haplotypes associated with serum CRP levels in the general population. Two variants were associated with increased levels of serum CRP: SNP rs3093058 (in linkage disequilibrium with a CRP promoter SNP rs3093062) in the non-Hispanic black sample and the triallelic promoter SNP rs3091244 in the non-Hispanic black and Mexican American samples. Two other SNPs were associated with decreased levels of serum CRP in either the non-Hispanic black (rs1205 and rs2808630) or Mexican American (rs1205) samples. Three haplotypes inferred from 7 SNPs (ATTGCGA, TTAGCGA, and AAAGAGA) were associated (P0.01) with increased levels of serum CRP in the non-Hispanic black sample; 2 haplotypes (ATTGCGA and AAAGCGA) were associated (P<0.05) with increased levels in the Mexican American sample; and 1 haplotype (AAAGCGA) was associated (P<0.03) with increased levels in the non-Hispanic white sample. Post hoc analysis suggests that the AA genotype of the triallelic SNP rs3091244, after adjustment for covariates, was associated with prevalent coronary heart disease in the non-Hispanic white population sample.

Conclusions--Genetic variation within CRP is associated with serum CRP levels in the general population and may be associated with prevalent coronary heart disease.

Key words: C-reactive protein • epidemiology • genes • genetics • inflammation • population

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