The genetics of human C-reactive protein and complement C3 expression in health and disease

Abstract

C-reactive protein (CRP) and complement component C3 are both plasma proteins involved in antigen recognition by the innate immune system. They may play a role in the pathogenesis of immune-mediated diseases including systemic lupus erythematosus (SLE) and coronary heart disease. CRP is heritable, but there is uncertainty over the key genetic variants influencing expression. C3 heritability has not been demonstrated, although a single report suggests C3 variation influences serum C3 level and susceptibility to SLE. This thesis presents an association analysis of CRP genotype and serum CRP from four ethnically diverse cohorts. Two cohorts were diseased based (UK European and Filipino SLE family cohorts) allowing the additional analysis of CRP genotype/disease association, and one (UK rheumatoid arthritis cases) consisted of individuals with active inflammatory disease. CRP genotype was associated with serum CRP in all cohorts. Analysis of an African- American cohort (which had an informative pattern of linkage disequilibrium at CRP) highlighted a single CRP SNP, rs3091244, likely to be a key regulator of expression at this locus. No association was observed between CRP genotype and SLE. The UK European SLE cohort was also used to demonstrate C3 heritability and explore associations between C3 genotype, serum C3 and SLE. Cis-acting associations were identified with both serum C3 and SLE. The recognition that serum CRP and C3 levels are, in part, genetically determined traits has implications for their use in the monitoring and diagnosis of disease. For neither protein does a single cis-acting variant explain most of the variation in serum level: this may be determined by multiple interacting variants, many of which have yet to be identified