Identification of a locus modulating serum C-reactive protein levels on chromosome 5p15

Individual propensity to chronic, low-grade inflammation--a determinant of atherosclerosis-is in part under the control of genetic factors. To identify genes involved in this modulation, we performed a 10cM genome screen for linkage with plasma C-reactive protein in 38 extended families including 317 non-diabetic and 177 type 2 diabetic family members (2547 relative pairs).

In a variance component analysis, heritability of CRP values was significant (h(2)=0.39, p<0.0001). This effect was independent of BMI and was present in both diabetic (h(2)=0.42, p=0.003) and non-diabetic (h(2)=0.34, p=0.0015) relatives. The strongest evidence of linkage with CRP was on chromosome 5p15, where the LOD score reached genome-wide significance (LOD=3.41, genome-wide p=0.013). Both diabetic and non-diabetic family members contributed to linkage at this location. Smaller linkage peaks were detected on chromosomes 5q35 (LOD=1.35) and 17p11 (LOD=1.33). When the analysis was restricted to diabetic family members, another peak of moderate intensity (LOD=2.17) was evident at 3p21.

A major gene influencing CRP levels appears to be located on chromosome 5p15, with an effect that is independent of diabetes. Another gene on 3p21 may control CRP variation but only in the presence of a diabetic or insulin-resistant environment.