Evidence for haplotype-based association in SLE at the c-reactive protein locus: Population-based and family-based association studies

Systemic lupus erythematosus (SLE) is a major public health problem in the U.S. Cardiovascular disease (CVD) risk increases significantly in SLE patients, resulting in serious morbidity and mortality. Accelerated atherosclerosis and markedly higher prevalence of CVD risk factors (intermediate phenotypes) are thought to directly contribute to these consequences. Given the significant mortality and morbidity associated with SLE and high prevalence of CVD in SLE, identifying genetic variation associated with both SLE risk and intermediate phenotypes of CVD is of significant importance.;The association between CRP and SLE risk, assessed in two independently-ascertained SLE cohorts, was tested in a case-control Caucasian sample of 337 SLE and 448 healthy controls from Pittsburgh and a family-based sample of 203 Caucasian SLE trios from Los Angeles. While none of the SNPs were found to be associated with SLE risk individually, global haplotype statistics revealed significant association (p < 0.000001) in the Pittsburgh cohort whereas all those haplotypes containing two potentially functional SNPs (-390 and +90) showed association with SLE risk in the Los Angeles cohort (p = 0.01--0.06). The association study between CRP and intermediate phenotypes of CVD and stroke risk was tested in 237 of the SLE women from the Pittsburgh cohort. Four of the five tagSNPs (-861, -390, +90, and +838) examined revealed significant association with risk of intermediate phenotypes of CVD (p < 0.001 to 0.04).;In summary, our data did not confirm previously observed individual SNP association with SLE, but suggested that unique haplotype combinations in the CRP gene may modify the risk of developing SLE, and that variation in CRP may contribute to the accelerated atherosclerosis in SLE.;C-reactive protein (CRP) is a sensitive marker of inflammation. Increased CRP levels have been found to be associated with cardiovascular events in a large number of healthy populations and may contribute to atherosclerosis. The gene coding for CRP is located on chromosome 1q23.2, which falls within a linkage region thought to harbor a systemic lupus erythematosus (SLE) susceptibility gene. Moreover, two single nucleotide polymorphisms (SNPs) in the CRP gene have recently been shown to be associated with CRP levels and/or SLE risk in a British family-based cohort. This study was aimed to assess the genetic association between five CRP tagSNPs with SLE risk and intermediate phenotypes of CVD.