Sequence variation in gene promoters is often associated with disease risk. In this study, we tested the hypothesis that common promoter variation in the APOH gene (encoding for β2-glycoprotein I) is associated with systemic lupus erythematosus (SLE) risk and SLE-related clinical phenotypes in a Caucasian cohort.
We used a case-control design and genotyped 345 SLE women and 454 healthy control women for 8 APOH promoter single nucleotide polymorphisms (SNPs) (−1284C>G, −1219G>A, −1190G>C, −759 A>G, − 700C>A, −643T>C, −38G>A, and −32C>A). Association analyses were performed on single SNPs and haplotypes. Haplotype analyses were performed using EH (Estimate Haplotype-frequencies) and Haploview programs. In vitro reporter gene assay was performed in COS-1 cells. Electrophoretic mobility shift assay (EMSA) was performed using HepG2 nuclear cells.
Overall haplotype distribution of the APOH promoter SNPs was significantly different between cases and controls (P = 0.009). The −643C allele was found to be protective against carotid plaque formation (adjusted OR = 0.37, P = 0.013) among SLE patients. The −643C allele was associated with a ~ 2-fold decrease in promoter activity as compared to wild-type −643T allele (mean ± standard deviation: 3.94 ± 0.05 vs. 6.99 ± 0.68, P = 0.016). EMSA showed that the −643T>C SNP harbors a binding site for a nuclear factor. The −1219G>A SNP showed a significant association with the risk of lupus nephritis (age-adjusted OR = 0.36, P = 0.016).
Our data indicate that APOH promoter variants may be involved in the etiology of SLE, especially the risk for autoimmune-mediated cardiovascular disease.