Apolipoprotein H Promoter Polymorphisms in Relation to Lupus and Lupus-related Phenotypes

• Published in: Journal of rheumatology 2009-02, Vol.36 (2), p.315-322
• Main Authors: SURESH, SANGITA, DEMIRCI, F. YESIM K., JACOBS, ERIN, KAO, AMY H., RHEW, ELISA Y., SANGHERA, DHARAMBIR K., SELZER, FAITH, SUTTON-TYRRELL, KIM, McPHERSON, DAVID, BONTEMPO, FRANKLIN A., KAMMERER, CANDACE M., RAMSEY-GOLDMAN, ROSALIND, MANZI, SUSAN, KAMBOH, M. ILYAS
• Format: Article
• Language: English
• Subjects: Adult; beta 2-Glycoprotein I - genetics; Binding Sites - genetics; Biological and medical sciences; Carotid Stenosis - epidemiology; Carotid Stenosis - genetics; Carotid Stenosis - metabolism; Case-Control Studies; Cohort Studies; Comorbidity; Diseases of the osteoarticular system; DNA Mutational Analysis; Electrophoretic Mobility Shift Assay; Female; Gene Frequency - genetics; Genetic Predisposition to Disease - genetics; Genetic Testing; Haplotypes; Humans; Lupus Erythematosus, Systemic - epidemiology; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - metabolism; Lupus Nephritis - epidemiology; Lupus Nephritis - genetics; Lupus Nephritis - metabolism; Medical sciences; Middle Aged; Phenotype; Polymorphism, Single Nucleotide - genetics; Promoter Regions, Genetic - genetics; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis
• ISSN: 0315-162X; 1499-2752
• DOI: 10.3899/jrheum.080482

Objective. Sequence variation in gene promoters is often associated with disease risk. We tested the hypothesis that common promoter variation in the APOH gene (encoding for ß 2 -glycoprotein I) is associated with systemic lupus erythematosus (SLE) risk and SLE-related clinical phenotypes in a Caucasian cohort. Methods. We used a case-control design and genotyped 345 women with SLE and 454 healthy control women for 8 APOH promoter single-nucleotide polymorphisms (SNP; –1284C>G, –1219G>A, –1190G>C, –759A>G, –700C>A, –643T>C, –38G>A, and –32C>A).Association analyses were performed on single SNP 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. Results. Overall haplotype distribution of the APOH promoter SNP 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 patients with SLE. 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). Conclusion. Our data indicate that APOH promoter variants may be involved in the etiology of SLE, especially the risk for autoimmune-mediated cardiovascular disease.