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SANGITA SURESH, F. YESIM K. DEMIRCI, ERIN JACOBS, AMY H. KAO, ELISA Y. RHEW, DHARAMBIR K. SANGHERA, FAITH SELZER, KIM SUTTON-TYRRELL, DAVID McPHERSON, FRANKLIN A. BONTEMPO, CANDACE M. KAMMERER, ROSALIND RAMSEY-GOLDMAN, SUSAN MANZI, and M. ILYAS KAMBOH ABSTRACT. 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 ß2-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, –759 A>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. (J Rheumatol First Release Dec 15 2008; doi:10.3899/jrheum.080482) Key Indexing Terms: APOLIPOPROTEIN H ß2-GLYCOPROTEIN I PROMOTER SYSTEMIC LUPUS ERYTHEMATOSUS LUPUS POLYMORPHISM From the Departments of Human Genetics and Epidemiology, Graduate School of Public Health; Division of Rheumatology and Clinical Immunology, Lupus Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania; Northwestern University, Feinberg School of Medicine, Division of Rheumatology and Feinberg Cardiovascular Research Institute, Chicago, Illinois; and the Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. Supported by the National Heart, Lung, and Blood Institute Grant HL 54900; grants from the National Institutes of Health F32-AR51681, K23-AR054418, and Mary Kirkland Center for Lupus Research and Rheuminations, Inc.; K24-AR02318, P60-AR30692, P60-AR48098, NCRR/GCRC M01-RR00048. S. Suresh, MS; F.Y.K. Demirci, MD, Research Assistant Professor; E. Jacobs, MS, Department of Human Genetics, Graduate School of Public Health; A.H. Kao, MD, MPH, Assistant Professor, Division of Rheumatology and Clinical Immunology, Lupus Center of Excellence; E.Y. Rhew, MD, MSCI, Instructor, Northwestern University, Feinberg School of Medicine, Division of Rheumatology; D.K. Sanghera, PhD, Associate Professor, Department of Human Genetics, Graduate School of Public Health; F. Selzer, PhD, Research Assistant Professor; K. Sutton-Tyrrell, DrPH, Professor, Department of Epidemiology, Graduate School of Public Health; D. McPherson, MD, Professor, Northwestern University, Feinberg School of Medicine, Feinberg Cardiovascular Research Institute; F.A. Bontempo, MD, Associate Professor, Department of Medicine, School of Medicine, University of Pittsburgh; C.M. Kammerer, PhD, Associate Professor, Department of Human Genetics, Graduate School of Public Health; R. Ramsey-Goldman, MD, DrPH, Professor, Northwestern University, Feinberg School of Medicine, Division of Rheumatology; S. Manzi, MD, MPH, Associate Professor, Division of Rheumatology and Clinical Immunology, Lupus Center of Excellence; M.I. Kamboh, PhD, Professor, Department of Human Genetics, Graduate School of Public Health. Dedicated to Prof. Robert E. Ferrell on his 65th birthday. Address reprint requests to Dr. M.I. Kamboh, Department of Human Genetics, Graduate School of Public Health, A300 Crabtree Hall, 130 DeSoto Street, Pittsburgh, PA 15261. E-mail: ikamboh@hgen.pitt.edu Accepted for publication September 4, 2008. |
