Presentation: Polymorphisms in the Osteopontin (SPP1) Gene are Associated with Increased Risk of Developing SLE in Males (2007)

839 Polymorphisms in the Osteopontin (SPP1) Gene are Associated with Increased Risk of Developing SLE in Males

Purpose: Osteopontin (SPP1) is a key mediator in bone biology recently found to have key roles in inflammation and immunity. Associations of genetic polymorphisms and increased osteopontin protein levels with SLE have been reported in small patient cohorts. This study tests association between SPP1 polymorphisms and SLE in a large, multi-ethnic collection.

Methods: A case-control study using 1488 unrelated SLE patients (707 EA, 549 AA, 232 HIS), including 151 males, and 2321 unrelated controls (1309 EA, 834 AA, 178 HIS) tested 32 SNPs within SPP1. Single SNP as well as haplotype associations were evaluated. Conditional analysis was employed to identify the SNP(s) that could explain the association. To control for potential admixture and population stratification, admixture adjusted logistic regression, genomic control (GC), structured association (STRAT) and principle components analysis (PCA) based correction were utilized. All significant findings were verified by testing 100,000 permutations.

Results: Twelve SNPs in Hardy-Weinberg equilibrium with minor allele frequencies >1% were selected for further analysis. All 3 ethnic groups showed association in males, but not in females. AA subgroup analysis, stratified by gender, demonstrated 5 borderline significant SNPs (SNP9, SNP16, SNP27, SNP29 and SNP31). A strong association was revealed by a 5 SNP haplotype analysis (global P=0.00004). The risk haplotype (TTTAC) was significantly increased in male cases compared with male controls (22% vs.7%, admixture adjusted OR=4.6, 95%CI 2.2-9.2). In EA, 3 SNPs (SNP27, SNP29 and SNP31) demonstrated a significant association in males (P=0.003, P=0.03 and P=0.003, respectively) and the 3 SNP global haplotype association was significant (P=0.016). The frequency of the haplotype (TGC) was also increased in male cases compared with male controls (27% vs. 19%, OR=1.5, 95%CI 1.1-2.3). For HIS, association was detected for SNP 6 (P=0.03) and SNP 16 (P=0.04); however, no haplotype and gender effects were detected. All the associations remained consistent with GC, STRAT or PCA in males.
Combined and conditional analysis using 12 SNPs on all ethnic groups adjusted by admixture proportion identified SNP27 and SNP31 to explain the male SLE association. Risk increased significantly in patients carrying the risk haplotype (TC) (33% vs. 22%, P = 0.0003, OR=1.7, 95%CI 1.3-2.2). Additionally, significant interactions between SNPs and gender were detected for SNP27 (exonic) and SNP31 (3’UTR) (P=0.005 and P=0.004).

Conclusion: Our data suggest that SPP1 is associated with SLE in males. To our knowledge, this report serves as the first description of a human male SLE genetic risk.

 S. Han, None; I. Harley, None; A.L. Sestak, None; X. Kim-Howard, None; K.M. Kaufman, None; G.R. Bruner, None; J.M. Guthridge, None; G.S. Gilkeson, None; J.B. Harley, None; J.A. James, None; S.K. Nath, None.