Abstract
Osteopontin (SPP1) is an important bone matrix mediator found to have key roles in inflammation and immunity. SPP1 genetic polymorphisms and increased osteopontin protein levels have been reported to be associated with SLE in small patient collections. The present study evaluates association between SPP1 polymorphisms and SLE in a large cohort of 1141 unrelated SLE patients [707 European-American (EA) and 434 African-American (AA)], and 2009 unrelated controls (1309 EA and 700 AA). Population-based case-control association analyses were performed. To control for potential population stratification, admixture adjusted logistic regression, genomic control (GC), structured association (STRAT), and principal components analysis (PCA) were applied. Combined analysis of 2 ethnic groups, showed the minor allele of 2 SNPs (rs1126616T and rs9138C) significantly associated with higher risk of SLE in males (P = 0.0005, OR = 1.73, 95% CI = 1.28–2.33), but not in females. Indeed, significant gene-gender interactions in the 2 SNPs, rs1126772 and rs9138, were detected (P = 0.001 and P = 0.0006, respectively). Further, haplotype analysis identified rs1126616T-rs1126772A-rs9138C which demonstrated significant association with SLE in general (P = 0.02, OR = 1.30, 95%CI 1.08–1.57), especially in males (P = 0.0003, OR = 2.42, 95%CI 1.51–3.89). Subgroup analysis with single SNPs and haplotypes also identified a similar pattern of gender-specific association in AA and EA. GC, STRAT, and PCA results within each group showed consistent associations. Our data suggest SPP1 is associated with SLE, and this association is especially stronger in males. To our knowledge, this report serves as the first association of a specific autosomal gene with human male lupus.
Highlights
Systemic Lupus Erythematosus (SLE) is a prototypic human autoimmune disease characterized by impaired T cell responses, dysregulated B cell activation, hyperactive B cells and autoantibody production leading to inflammation and potential end-organ damage
We evaluated the association of each polymorphism with SLE, adjusting for the admixture proportion utilizing logistic regression under the multiplicative genetic model for minor alleles by combined analysis
Previous studies have suggested that increased secreted phosphoprotein 1 (SPP1) plasma concentration, as a result of increased gene/protein expression and local production, was associated with SLE [13]
Summary
Systemic Lupus Erythematosus (SLE) is a prototypic human autoimmune disease characterized by impaired T cell responses, dysregulated B cell activation, hyperactive B cells and autoantibody production leading to inflammation and potential end-organ damage. While the etiology of SLE remains complex, genetic factors are known to be important in the pathogenesis of SLE [1,2]. The current collection of genetic information suggests that SLE susceptibility arises from specific combinations of multiple gene-gene and gene-environment interactions. Among the genetic factors believed to influence SLE susceptibility, the major histocompatibility complex (MHC) alleles show the most significant association, but these do not explain the total genetic background of the disease. Several recent studies show that non-HLA genes play a role in SLE development [3,4,5,6,7]. Several lines of evidence suggest that secreted phosphoprotein 1 (SPP1) located at 4q22, called osteopontin and early T-lymphocyte activation 1, may have a role in the pathogenesis of SLE as well as other autoimmune disorders
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