The coding variant with in ITGAM influences lupus nephritis

Abstract

Purpose: We recently demonstrated genetic association between a novel non-synonymous (R77H) variant (rs1143679) at exon-3 of ITGAM and systemic lupus erythematosus (SLE), a clinically heterogeneous disease. The relationship between this variant and clinical sub-phenotypes have not been studied. We hypothesized that rs1143679 could predict specific clinical outcomes (sub-phenotypes). Method: We used 2366 SLE cases and 2931 unaffected controls of European descent to assess association between this coding variant and clinical sub-phenotypes. SLE patients were classified by the presence or absence of individual ACR criteria. Logistic regression and Pearson chi-square tests were used to assess statistical significance with rs1143679 in case-control and case-only analyses. Results: First, for overall case-control analysis between SLE and rs1143679, we detected highly significant (P = 2.22x10-21, OR = 1.73) genetic association. Second, we performed case-only analysis between individual ACR criteria positive cases and negative cases. This variant was significantly associated with lupus nephritis (P = 0.0003, OR = 1.39), discoid rash (P = 0.02, OR = 1.27) and immunologic criteria (P = 0.04, OR = 1.30). Third, to further assess the magnitude of associations between significant ACR criteria, we compared them with normal controls. The strongest statistical association was with lupus nephritis versus controls (P = 4.69x10-22, OR = 2.15), and immunologic manifestations versus controls (P = 3.49x10-22, OR = 1.86); both were more significant than all SLE cases together versus controls. Conversely, significant associations were also detected with ACR-negative versus controls for nephritis (P = 4.05x10-7, OR = 1.50) and discoid rash negative (P = 2.58x10-6, OR = 1.55). However, significantly different ORs were only detected between nephritis positive and nephritis negative cases when compare with all controls. The minor allele frequency increased from 10.6% (controls) to 17.0% (SLE cases) and 20.4% (lupus nephritis). All associations remained significant after 10,000 permutations. Conclusion: Clinical sub-grouping yielded the strongest association with rs1143679 in SLE patients with lupus nephritis, both in case-only and case-control analyses. SLE nephritis patients were highly enriched with the risk allele.