Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci

Abstract

Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (lambda(S) = approximately 30). We performed a genome-wide association scan using 317,501 SNPs in 720 women of European ancestry with SLE and in 2,337 controls, and we genotyped consistently associated SNPs in two additional independent sample sets totaling 1,846 affected women and 1,825 controls. Aside from the expected strong association between SLE and the HLA region on chromosome 6p21 and the previously confirmed non-HLA locus IRF5 on chromosome 7q32, we found evidence of association with replication (1.1 x 10(-7) < P(overall) < 1.6 x 10(-23); odds ratio = 0.82-1.62) in four regions: 16p11.2 (ITGAM), 11p15.5 (KIAA1542), 3p14.3 (PXK) and 1q25.1 (rs10798269). We also found evidence for association (P < 1 x 10(-5)) at FCGR2A, PTPN22 and STAT4, regions previously associated with SLE and other autoimmune diseases, as well as at > or =9 other loci (P < 2 x 10(-7)). Our results show that numerous genes, some with known immune-related functions, predispose to SLE.

Figure 1

Combined association results for the extended HLA region (chromosome 6, 26–34 Mb). SNPs with P < 0.001 in the overall joint analysis are represented, color-coded by odds ratio (OR) strata. SNPs of interest include (i) rs3131379 (position 31.829012 Mb, gene MSH5; OR = 2.36, P = 1.7 × 10⁻⁵²); (ii) rs1270942 (position 32.026839 Mb, gene RDBP; OR 2.35, 32.369230 = P = 1.3 × 10⁻⁵¹); (iii) rs7775397 (position 32.369230 Mb, gene C6orf10; OR = 2.28, P = 8.0 × 10⁻⁴⁷); (iv) rs9275572 (position 32.786977 Mb, no gene known; OR = 1.69, P = 7.0 × 10⁻⁴⁸); (v) rs1794282 (position 32.774504 Mb, no gene known; OR = 2.26, P = 2.6 × 10⁻⁴⁶) and (vi) rs7192 (position 32.519624 Mb, gene HLA-DRA; OR = 1.61, P = 6.2 × 10⁻⁴⁰).