THU0002 SOLVING THE COMPLEX MHC ASSOCIATIONS IN SLE IDENTIFIES SEX-RELATED GENE EFFECTS

Abstract

Background:Genome-wide association analyses reveal that the Major Histocompatibility Complex (MHC) is the site of the strongest association signals in SLE and Sjögren’s syndrome. This associations in lupus and Sjögren’s syndrome are linked toHLAalleles: HLA-DRB1*03:01 and HLA-DRB1*15:01 (in Europeans). The DRB1*03:01 allele resides on an extended MHC haplotype which includes loss of the complement C4A gene. Whether C4 makes a genetic contribution to SLE/Sjogren’s risk has been a long standing issue of contention1. In comparison, it has been shown that elevated copy number of C4 is a genetic risk factor for schizophrenia2.Objectives:To define the causal MHC genes in SLE/Sjogren’s accommodating both structural and highly polymorphic variation.Methods:Use NG sequencing data from across the MHC to generate a panel of variants that inform class III structural variation involving the candidate genes coding complementC4AandC4Bas described2. To further improve the resolution of the association using transancestral mapping approach in SLE: examining cohorts of European ancestry (from ImmunoChip) and data from the MHC region of an African-American GWAS in SLE.Results:Comparing European and African data, we have shown that the association signals in SLE can be best explained by signals arising from 1) copy number variation of the complement component 4 (C4) genes in the MHC locus (Fig. 1) and 2) by a shared region in the class II region on the HLA-DRB1*15:01 (in Europeans) and HLA-DRB1*15:03 (in Africans) that likely operates to elevated HLA class II gene expression (Fig. 2). TheC4locus generates a 7-fold variation in risk for lupus (95% CI: 5.88-8.61;p<10-117in total) and 16-fold variation in risk for Sjögren’s syndrome (95% CI: 8.59-30.89;p<10-23in total), withC4Aprotecting more strongly thanC4Bin both illnesses. In schizophrenia, elevated C4 copy number elevates disease risk, whereas in SLE and Sjögren’s lower copy numbers ofC4genes correlate with higher disease risk. In all three illnesses,C4alleles acted more strongly in men than in women: common combinations ofC4AandC4Bgenerated 14-fold variation in risk for lupus and 31-fold variation in risk for Sjögren’s syndrome in men (versus 6-fold and 15-fold among women respectively) and affected schizophrenia risk about twice as strongly in men as in women. At a protein level, both C4 and its effector (C3) were present at greater levels in men than women in cerebrospinal fluid (p<10-5for both C4 and C3) and plasma among adults ages 20-50, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help explain the larger effects ofC4alleles in men, women’s greater risk of SLE and Sjogren’s, and men’s greater vulnerability in schizophrenia.Figure 1.Loss ofC4is risk in African and European ancestry cohorts. A = C4A, B = C4B, A-B = C4A + C4B (L) = Long form (with HERV), (S) = short formFigure 2.Common class II association after removing C4 signalConclusion:These results nominate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.