Sex influences eQTL effects of SLE and Sjögren’s syndrome-associated genetic polymorphisms

Background Systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS) are autoimmune disorders characterized by autoantibodies, dysregulated B cells, and notably high female-to-male incidence ratios. Genome-wide association studies have identified several susceptibility SNPs for both diseases. Many SNPs in the genome are expression quantitative trait loci (eQTLs), with context-dependent effects. Assuming that sex is a biological context, we investigated whether SLE/pSS SNPs act as eQTLs in B cells and used a disease-targeted approach to understand if they display sex-specific effects. Methods We used genome-wide genotype and gene expression data from primary B cells from 125 males and 162 females. The MatrixEQTL R package was used to identify eQTLs within a genomic window of 2 Mb centered on each of 22 established SLE and/or pSS susceptibility SNPs. To find sex-specific eQTLs, we used a linear model with a SNP * sex interaction term. Results We found ten SNPs affecting the expression of 16 different genes (FDR < 0.05). rs7574865- INPP1 , rs7574865- MYO1B , rs4938573- CD3D , rs11755393- SNRPC , and rs4963128- PHRF1 were novel observations for the immune compartment and B cells. By analyzing the SNP * sex interaction terms, we identified six genes with differentially regulated expression in females compared to males, depending on the genotype of SLE/pSS-associated SNPs: SLC39A8 ( BANK1 locus), CD74 ( TNIP1 locus), PXK , CTSB ( BLK/FAM167A locus), ARCN1 ( CXCR5 locus), and DHX9 ( NCF2 locus). Conclusions We identified several unknown sex-specific eQTL effects of SLE/pSS-associated genetic polymorphisms and provide novel insight into how gene-sex interactions may contribute to the sex bias in systemic autoimmune diseases.