Genome-wide association study for systemic lupus erythematosus in an egyptian population

Abstract

Systemic lupus erythematosus (SLE) susceptibility has a strong genetic component. Genome-wide association studies (GWAS) across trans-ancestral populations show both common and distinct genetic variants of susceptibility across European and Asian ancestries, while many other ethnic populations remain underexplored. We conducted the first SLE GWAS on Egyptians–an admixed North African/Middle Eastern population–using 537 patients and 883 controls. To identify novel susceptibility loci and replicate previously known loci, we performed imputation-based association analysis with 6,382,276 SNPs while accounting for individual admixture. We validated the association analysis using adaptive permutation tests (n = 109). We identified a novel genome-wide significant locus near IRS1/miR-5702 (Pcorrected = 1.98 × 10−8) and eight novel suggestive loci (Pcorrected < 1.0 × 10−5). We also replicated (Pperm < 0.01) 97 previously known loci with at least one associated nearby SNP, with ITGAM, DEF6-PPARD and IRF5 the top three replicated loci. SNPs correlated (r2 > 0.8) with lead SNPs from four suggestive loci (ARMC9, DIAPH3, IFLDT1, and ENTPD3) were associated with differential gene expression (3.5 × 10−95 < p < 1.0 × 10−2) across diverse tissues. These loci are involved in cellular proliferation and invasion—pathways prominent in lupus and nephritis. Our study highlights the utility of GWAS in an admixed Egyptian population for delineating new genetic associations and for understanding SLE pathogenesis.

Cell-Free Genic Extrachromosomal Circular DNA Profiles of DNase Knockouts Associated with Systemic Lupus Erythematosus and Relation with Common Fragile Sites

“…DOCK10, dedicator of cytokinesis 10, belongs to a cytokinesis protein family, whose members are guanosine nucleotide exchange factors for Rho GTPases. It has been confirmed as a SLE locus (rs11462616) in an Egyptian population [24]. Sheng et al [25] suggested that overexpression of the transcriptional regulator BACH2 represses Th9 cell differentiation by suppressing IRF4 expression in SLE patients, and that it might be a potential target for SLE treatment.…”

Disentangling the Pathogenesis of Systemic Lupus Erythematosus: Close Ties between Immunological, Genetic and Environmental Factors

“…To date, almost a hundred susceptibility loci have been linked with SLE through genome-wide association studies (GWAS), including the cytotoxic T lymphocyte associated protein-4 (CTLA4) and TNF receptor-associated factor-3 (TRAF3) [ 49 , 50 , 51 ]. CTLA4 modulates T cell activation, induces immune tolerance, as well as inhibits T cell proliferation dan differentiation, pro-inflammatory cytokines production and cell cycle progression [ 52 ].…”