Abstract
We previously reported that the G allele of rs3853839 at 3′untranslated region (UTR) of Toll-like receptor 7 (TLR7) was associated with elevated transcript expression and increased risk for systemic lupus erythematosus (SLE) in 9,274 Eastern Asians [P = 6.5×10−10, odds ratio (OR) (95%CI) = 1.27 (1.17–1.36)]. Here, we conducted trans-ancestral fine-mapping in 13,339 subjects including European Americans, African Americans, and Amerindian/Hispanics and confirmed rs3853839 as the only variant within the TLR7-TLR8 region exhibiting consistent and independent association with SLE (P meta = 7.5×10−11, OR = 1.24 [1.18–1.34]). The risk G allele was associated with significantly increased levels of TLR7 mRNA and protein in peripheral blood mononuclear cells (PBMCs) and elevated luciferase activity of reporter gene in transfected cells. TLR7 3′UTR sequence bearing the non-risk C allele of rs3853839 matches a predicted binding site of microRNA-3148 (miR-3148), suggesting that this microRNA may regulate TLR7 expression. Indeed, miR-3148 levels were inversely correlated with TLR7 transcript levels in PBMCs from SLE patients and controls (R2 = 0.255, P = 0.001). Overexpression of miR-3148 in HEK-293 cells led to significant dose-dependent decrease in luciferase activity for construct driven by TLR7 3′UTR segment bearing the C allele (P = 0.0003). Compared with the G-allele construct, the C-allele construct showed greater than two-fold reduction of luciferase activity in the presence of miR-3148. Reduced modulation by miR-3148 conferred slower degradation of the risk G-allele containing TLR7 transcripts, resulting in elevated levels of gene products. These data establish rs3853839 of TLR7 as a shared risk variant of SLE in 22,613 subjects of Asian, EA, AA, and Amerindian/Hispanic ancestries (Pmeta = 2.0×10−19, OR = 1.25 [1.20–1.32]), which confers allelic effect on transcript turnover via differential binding to the epigenetic factor miR-3148.
Highlights
Systemic lupus erythematosus (SLE [OMIM 152700]) is a complex and heterogeneous autoimmune disease with a strong genetic component that is modified by environmental exposures
After applying quality control measures, 41 genotyped single nucleotide polymorphism (SNP) and 57–75 imputed SNPs/INDELs were assessed for association with systemic lupus erythematosus (SLE) in unrelated cases and healthy controls of European American (EA, 3,936 cases vs. 3,491 controls), African American (AA, 1,679 vs. 1,934) and Hispanic enriched for the Amerindian-European admixture (HS, 1,492 vs. 807) descent (Figure 1A)
We fine-mapped the Toll-like receptor 7 (TLR7)-TLR8 region and confirmed rs3853839 exhibiting the strongest association with SLE in European Americans, African Americans, and Amerindian/Hispanics
Summary
Systemic lupus erythematosus (SLE [OMIM 152700]) is a complex and heterogeneous autoimmune disease with a strong genetic component that is modified by environmental exposures. Recent genome-wide association (GWA) and follow-up studies have revealed the association of a number of polymorphic variants in genes encoding components of the TLR/type I IFN pathway with susceptibility to SLE (reviewed in [3,4]), providing insights at the molecular level to refine our understanding of this dysregulated pathway in the predisposition to SLE. Our previous study identified a single nucleotide polymorphism (SNP), rs3853839, in the 39 UTR of an X-linked gene TLR7 to be associated with SLE in 4,334 cases and 4,940 controls of Eastern Asian descent [5], providing the first convincing evidence for the genetic contribution of TLR7 to human SLE. By fine mapping the TLR7-TLR8 region, we confirmed that the previously reported functional SNP rs3853839, located within a predicted binding site of miR-3148, was most likely responsible for observed association with SLE in three populations of nonAsian ancestry. We demonstrated a differential miR-3148 modulation explaining the effect of allelic variation at rs3853839 on TLR7 expression
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