A functional variant in microRNA-146a promoter modulates its expression and confers disease risk for systemic lupus erythematosus

Systemic lupus erythematosus (sle) is a complex autoimmune disease with a strong genetic predisposition,characterized by an upregulated type i interferon pathway. micrornas are important regulators of immune homeostasis,and aberrant microrna expression has been demonstrated in patients with autoimmune diseases. we recently identified mir-146a as a negative regulator of the interferon pathway and linked the abnormal activation of this pathway to the underexpression of mir-146a in sle patients. to explore why the expression of mir-146a is reduced in sle patients,we conducted short parallel sequencing of potentially regulatory regions of mir-146a and identified a novel genetic variant (rs57095329) in the promoter region exhibiting evidence for association with sle that was replicated independently in 7,182 asians (pmeta = 2.74×10-8,odds ratio = 1.29 [1.18-1.40]). the risk-associated g allele was linked to reduced expression of mir-146a in the peripheral blood leukocytes of the controls. combined functional assays showed that the risk-associated g allele reduced the protein-binding affinity and activity of the promoter compared with those of the promoter containing the protective a allele. transcription factor ets-1,encoded by the lupus-susceptibility gene ets1,identified in recent genome-wide association studies,binds near this variant. the manipulation of ets-1 levels strongly affected mir-146a promoter activity in vitro; and the knockdown of ets-1,mimicking its reduced expression in sle,directly impaired the induction of mir-146a. we also observed additive effects of the risk alleles of mir-146a and ets1. our data identified and confirmed an association between a functional promoter variant of mir-146a and sle. this risk allele had decreased binding to transcription factor ets-1,contributing to reduced levels of mir-146a in sle patients. © 2011 luo et al.