Systemic lupus erythematosus is a complex and potentially fatal autoimmune disease, characterized by autoantibody production and multi-organ damage. By a genome-wide association study (320 patients and 1,500 controls) and subsequent replication altogether involving a total of 3,300 Asian SLE patients from Hong Kong, Mainland China, and Thailand, as well as 4,200 ethnically and geographically matched controls, genetic variants in ETS1 and WDFY4 were found to be associated with SLE (ETS1: rs1128334, P = 2.33×10−11, OR = 1.29; WDFY4: rs7097397, P = 8.15×10−12, OR = 1.30). ETS1 encodes for a transcription factor known to be involved in a wide range of immune functions, including Th17 cell development and terminal differentiation of B lymphocytes. SNP rs1128334 is located in the 3′-UTR of ETS1, and allelic expression analysis from peripheral blood mononuclear cells showed significantly lower expression level from the risk allele. WDFY4 is a conserved protein with unknown function, but is predominantly expressed in primary and secondary immune tissues, and rs7097397 in WDFY4 changes an arginine residue to glutamine (R1816Q) in this protein. Our study also confirmed association of the HLA locus, STAT4, TNFSF4, BLK, BANK1, IRF5, and TNFAIP3 with SLE in Asians. These new genetic findings may help us to gain a better understanding of the disease and the functions of the genes involved.

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Summary Purpose:  Previous studies found a strong association between HLA‐B*1502 and carbamazepine (CBZ)‐induced Stevens‐Johnson syndrome (SJS) in Han Chinese, but not in Caucasian populations. Even in Han Chinese, the HLA‐B*1502 was not associated with CBZ‐induced maculopapular eruptions (MPE). This study seeks to identify whether HLA‐B*1502 is associated with CBZ‐ or phenytoin (PHT)‐induced SJS or MPE in a Thai population. Methods:  Eighty‐one Thai epileptic patients between 1994 and 2007 from the Chulalongkorn Comprehensive Epilepsy Program were recruited. Thirty‐one subjects had antiepileptic drug (AED)‐induced SJS or MPE (6 CBZ‐SJS, 4 PHT‐SJS, 9 CBZ‐MPE, 12 PHT‐MPE), and 50 were AED‐tolerant controls. Results:  For the first time, a strong association between HLA‐B*1502 and PHT‐induced SJS was found (p = 0.005). A strong association was also found between the HLA‐B*1502 and CBZ‐induced SJS (p = 0.0005), making Thai the first non‐Chinese population demonstrating such an association. Some patients, who were HLA‐B*1502 and suffered from CBZ‐induced SJS, could be tolerant to PHT and vice versa. This suggests that HLA‐B*1502 may be a common attribute required for a Thai patient to develop SJS from these two AEDs; other different elements, however, are also needed for each AED. In addition, no association between HLA‐B alleles and CBZ‐ or PHT‐induced MPE was found. Conclusions:  CBZ‐ and PHT‐induced SJS, but not MPE, is associated with HLA‐B*1502 allele in Thai population.

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 (P meta = 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.

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic involvement and ethnic differences. Susceptibility genes identified so far only explain a small portion of the genetic heritability of SLE, suggesting that many more loci are yet to be uncovered for this disease. In this study, we performed a meta-analysis of genome-wide association studies on SLE in Chinese Han populations and followed up the findings by replication in four additional Asian cohorts with a total of 5,365 cases and 10,054 corresponding controls. We identified genetic variants in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with the disease. These findings point to potential roles of cell-cycle regulation, autophagy, and DNA demethylation in SLE pathogenesis. For the region involving TET3 and that involving CDKN1B, multiple independent SNPs were identified, highlighting a phenomenon that might partially explain the missing heritability of complex diseases.