ELF1 is associated with systemic lupus erythematosus in Asian populations

Abstract

Great progress has been made in revealing the genetic variants that predispose individuals to complex diseases through genome-wide association studies (GWAS). However, the genes discovered so far only explain a small portion of heritability for complex disease such as systemic lupus erythematosus (SLE). Imbalance in the populations studied may have prevented us from identifying the population-specific susceptibility genes. This may be especially true for SLE, which has an apparent population difference in both disease prevalence and severity. Through a multi-stage study including GWAS and replication in several Asian populations, which included a total of 3164 patients and 4482 matched controls, we identified ELF1, an Ets family transcription factor that is involved in T cell development and function, associated with SLE (rs7329174, OR = 1.26, joint P = 1.47X10-8). The SNP also showed more association in patients with renal nephritis comparing to patients without (OR = 1.14, joint P = 0.059). The risk allele for this SNP and other SNPs in LD with rs7329174 has extremely low allele frequencies in populations of European ancestry. Bioinformatics analysis of the ELF1 gene revealed evidence for 3 alternative first exons in a 40 kb region in this gene, indicative of a complex control for its transcription, and SNP rs7379174 was located upstream of the third exon1, E1C. The usage of the 3 distinct first-exons was confirmed in PBMC in all patients and healthy controls examined. Furthermore, a prominent alternative splicing variant coding for a 56 amino acid deletion form of the protein was detected also in both patients and controls, both with abundant expression level. Although direct association of rs7329174 with exon 1 usage or alternative splicing was not established, these findings suggest that ELF1 may play a role in SLE susceptibility and the gene is tightly regulated in expression and alternative splicing.