A Common Functional Variant at the Enhancer of the Rheumatoid Arthritis Risk Gene ORMDL3 Regulates its Expression Through Allele-Specific JunD Binding

Genome-wide association studies(GWASs)have identified over 100 loci associated with rheumatoid arthritis(RA);how-ever,the functionally affected genes and the underlying molecular mechanisms contributing to these associations are often unknown.In this study,we conducted an integrative genomic analysis incorporating multiple“omics”data and identified a functional regulatory DNA variant,rs56199421,and a plausible mechanism by which it regulates the expression of a puta-tive RA risk gene,ORMDL Sphingolipid Biosynthesis Regulator 3(ORMDL3).The T allele of rs56199421,located in the enhancer region of ORMDL3,exhibited stronger direct binding ability than the other C allele of rs56199421 did in vitro with the transcription factor JunD and demonstrated higher transcriptional activity.Moreover,the T allele of rs56199421 is associated with elevated RA risk,and ORMDL3 expression is increased in RA patients.Thus,these findings suggest that the T allele of rs56199421 enhances JunD transcription factor binding,increases enhancer activity,and elevates the expression of the RA risk gene ORMDL3.