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

作　　者：Wenjing Ye Yiyun Yu Xiaoxia Zhu Weiguo Wan Yun Liu Hejian Zou Zaihua Zhu 

机构地区：[1]Division of Rheumatology and Immunology,Huashan Hospital,Fudan University,Shanghai 200040,China [2]Institute of Rheumatology,Immunology and Allergy,Fudan University,Shanghai 200040,China [3]The Ministry of Education Key Laboratory of Metabolism and Molecular Medicine,Department of Biochemistry and Molecular Biology,School of Basic Medical Sciences,Fudan University,Shanghai 200032,China

出　　处：《Phenomics》2023年第5期485-495,共11页表型组学（英文）

基　　金：supported by the grants from the National Natural Science Foundation of China(No.31771451 to YL);Shanghai Municipal Science and Technology Major Project(No.2017SHZDZX01 to YL);the National Key R&D Program of China(No.2021YFC2701001 to YL).

摘　　要：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.

关 键 词：Rheumatoid arthritis Genome-wide association study ENHANCER ORMDL Sphingolipid Biosynthesis Regulator 3 

分 类 号：Q78[生物学—分子生物学]