Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity

作者：Prithvi P. Raj, Ekta Rai, Ran Song, Shaheen Khan, Benjamin Wakeland, Kasthuribai Viswanathan, Carlos Arana, Chaoying Liang, Bo Zhang, Igor M. Dozmorov, Ferdicia Carr-Johnson, Mitja Mitrovič, Graham B. Wiley, Jennifer A. Kelly, Bernard R. Lauwerys, Nancy J. Olsen, Chris J. Cotsapas, Christine Kim Garcia, Carol A. Wise, John B. Harley, Swapan Kumar Nath, Judith A. James, Chaim O. Jacob, Betty P. Tsao, Chandrashekhar Pasare, David R. Karp, Quan Zhen Li, Patrick M. Gaffney, Edward K. Wakeland · 发表于：eLife · 年份：2016 · DOI：10.7554/elife.12089 · 被引用次数：142 · 研究领域：T-cell and B-cell Immunology、Immune Cell Function and Interaction、Systemic Lupus Erythematosus Research

Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism. Variations modifying the consensus binding motifs of IRF4 and CTCF in the XL9 regulatory complex modified the transcription of HLA-DRB1, HLA-DQA1 and HLA-DQB1 in a chromosome-specific manner, resulting in a 2.5-fold increase in the surface expression of HLA-DR and DQ molecules on dendritic cells with SLE risk genotypes, which increases to over 4-fold after stimulation. Similar analyses of fifteen other SLE risk loci identified 1206 functional variants tightly linked with disease-associated SNPs and demonstrated that common disease alleles contain multiple causal variants modulating multiple immune system genes.