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

Prithvi Raj, Ekta Rai, Ran Song, Shaheen Khan, Benjamin E. Wakeland, Kasthuribai Viswanathan, Carlos Arana, Chaoying Liang, Bo Zhang, Igor Dozmorov, Ferdicia Carr-Johnson, Mitja Mitrovic, Graham B. Wiley, Jennifer A. Kelly, Bernard R. Lauwerys, Nancy J. Olsen, Chris Cotsapas, Christine K. Garcia, Carol A. Wise, John B. HarleySwapan K. Nath, Judith A. James, Chaim O. Jacob, Betty P. Tsao, Chandrashekhar Pasare, David R. Karp, Quan Zhen Li, Patrick M. Gaffney, Edward K. Wakeland

Research output: Contribution to journalArticlepeer-review

98 Scopus citations


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 c hromosome-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.

Original languageEnglish (US)
Article numbere12089
Issue numberFEBRUARY2016
StatePublished - Feb 15 2016

All Science Journal Classification (ASJC) codes

  • General Neuroscience
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology


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