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. Harley & 9 others Swapan 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 journalArticle

41 Citations (Scopus)

Abstract

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
JournaleLife
Volume5
Issue numberFEBRUARY2016
DOIs
StatePublished - Feb 15 2016

Fingerprint

Polymorphism
Autoimmunity
Systemic Lupus Erythematosus
Molecules
D region
HLA-D Antigens
HLA-DQ Antigens
HLA-DRB1 Chains
Immune system
Nucleic Acid Regulatory Sequences
HLA-DR Antigens
Transcription
Transcription Factors
Genes
Binding Sites
Dendritic Cells
Single Nucleotide Polymorphism
Immune System
Alleles
Genotype

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Medicine(all)
  • Neuroscience(all)

Cite this

Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity. / Raj, Prithvi; Rai, Ekta; Song, Ran; Khan, Shaheen; Wakeland, Benjamin E.; Viswanathan, Kasthuribai; Arana, Carlos; Liang, Chaoying; Zhang, Bo; Dozmorov, Igor; Carr-Johnson, Ferdicia; Mitrovic, Mitja; Wiley, Graham B.; Kelly, Jennifer A.; Lauwerys, Bernard R.; Olsen, Nancy J.; Cotsapas, Chris; Garcia, Christine K.; Wise, Carol A.; Harley, John B.; Nath, Swapan K.; James, Judith A.; Jacob, Chaim O.; Tsao, Betty P.; Pasare, Chandrashekhar; Karp, David R.; Li, Quan Zhen; Gaffney, Patrick M.; Wakeland, Edward K.

In: eLife, Vol. 5, No. FEBRUARY2016, e12089, 15.02.2016.

Research output: Contribution to journalArticle

Raj, P, Rai, E, Song, R, Khan, S, Wakeland, BE, Viswanathan, K, Arana, C, Liang, C, Zhang, B, Dozmorov, I, Carr-Johnson, F, Mitrovic, M, Wiley, GB, Kelly, JA, Lauwerys, BR, Olsen, NJ, Cotsapas, C, Garcia, CK, Wise, CA, Harley, JB, Nath, SK, James, JA, Jacob, CO, Tsao, BP, Pasare, C, Karp, DR, Li, QZ, Gaffney, PM & Wakeland, EK 2016, 'Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity', eLife, vol. 5, no. FEBRUARY2016, e12089. https://doi.org/10.7554/eLife.12089
Raj, Prithvi ; Rai, Ekta ; Song, Ran ; Khan, Shaheen ; Wakeland, Benjamin E. ; Viswanathan, Kasthuribai ; Arana, Carlos ; Liang, Chaoying ; Zhang, Bo ; Dozmorov, Igor ; Carr-Johnson, Ferdicia ; Mitrovic, Mitja ; Wiley, Graham B. ; Kelly, Jennifer A. ; Lauwerys, Bernard R. ; Olsen, Nancy J. ; Cotsapas, Chris ; Garcia, Christine K. ; Wise, Carol A. ; Harley, John B. ; Nath, Swapan K. ; James, Judith A. ; Jacob, Chaim O. ; Tsao, Betty P. ; Pasare, Chandrashekhar ; Karp, David R. ; Li, Quan Zhen ; Gaffney, Patrick M. ; Wakeland, Edward K. / Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity. In: eLife. 2016 ; Vol. 5, No. FEBRUARY2016.
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AU - Harley, John B.

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AU - Tsao, Betty P.

AU - Pasare, Chandrashekhar

AU - Karp, David R.

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