Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity.
(2016) eLife — Vol. 5, p. e1208 [1-52] (2016)
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- 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 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 >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.
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Raj, P., Rai, E., Song, R., Khan, S., Wakeland, B. E., Viswanathan, K., Arana, C., Liang, C., Zhang, B., Dozmorov, I., Carr-Johnson, F., Mitrovic, M., Wiley, G. B., Kelly, J. A., Lauwerys, B., Olsen, N. J., Cotsapas, C., Garcia, C. K., Wise, C. A., et al. (2016). Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity. eLife, 5, e1208 [1-52]. https://doi.org/10.7554/eLife.12089 (Original work published 2016)