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Class II HLA interactions modulate genetic risk for multiple sclerosis

2015; Nature Portfolio; Volume: 47; Issue: 10 Linguagem: Inglês

10.1038/ng.3395

1546-1718

Loukas Moutsianas, Luke Jostins-Dean, Ashley Beecham, Alexander Dilthey, Dionysia K Xifara, Maria Ban, Tejas Shah, Nikolaos A. Patsopoulos, Lars Alfredsson, Carl A. Anderson, Kathrine E. Attfield, Sergio E. Baranzini, Jeffrey C. Barrett, Thomas M.C. Binder, David R. Booth, Dorothea Buck, Elisabeth Gulowsen Celius, Chris Cotsapas, Sandra D’Alfonso, Calliope A. Dendrou, Peter Donnelly, Bénédicte Dubois, Bertrand Fontaine, Lars Fugger, An Goris, Pierre‐Antoine Gourraud, Christiane Graetz, Bernhard Hemmer, Jan Hillert, Ingrid Kockum, Stephen Leslie, Christina M. Lill, Filippo Martinelli Boneschi, Jorge R. Oksenberg, Tomas Olsson, Annette Oturai, Janna Saarela, Helle Bach Søndergaard, Anne Spurkland, Bruce Taylor, Juliane Winkelmann, Frauke Zipp, Jonathan L. Haines, Margaret A. Pericak‐Vance, Chris C. A. Spencer, Graeme J. Stewart, David A. Hafler, Adrian J. Ivinson, Hanne F. Harbo, Stephen L. Hauser, Philip L. De Jager, Alastair Compston, Jacob L. McCauley, Stephen Sawcer, Gil McVean,

Genetic Associations and Epidemiology

Gil McVean and colleagues report a meta-analysis of Immunochip studies including over 17,000 multiple sclerosis cases and 30,000 controls, with imputation of classical HLA alleles. They find two interactions involving class II HLA alleles but no evidence for significant epistatic interactions or interactions between HLA and non-HLA risk variants. Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles. Among new and previously identified class II risk alleles (HLA-DRB1*15:01, HLA-DRB1*13:03, HLA-DRB1*03:01, HLA-DRB1*08:01 and HLA-DQB1*03:02) and class I protective alleles (HLA-A*02:01, HLA-B*44:02, HLA-B*38:01 and HLA-B*55:01), we find evidence for two interactions involving pairs of class II alleles: HLA-DQA1*01:01–HLA-DRB1*15:01 and HLA-DQB1*03:01–HLA-DQB1*03:02. We find no evidence for interactions between classical HLA alleles and non-HLA risk-associated variants and estimate a minimal effect of polygenic epistasis in modulating major risk alleles.