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RESEARCH PRODUCT

Class II HLA interactions modulate genetic risk for multiple sclerosis

Nikolaos A. PatsopoulosGil McveanJuliane WinkelmannF. Martinelli-boneschiAn GorisA CompstonGourraud P-a.Hanne F. HarboCalliope A. DendrouAnnette Bang OturaiElisabeth Gulowsen CeliusDionysia Kiara XifaraSandra D'alfonsoB. HemmerLars FuggerHelle Bach SøndergaardPeter DonnellyLuke JostinsSergio E. BaranziniFrauke ZippBinder Tmc.Tomas OlssonLars AlfredssonAshley BeechamCarl A. AndersonBénédicte DuboisDavid A. HaflerJanna SaarelaMaria BanJorge R. OksenbergIngrid KockumMargaret A. Pericak-vanceJan HillertJacob L. MccauleyStephen SawcerKathrine E. AttfieldBertrand FontaineChris CotsapasChristiane GraetzP. L. De JagerChristina M. LillBruce V. TaylorStephen LeslieJonathan L. HainesDorothea BuckStephen L. HauserAnne SpurklandJeffrey C. BarrettTejas ShahSpencer Cca.David R. BoothLoukas MoutsianasAdrian J. IvinsonAlexander T. DiltheyGraeme J. Stewart

subject

Geneticsmusculoskeletal diseasesMultiple SclerosisHistocompatibility Antigens Class IISingle-nucleotide polymorphismGenome-wide association studyEpistasis GeneticHuman leukocyte antigenBiologyPolymorphism Single NucleotideArticleHistocompatibilityGenetic variationGeneticsHumansGenetic Predisposition to DiseaseAllele10. No inequalityHLA-DRB1AllelesGenetic association

description

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.

yearjournalcountryeditionlanguage
2015-09-07
10.1038/ng.3395https://europepmc.org/articles/PMC4874245/