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HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy

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  • Hanna M Ollila
  • Jean-Marie Ravel
  • Fang Han
  • Juliette Faraco
  • Ling Lin
  • Xiuwen Zheng
  • Giuseppe Plazzi
  • Yves Dauvilliers
  • Fabio Pizza
  • Seung-Chul Hong
  • Poul Jennum
  • Stine Knudsen
  • Birgitte R Kornum
  • Xiao Song Dong
  • Han Yan
  • Heeseung Hong
  • Cristin Coquillard
  • Joshua Mahlios
  • Otto Jolanki
  • Mali Einen
  • Isabelle Arnulf
  • Sophie Lavault
  • Birgit Högl
  • Birgit Frauscher
  • Catherine Crowe
  • Markku Partinen
  • Yu Shu Huang
  • Patrice Bourgin
  • Outi Vaarala
  • Alex Désautels
  • Jacques Montplaisir
  • Steven J Mack
  • Michael Mindrinos
  • Marcelo Fernandez-Vina
  • Emmanuel Mignot
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Type 1 narcolepsy, a disorder caused by a lack of hypocretin (orexin), is so strongly associated with human leukocyte antigen (HLA) class II HLA-DQA1(∗)01:02-DQB1(∗)06:02 (DQ0602) that very few non-DQ0602 cases have been reported. A known triggering factor for narcolepsy is pandemic 2009 influenza H1N1, suggesting autoimmunity triggered by upper-airway infections. Additional effects of other HLA-DQ alleles have been reported consistently across multiple ethnic groups. Using over 3,000 case and 10,000 control individuals of European and Chinese background, we examined the effects of other HLA loci. After careful matching of HLA-DR and HLA-DQ in case and control individuals, we found strong protective effects of HLA-DPA1(∗)01:03-DPB1(∗)04:02 (DP0402; odds ratio [OR] = 0.51 [0.38-0.67], p = 1.01 × 10(-6)) and HLA-DPA1(∗)01:03-DPB1(∗)04:01 (DP0401; OR = 0.61 [0.47-0.80], p = 2.07 × 10(-4)) and predisposing effects of HLA-DPB1(∗)05:01 in Asians (OR = 1.76 [1.34-2.31], p = 4.71 × 10(-05)). Similar effects were found by conditional analysis controlling for HLA-DR and HLA-DQ with DP0402 (OR = 0.45 [0.38-0.55] p = 8.99 × 10(-17)) and DP0501 (OR = 1.38 [1.18-1.61], p = 7.11 × 10(-5)). HLA-class-II-independent associations with HLA-A(∗)11:01 (OR = 1.32 [1.13-1.54], p = 4.92 × 10(-4)), HLA-B(∗)35:03 (OR = 1.96 [1.41-2.70], p = 5.14 × 10(-5)), and HLA-B(∗)51:01 (OR = 1.49 [1.25-1.78], p = 1.09 × 10(-5)) were also seen across ethnic groups in the HLA class I region. These effects might reflect modulation of autoimmunity or indirect effects of HLA class I and HLA-DP alleles on response to viral infections such as that of influenza.

Original languageEnglish
JournalAmerican Journal of Human Genetics
Volume96
Issue number1
Pages (from-to)136-46
Number of pages11
ISSN0002-9297
DOIs
Publication statusPublished - 8 Jan 2015

    Research areas

  • Alleles, Asian Continental Ancestry Group, Case-Control Studies, Cohort Studies, European Continental Ancestry Group, Female, Genetic Loci, HLA-B Antigens, HLA-DP Antigens, HLA-DP beta-Chains, HLA-DQ alpha-Chains, HLA-DR Antigens, Haplotypes, Histocompatibility Antigens Class I, Humans, Influenza A Virus, H1N1 Subtype, Male, Narcolepsy, Risk Factors

ID: 45908228