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

Hanna M Ollila¹, Jean-Marie Ravel¹, Fang Han², Juliette Faraco¹, Ling Lin¹, Xiuwen Zheng³, Giuseppe Plazzi⁴, Yves Dauvilliers⁵, Fabio Pizza⁴, Seung-Chul Hong⁶, Poul Jennum⁷, Stine Knudsen⁸, Birgitte R Kornum⁹, Xiao Song Dong², Han Yan², Heeseung Hong¹, Cristin Coquillard¹⁰, Joshua Mahlios¹, Otto Jolanki¹, Mali Einen¹, Isabelle Arnulf, Birgit Högl¹¹, Birgit Frauscher¹¹, Catherine Crowe¹², Markku Partinen¹³, Yu Shu Huang¹⁴, Patrice Bourgin¹⁵, Outi Vaarala¹⁶, Alex Désautels¹⁷, Jacques Montplaisir¹⁸, Steven J Mack¹⁹, Michael Mindrinos²⁰, Marcelo Fernandez-Vina¹⁰, Emmanuel Mignot²¹

Affiliations

¹ Stanford University Center for Sleep Sciences, Palo Alto, CA 94304, USA.
² Department of Pulmonary Medicine, Peking University People's Hospital, 100044 Beijing, China.
³ Department of Biostatistics, University of Washington, PO box 357232, Seattle, WA 98195, USA.
⁴ Department of Biomedical and Neuromotor Sciences, University of Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy; IRCCS Institute of Neurological Sciences, 40139 Bologna, Italy.
⁵ INSERM U1061, Reference Center for Narcolepsy, Sleep-Wake Disorders Center, Department of Neurology, Gui-de-Chauliac Hospital, Centre Hospitalier Régional Universitaire Montpellier, 34090 Montpellier, France.
⁶ Department of Psychiatry, St. Vincent's Hospital, The Catholic University of Korea, 442-723 Suwon, Korea.
⁷ Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, University of Copenhagen, Glostrup Hospital, 2600 Glostrup, Denmark.
⁸ Norwegian Resource Center for ADHD, TS, and Narcolepsy, Oslo University Hospital, 0450 Ullevål, Norway.
⁹ Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, University of Copenhagen, Glostrup Hospital, 2600 Glostrup, Denmark; Molecular Sleep Laboratory, Department of Diagnostics, Glostrup Hospital, 2600 Glostrup, Denmark.
¹⁰ Department of Pathology, Stanford University School of Medicine, Stanford, CA 94304, USA.
¹¹ Department of Neurology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
¹² Mater Private Hospital, Dublin 7, Ireland.
¹³ Helsinki Sleep Clinic, Vitalmed Research Centre, 00420 Helsinki, Finland; Department of Clinical Neurosciences, University of Helsinki, 00100 Helsinki, Finland.
¹⁴ Chang Gung Memorial Hospital and University, Taipei 10591, Taiwan.
¹⁵ Department of Sleep Medicine, Strasbourg University Hospital, Strasbourg University, 67084 Strasbourg, France.
¹⁶ Institute of Clinical Medicine, University of Helsinki, 00100 Helsinki, Finland.
¹⁷ Center for Advanced Research in Sleep Medicine, Hôpital du Sacré-Coeur and Department of Neurosciences, University of Montreal, Montreal, QC H3T 1J4, Canada.
¹⁸ Center for Advanced Research in Sleep Medicine, Hôpital du Sacré-Coeur and Department of Psychiatry, University of Montreal, Montreal QC H3T 1J4, Canada.
¹⁹ Children's Hospital Oakland Research Institute, 5700 Martin Luther King Junior Way, Oakland, CA 94609-1673, USA.
²⁰ Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94304, USA.
²¹ Stanford University Center for Sleep Sciences, Palo Alto, CA 94304, USA. Electronic address: mignot@stanford.edu.

PMID: 25574827
PMCID: PMC4289679
DOI: 10.1016/j.ajhg.2014.12.010

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

Hanna M Ollila et al. Am J Hum Genet. 2015.

. 2015 Jan 8;96(1):136-46.

doi: 10.1016/j.ajhg.2014.12.010.

Authors

Affiliations

¹ Stanford University Center for Sleep Sciences, Palo Alto, CA 94304, USA.
² Department of Pulmonary Medicine, Peking University People's Hospital, 100044 Beijing, China.
³ Department of Biostatistics, University of Washington, PO box 357232, Seattle, WA 98195, USA.
⁴ Department of Biomedical and Neuromotor Sciences, University of Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy; IRCCS Institute of Neurological Sciences, 40139 Bologna, Italy.
⁵ INSERM U1061, Reference Center for Narcolepsy, Sleep-Wake Disorders Center, Department of Neurology, Gui-de-Chauliac Hospital, Centre Hospitalier Régional Universitaire Montpellier, 34090 Montpellier, France.
⁶ Department of Psychiatry, St. Vincent's Hospital, The Catholic University of Korea, 442-723 Suwon, Korea.
⁷ Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, University of Copenhagen, Glostrup Hospital, 2600 Glostrup, Denmark.
⁸ Norwegian Resource Center for ADHD, TS, and Narcolepsy, Oslo University Hospital, 0450 Ullevål, Norway.
⁹ Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, University of Copenhagen, Glostrup Hospital, 2600 Glostrup, Denmark; Molecular Sleep Laboratory, Department of Diagnostics, Glostrup Hospital, 2600 Glostrup, Denmark.
¹⁰ Department of Pathology, Stanford University School of Medicine, Stanford, CA 94304, USA.
¹¹ Department of Neurology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
¹² Mater Private Hospital, Dublin 7, Ireland.
¹³ Helsinki Sleep Clinic, Vitalmed Research Centre, 00420 Helsinki, Finland; Department of Clinical Neurosciences, University of Helsinki, 00100 Helsinki, Finland.
¹⁴ Chang Gung Memorial Hospital and University, Taipei 10591, Taiwan.
¹⁵ Department of Sleep Medicine, Strasbourg University Hospital, Strasbourg University, 67084 Strasbourg, France.
¹⁶ Institute of Clinical Medicine, University of Helsinki, 00100 Helsinki, Finland.
¹⁷ Center for Advanced Research in Sleep Medicine, Hôpital du Sacré-Coeur and Department of Neurosciences, University of Montreal, Montreal, QC H3T 1J4, Canada.
¹⁸ Center for Advanced Research in Sleep Medicine, Hôpital du Sacré-Coeur and Department of Psychiatry, University of Montreal, Montreal QC H3T 1J4, Canada.
¹⁹ Children's Hospital Oakland Research Institute, 5700 Martin Luther King Junior Way, Oakland, CA 94609-1673, USA.
²⁰ Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94304, USA.
²¹ Stanford University Center for Sleep Sciences, Palo Alto, CA 94304, USA. Electronic address: mignot@stanford.edu.

PMID: 25574827
PMCID: PMC4289679
DOI: 10.1016/j.ajhg.2014.12.010

Erratum in

Am J Hum Genet. 2015 May 7;96(5):852. Lavault, Sophie [removed]; Arnulf, Isabelle [added]

Abstract

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.

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Figures

**Figure 1**
Association between HLA Loci and Narcolepsy (A) Association of SNPs in the HLA region (Chr6: 29–36 Mb) reveals an overwhelming signal peaking at the level of *HLA-DQB1* in white (from Immunochip, see Faraco et al.³⁹) and chinese (from Affymetrix CHB data, see Han et al.⁵) individuals. Extended LD and association signal within the *HLA-DR-DQ* region obscure all other signals. (B) After conditioning for *HLA-DRB1*, *HLA-DQA1*, and *HLA-DQB1* (significant alleles from the stepwise analysis), a residual association is seen in the *HLA-DP* region. (C) After conditioning for all significant HLA class II alleles, a remaining association is seen in the HLA class I region and is most visible proximal to *HLA-B*. A possible additional peak is seen in white individuals only in the vicinity of *PSORS1*.

See this image and copyright information in PMC

References

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

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

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