BACKGROUND AND OBJECTIVES: Isolated/idiopathic REM sleep behavior disorder (iRBD) and Lewy body dementia (LBD) are synucleinopathies that have partial genetic overlap with Parkinson's disease (PD). Previous studies have shown that neuroinflammation plays a substantial role in these disorders. In PD, specific residues of the human leukocyte antigen ( HLA ) were suggested to be associated with a protective effect. This study examined whether the HLA locus plays a similar role in iRBD, LBD and PD. METHODS: We performed HLA imputation on iRBD genotyping data (1,072 patients and 9,505 controls) and LBD whole-genome sequencing (2,604 patients and 4,032 controls) using the multi-ethnic HLA reference panel v2 from the Michigan Imputation Server. Using logistic regression, we tested the association of HLA alleles, amino acids and haplotypes with disease susceptibility. We included age, sex and the top 10 principal components as covariates. We also performed an omnibus test to examine which HLA residue positions explain the most variance. RESULTS: In iRBD, HLA-DRB1 *11:01 was the only allele passing FDR correction (OR=1.57, 95% CI=1.27-1.93, p =2.70e-05). We also discovered associations between iRBD and HLA-DRB1 70D (OR=1.26, 95%CI=1.12-1.41, p =8.76e-05), 70Q (OR=0.81, 95% CI=0.72-0.91, p =3.65e-04) and 71R (OR=1.21, 95% CI=1.08-1.35, p =1.35e-03). In HLA-DRB1 , position 71 ( p omnibus =0.00102) and 70 ( p omnibus =0.00125) were associated with iRBD. We found no association in LBD. DISCUSSION: This study identified an association between HLA-DRB1 11:01 and iRBD, distinct from the previously reported association in PD. Therefore, the HLA locus may play different roles across synucleinopathies. Additional studies are required better to understand HLA's role in iRBD and LBD.

Center for Advanced Research in Sleep Medicine Centre Intégré Universitaire de Santé et de Services Sociaux du Nord de l'île de Montréal Hopital du Sacré Coeur de Montréal Montréal QC Canada

Clinical Neurology Unit Department of Neurosciences University Hospital of Udine Udine Italy

Department for Sleep Medicine and Neuromuscular disease University Hospital Muenster Muenster Germany

Department of Biomedical Metabolic and Neural Sciences University of Modena and Reggio Emilia Modena Italy

Department of Human Genetics McGill University Montréal QC Canada

Department of Medical Sciences and Public Health Sleep Disorder Research Center University of Cagliari Cagliari Italy

Department of Medicine University of Udine Udine Italy

Department of Neurological Sciences Università Vita Salute San Raffaele Milan Italy

Department of Neurology and Centre of Clinical Neuroscience Charles University 1st Faculty of Medicine and General University Hospital Prague Czech Republic

Department of Neurology and Neurosurgery McGill University Montréal QC Canada

Department of Neurology Johns Hopkins University Medical Center Baltimore MD USA

Department of Neurology Mayo Clinic Rochester MN USA

Department of Neurology Philipps University Marburg Germany

Department of Neurology St Dimpna Regional Hospital Geel Belgium

Department of Neurology University Hospital Antwerp Edegem Antwerp Belgium

Department of Neurosciences Universite de Montréal Montréal QC Canada

Department of Neurosurgery University Medical Centre Gættingen Gottingen Germany

Department of Psychiatry Université de Montréal Montréal QC Canada

Department of Psychology Université du Québec à Montreal Montréal QC Canada

Division of Neurology Nuffield Department of Clinical Neurosciences University of Oxford Oxford United Kingdom

EuroMov Digital Health in Motion University of Montpellier IMT Mines Ales Montpellier France

IRCCS Institute of Neurological Sciences of Bologna Bologna Italy

Laboratory for Sleep Disorders St Dimpna Regional Hospital Geel Belgium

National Reference Center for Narcolepsy Sleep Unit Department of Neurology Gui de Chauliac Hospital CHU Montpellier University of Montpellier Inserm U1061 Montpellier France

Neurodegenerative Diseases Research Unit National Institute of Neurological Disorders and Stroke Bethesda MD USA

Neurology Unit Movement Disorders Division Department of Neurosciences Biomedicine and Movement Sciences University of Verona Verona Italy

Neuromuscular Diseases Research Section National Institute on Aging Bethesda MD USA

Oxford Parkinson's Disease Centre University of Oxford Oxford United Kingdom

Paracelsus Elena Klinik Kassel Germany

Sleep and Neurology Unit Beau Soleil Clinic Montpellier France

Sleep disorder Unit Carémeau Hospital University Hospital of Nîmes France

Sleep Disorders Clinic Department of Neurology Medical University of Innsbruck Innsbruck Austria

Sleep Disorders Unit Pitié Salpêtrière Hospital Paris Brain Institute and Sorbonne University Paris France

The Neuro McGill University Montréal QC Canada

Ann Clin Transl Neurol. 2023 Sep;10(9):1682-1687. doi: 10.1002/acn3.51841. PubMed

Zobrazit více v PubMed

Dauvilliers Y, Schenck CH, Postuma RB, et al. REM sleep behaviour disorder. Nature reviews Disease primers. 2018;4(1):1–16. PubMed

Postuma RB, Iranzo A, Hu M, et al. Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study. Brain. Mar 1 2019;142(3):744–759. doi:10.1093/brain/awz030 PubMed DOI PMC

Krohn L, Heilbron K, Blauwendraat C, et al. Genome-wide association study of REM sleep behavior disorder identifies polygenic risk and brain expression effects. Nature Communications. 2022;13(1):1–16. PubMed PMC

Stokholm MG, Iranzo A, Østergaard K, et al. Assessment of neuroinflammation in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case-control study. The Lancet Neurology. 2017/10/01/ 2017;16(10):789–796. doi:10.1016/S1474-4422(17)30173-4 PubMed DOI

Hirsch EC, Vyas S, Hunot S. Neuroinflammation in Parkinson’s disease. Parkinsonism & related disorders. 2012;18:S210–S212. PubMed

Amin J, Holmes C, Dorey RB, et al. Neuroinflammation in dementia with Lewy bodies: a human post-mortem study. Translational psychiatry. 2020;10(1):1–11. PubMed PMC

Yu E, Ambati A, Andersen MS, et al. Fine mapping of the HLA locus in Parkinson’s disease in Europeans. npj Parkinson’s Disease. 2021;7(1):1–7. PubMed PMC

Chia R, Sabir MS, Bandres-Ciga S, et al. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture. Nat Genet. Mar 2021;53(3):294–303. doi:10.1038/s41588-021-00785-3 PubMed DOI PMC

Emre M, Aarsland D, Brown R, et al. Clinical diagnostic criteria for dementia associated with Parkinson’s disease. Mov Disord. Sep 15 2007;22(12):1689–707; quiz 1837. doi:10.1002/mds.21507 PubMed DOI

McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology. 2017;89(1):88–100. PubMed PMC

Yang J, Lee SH, Goddard ME, Visscher PM. GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet. Jan 7 2011;88(1):76–82. doi: 10.1016/j.ajhg.2010.11.011 PubMed DOI PMC

Luo Y, Kanai M, Choi W, et al. A high-resolution HLA reference panel capturing global population diversity enables multi-ancestry fine-mapping in HIV host response. Nature Genetics. 2021/10/01 2021;53(10):1504–1516. doi:10.1038/s41588-021-00935-7 PubMed DOI PMC

Haba-Rubio J, Frauscher B, Marques-Vidal P, et al. Prevalence and determinants of rapid eye movement sleep behavior disorder in the general population. Sleep. 2017;41(2)doi:10.1093/sleep/zsx197 PubMed DOI

Kane JPM, Surendranathan A, Bentley A, et al. Clinical prevalence of Lewy body dementia. Alzheimer’s Research & Therapy. 2018/02/15 2018;10(1):19. doi:10.1186/s13195-018-0350-6 PubMed DOI PMC

Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. Nov 1987;30(11):1205–13. doi:10.1002/art.1780301102 PubMed DOI

Hollenbach JA, Norman PJ, Creary LE, et al. A specific amino acid motif of HLA-DRB1 mediates risk and interacts with smoking history in Parkinson’s disease. Proc Natl Acad Sci U S A. Apr 9 2019;116(15):7419–7424. doi:10.1073/pnas.1821778116 PubMed DOI PMC

Guen YL, Luo G, Ambati A, et al. Protective association of HLA-DRB1*04 subtypes in neurodegenerative diseases implicates acetylated Tau PHF6 sequences. medRxiv. 2021:2021.12.26.21268354. doi:10.1101/2021.12.26.21268354 DOI

Schenck CH, Garcia-Rill E, Segall M, Noreen H, Mahowald MW. HLA class II genes associated with REM sleep behavior disorder. Annals of neurology. 1996;39(2):261–263. PubMed

Farmen K, Nissen SK, Stokholm MG, et al. Monocyte markers correlate with immune and neuronal brain changes in REM sleep behavior disorder. Proceedings of the National Academy of Sciences. 2021;118(10):e2020858118. PubMed PMC

Gate D, Tapp E, Leventhal O, et al. CD4+ T cells contribute to neurodegeneration in Lewy body dementia. Science. 2021;374(6569):868–874. doi:doi:10.1126/science.abf7266 PubMed DOI PMC

De Francesco E, Terzaghi M, Storelli E, et al. CD4+ T-cell Transcription Factors in Idiopathic REM Sleep Behavior Disorder and Parkinson’s Disease. Movement Disorders. 2021;36(1):225–229. doi:10.1002/mds.28137 PubMed DOI

Knudsen K, Fedorova TD, Hansen AK, et al. Objective intestinal function in patients with idiopathic REM sleep behavior disorder. Parkinsonism & Related Disorders. 2019/01/01/ 2019;58:28–34. doi:10.1016/j.parkreldis.2018.08.011 PubMed DOI

Negi S, Singh H, Mukhopadhyay A. Gut bacterial peptides with autoimmunity potential as environmental trigger for late onset complex diseases: In–silico study. PloS one. 2017;12(7):e0180518. PubMed PMC