title: HLA dosage effect in narcolepsy with cataplexy.
abstract: Narcolepsy with cataplexy is a sleep disorder caused by the loss of hypocretin-producing neurons in the hypothalamus. It is tightly associated with a specific human leukocyte antigen (HLA)-allele: HLA-DQB1*06:02. Based on this, an autoimmune process has been hypothesized. A functional HLA-DQ molecule consists of a DQα and a DQβ chain. HLA-DQB1*06:02 (DQβ) has a strong preference for binding to HLA-DQA1*01:02 (DQα), and together they form the functional DQ0602 dimer. A dosage effect would be expected if the HLA-DQ0602 dimer itself is directly involved in the aetiology. An increased expression of the HLA-DQ0602 dimer is expected in individuals homozygous for HLA-DQB1*06:02-DQA1*01:02, but is also hypothesized in individuals heterozygous for HLA-DQB1*06:02 and homozygous for HLA-DQA1*01:02. To study the impact of the expression of the HLA-DQ0602 dimer on narcolepsy susceptibility, 248 Dutch narcolepsy patients and 1272 Dutch control subjects, all of them positive for DQB1*06:02 (heterozygous and homozygous), were HLA-genotyped with attention not only to DQB1 but also to DQA1*01:02. DQB1*06:02-DQA1*01:02 homozygosity was significantly more often seen in patients compared to controls (O.R. 2.29) confirming previous observations. More importantly, a significantly higher prevalence of homozygosity for DQA1*01:02 was found in HLA-DQB1*06:02 heterozygous patients compared to controls (O.R. 2.37, p < 0.001). The latter finding clearly supports a direct role of the HLA-DQ molecule in the development of disease.
authors.affiliation: Department of Neurology and Clinical Neurophysiology, Leiden University Medical Center, PO Box 9600, 2300, Leiden, The Netherlands, a.van_der_heide@lumc.nl.
authors.forename: Astrid
authors.initials: A
authors.lastname: van der Heide
authors.forename: Willem
authors.initials: W
authors.lastname: Verduijn
authors.forename: Geert W
authors.initials: GW
authors.lastname: Haasnoot
authors.forename: Jos J M
authors.initials: JJ
authors.lastname: Drabbels
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Lammers
authors.forename: Frans H J
authors.initials: FH
authors.lastname: Claas
mesh_terms: D000483:Alleles; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D020022:Genetic Predisposition to Disease; D059866:HLA-DQ beta-Chains / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D006579:Heterozygote; D006650:Histocompatibility Testing; D006720:Homozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism; D009290:Narcolepsy / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D009474:Neurons / Q000276:immunology* / Q000378:metabolism; D009479:Neuropeptides / Q000276:immunology / Q000378:metabolism; D000068797:Orexins
chemical_list: D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins