HLA dosage effect in narcolepsy with cataplexy

Immunogenetics. 2015 Jan;67(1):1-6. doi: 10.1007/s00251-014-0808-z. Epub 2014 Oct 3.


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.

MeSH terms

  • Alleles
  • Autoimmune Diseases / genetics*
  • Autoimmune Diseases / immunology
  • Genetic Predisposition to Disease
  • HLA-DQ beta-Chains / chemistry
  • HLA-DQ beta-Chains / genetics*
  • HLA-DQ beta-Chains / immunology
  • Heterozygote
  • Histocompatibility Testing
  • Homozygote
  • Humans
  • Intracellular Signaling Peptides and Proteins / immunology
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Narcolepsy / etiology
  • Narcolepsy / genetics
  • Narcolepsy / immunology*
  • Neurons / immunology*
  • Neurons / metabolism
  • Neuropeptides / immunology
  • Neuropeptides / metabolism
  • Orexins


  • HLA-DQ beta-Chains
  • HLA-DQB1 antigen
  • Intracellular Signaling Peptides and Proteins
  • Neuropeptides
  • Orexins