Advertisement

Immunogenetics

, Volume 67, Issue 1, pp 1–6 | Cite as

HLA dosage effect in narcolepsy with cataplexy

  • Astrid van der HeideEmail author
  • Willem Verduijn
  • Geert W. Haasnoot
  • Jos J. M. Drabbels
  • Gert J. Lammers
  • Frans H. J. Claas
Original Paper

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.

Keywords

Narcolepsy Autoimmune HLA Susceptibility 

Notes

Ethical standards

This study has been approved by the local ethics committee and has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

All persons gave their informed consent prior to their inclusion in the study.

Conflict of interest

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Dr. Lammers has served as a paid member of the UCB advisory board and received lecture fees and conference travel support from UCB pharma. Dr. Lammers also did consultancy for UCB pharma and provided expert testimony for UCB pharma, Jazz pharmaceuticals, and Bioprojet. The other authors report no financial conflict of interest.

References

  1. American Academy of Sleep Medicine (2014) International classification of sleep disorders—third edition (ICSD-3). Darien, IllinoisGoogle Scholar
  2. Dauvilliers Y, Arnulf I, Mignot E (2007) Narcolepsy with cataplexy. Lancet 369:499–511PubMedCrossRefGoogle Scholar
  3. Eerligh P, van Lummel M, Zaldumbide A et al (2011) Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes. Genes Immun 12:415–427PubMedCrossRefGoogle Scholar
  4. Ellis MC, Hetisimer AH, Ruddy DA et al (1997) HLA class II haplotype and sequence analysis support a role for DQ in narcolepsy. Immunogenetics 46:410–417PubMedCrossRefGoogle Scholar
  5. Good IJ (1982) Standardized tail-area probabilities. J Stat Comp Simul 16:65–66CrossRefGoogle Scholar
  6. Haldane JB (1956) The estimation and significance of the logarithm of a ratio of frequencies. Ann Hum Genet 20:309–311PubMedCrossRefGoogle Scholar
  7. Han F, Lin L, Li J et al (2012) HLA-DQ association and allele competition in Chinese narcolepsy. Tissue Antigens 80:328–335PubMedCrossRefGoogle Scholar
  8. Hong S-C, Lin L, Lo B et al (2007) DQB1*0301 and DQB1*0601 modulate narcolepsy susceptibility in Koreans. Hum Immunol 68:59–68PubMedCrossRefGoogle Scholar
  9. Hor H, Kutalik Z, Dauvilliers Y et al (2010) Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy. Nat Genet 1–5Google Scholar
  10. Khalil I, Deschamps I, Lepage V et al (1992) Dose effect of cis- and trans-encoded HLA-DQ alpha beta heterodimers in IDDM susceptibility. Diabetes 41:378–384PubMedCrossRefGoogle Scholar
  11. Koeleman BPC, Lie BA, Undlien DE et al (2004) Genotype effects and epistasis in type 1 diabetes and HLA-DQ trans dimer associations with disease. Genes Immun 5:381–388PubMedCrossRefGoogle Scholar
  12. Kwok WW, Kovats S, Thurtle P, Nepom GT (1993) HLA-DQ allelic polymorphisms constrain patterns of class II heterodimer formation. J Immunol 150:2263–2272PubMedGoogle Scholar
  13. Luca G, Haba-Rubio J, Dauvilliers Y et al (2013) Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study. J Sleep Res 22:482–495PubMedCrossRefGoogle Scholar
  14. Lundin KE, Sollid LM, Qvigstad E et al (1990) T lymphocyte recognition of a celiac disease-associated cis- or trans-encoded HLA-DQ alpha/beta-heterodimer. J Immunol 145:136–139PubMedGoogle Scholar
  15. Matsuki K, Grumet FC, Lin X et al (1992) DQ (rather than DR) gene marks susceptibility to narcolepsy. Lancet 339:1052–1052PubMedCrossRefGoogle Scholar
  16. Mignot E, Lin X, Arrigoni J et al (1994) DQB1*0602 and DQA1*0102 (DQ1) are better markers than DR2 for narcolepsy in Caucasian and black Americans. Sleep 17:S60–S67PubMedGoogle Scholar
  17. Mignot E, Hayduk R, Black J et al (1997a) HLA DQB1*0602 is associated with cataplexy in 509 narcoleptic patients. Sleep 20:1012–1020PubMedGoogle Scholar
  18. Mignot E, Kimura A, Lattermann A et al (1997b) Extensive HLA class II studies in 58 non-DRB1*15 (DR2) narcoleptic patients with cataplexy. Tissue Antigens 49:329–341PubMedCrossRefGoogle Scholar
  19. Mignot E, Lin L, Rogers W et al (2001) Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am J Hum Genet 68:686–699PubMedCentralPubMedCrossRefGoogle Scholar
  20. Nishino S, Ripley B, Overeem S et al (2000) Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355:39–40PubMedCrossRefGoogle Scholar
  21. Pelin Z, Guilleminault C, Risch N et al (1998) HLA-DQB1*0602 homozygosity increases relative risk for narcolepsy but not disease severity in two ethnic groups. US Modafinil in Narcolepsy Multicenter Study Group. Tissue Antigens 51:96–100PubMedCrossRefGoogle Scholar
  22. Peyron C, Faraco J, Rogers W et al (2000) A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 6:991–997PubMedCrossRefGoogle Scholar
  23. Šidàk Z (1967) Rectangular confidence region for the means of multivariate normal distributions. J Am Stat Assoc 62:626–633Google Scholar
  24. Tafti M, Hor H, Dauvilliers Y et al (2014) DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe. Sleep 37:19–25PubMedCentralPubMedGoogle Scholar
  25. Thannickal TC, Moore RY, Nienhuis R et al (2000) Reduced number of hypocretin neurons in human narcolepsy. Neuron 27:469–474PubMedCrossRefGoogle Scholar
  26. Thorsby E (1997) Invited anniversary review: HLA associated diseases. Hum Immunol 53:1–11PubMedCrossRefGoogle Scholar
  27. Vader W, Stepniak D, Kooy Y et al (2003) The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T cell responses. Proc Natl Acad Sci U S A 100:12390–12395PubMedCentralPubMedCrossRefGoogle Scholar
  28. van Rooijen DE, Roelen DL, Verduijn W et al (2012) Genetic HLA associations in complex regional pain syndrome with and without dystonia. J Pain 13:784–789PubMedCrossRefGoogle Scholar
  29. Verduyn W, Doxiadis II, Anholts J et al (1993) Biotinylated DRB sequence-specific oligonucleotides. Comparison to serologic HLA-DR typing of organ donors in eurotransplant. Hum Immunol 37:59–67PubMedCrossRefGoogle Scholar
  30. Woolf B (1955) On estimating the relation between blood group and disease. Ann Hum Genet 19:251–253PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Astrid van der Heide
    • 1
    Email author
  • Willem Verduijn
    • 2
  • Geert W. Haasnoot
    • 2
  • Jos J. M. Drabbels
    • 2
  • Gert J. Lammers
    • 1
    • 3
  • Frans H. J. Claas
    • 2
  1. 1.Department of Neurology and Clinical NeurophysiologyLeiden University Medical CenterLeidenThe Netherlands
  2. 2.Department of Immunohaematology and Blood TransfusionLeiden University Medical CenterLeidenThe Netherlands
  3. 3.SleepWake Center SEINHeemstedeThe Netherlands

Personalised recommendations