DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe

Sleep. 2014 Jan 1;37(1):19-25. doi: 10.5665/sleep.3300.

Abstract

Study objective: Prior research has identified five common genetic variants associated with narcolepsy with cataplexy in Caucasian patients. To replicate and/or extend these findings, we have tested HLA-DQB1, the previously identified 5 variants, and 10 other potential variants in a large European sample of narcolepsy with cataplexy subjects.

Design: Retrospective case-control study.

Setting: A recent study showed that over 76% of significant genome-wide association variants lie within DNase I hypersensitive sites (DHSs). From our previous GWAS, we identified 30 single nucleotide polymorphisms (SNPs) with P < 10(-4) mapping to DHSs. Ten SNPs tagging these sites, HLADQB1, and all previously reported SNPs significantly associated with narcolepsy were tested for replication.

Patients and participants: For GWAS, 1,261 narcolepsy patients and 1,422 HLA-DQB1*06:02-matched controls were included. For HLA study, 1,218 patients and 3,541 controls were included.

Measurements and results: None of the top variants within DHSs were replicated. Out of the five previously reported SNPs, only rs2858884 within the HLA region (P < 2x10(-9)) and rs1154155 within the TRA locus (P < 2x10(-8)) replicated. DQB1 typing confirmed that DQB1*06:02 confers an extraordinary risk (odds ratio 251). Four protective alleles (DQB1*06:03, odds ratio 0.17, DQB1*05:01, odds ratio 0.56, DQB1*06:09 odds ratio 0.21, DQB1*02 odds ratio 0.76) were also identified.

Conclusion: An overwhelming portion of genetic risk for narcolepsy with cataplexy is found at DQB1 locus. Since DQB1*06:02 positive subjects are at 251-fold increase in risk for narcolepsy, and all recent cases of narcolepsy after H1N1 vaccination are positive for this allele, DQB1 genotyping may be relevant to public health policy.

Keywords: Autoimmunity; GWAS; H1N1 vaccination; genetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Cataplexy / genetics*
  • Deoxyribonuclease I / metabolism
  • Europe / epidemiology
  • Europe / ethnology
  • Exome / genetics
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study
  • HLA-DQ beta-Chains / genetics*
  • Humans
  • Influenza A Virus, H1N1 Subtype / immunology
  • Influenza Vaccines / administration & dosage
  • Narcolepsy / genetics*
  • Odds Ratio
  • Polymorphism, Single Nucleotide / genetics
  • Retrospective Studies
  • Vaccination
  • Whites / genetics

Substances

  • HLA-DQ beta-Chains
  • HLA-DQB1 antigen
  • Influenza Vaccines
  • Deoxyribonuclease I