Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups

Emmanuel Mignot, Ling Lin, William Rogers, Yutaka Honda, Xiaohong Qiu, Xiaoyan Lin, Michele Okun, Hirohiko Hohjoh, Tetsuro Miki, Susan H. Hsu, Mary S. Leffell, F. Carl Grumet, Marcelo Fernandez-Vina, Hirohiko Hohjoh, Neil Risch

Research output: Contribution to journalArticlepeer-review

Abstract

Human narcolepsy-cataplexy, a sleep disorder associated with a centrally mediated hypocretin (orexin) deficiency, is tightly associated with HLA-DQB1 * 0602. Few studies have investigated the influence that additional HLA class II alleles have on susceptibility to this disease. In this work, 1,087 control subjects and 420 narcoleptic subjects with cataplexy, from three ethnic groups, were HLA typed, and the effects of HLA-DRB1, -DQA1, and -DQB1 were analyzed. As reported elsewhere, almost all narcoleptic subjects were positive for both HLA-DQA1 * 0102 and -DQB1 * 0602. A strong predisposing effect was observed in DQB1 * 0602 homozygotes, across all ethnic groups. Relative risks for narcolepsy were next calculated for heterozygous DQB1 * 0602/other HLA class II allelic combinations. Nine HLA class II alleles carried in trans with DQB1 * 0602 were found to influence disease predisposition. Significantly higher relative risks were observed for heterozygote combinations including DQB1 * 0301, DQA1 * 06, DRB1 * 04, DRB1 * 08, DRB1 * 11, and DRB1 * 12. Three alleles - DQB1 * 0601, DQB1 * 0501, and DQA1 * 01 (non-DQA1 * 0102) - were found to be protective. The genetic contribution of HLA-DQ to narcolepsy susceptibility was also estimated by use of λ statistics. Results indicate that complex HLA-DR and -DQ interactions contribute to the genetic predisposition to human narcolepsy but that additional susceptibility loci are also most likely involved. Together with the recent hypocretin discoveries, these findings are consistent with an immunologically mediated destruction of hypocretin-containing cells in human narcolepsy-cataplexy.

Original languageEnglish (US)
Pages (from-to)686-699
Number of pages14
JournalAmerican journal of human genetics
Volume68
Issue number3
DOIs
StatePublished - 2001

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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