TY - JOUR
T1 - Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups
AU - Mignot, Emmanuel
AU - Lin, Ling
AU - Rogers, William
AU - Honda, Yutaka
AU - Qiu, Xiaohong
AU - Lin, Xiaoyan
AU - Okun, Michele
AU - Hohjoh, Hirohiko
AU - Miki, Tetsuro
AU - Hsu, Susan H.
AU - Leffell, Mary S.
AU - Grumet, F. Carl
AU - Fernandez-Vina, Marcelo
AU - Hohjoh, Hirohiko
AU - Risch, Neil
N1 - Funding Information:
This work was supported by NIH grant NS33797 (to E.M.). African American control samples were collected and studied as part of the American Society of Human Immunogenetics minority workshop, partially funded by National Institutes of Health contract NO I-AI-82514. We thank Anna Voros for technical assistance and Dr. K. Tokunaga and A. Kimura for suggestions and assistance.
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
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U2 - 10.1086/318799
DO - 10.1086/318799
M3 - Article
C2 - 11179016
AN - SCOPUS:0035091595
SN - 0002-9297
VL - 68
SP - 686
EP - 699
JO - American journal of human genetics
JF - American journal of human genetics
IS - 3
ER -