RGD Reference Report - Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. - Rat Genome Database

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

Authors: Mignot, E  Lin, L  Rogers, W  Honda, Y  Qiu, X  Lin, X  Okun, M  Hohjoh, H  Miki, T  Hsu, S  Leffell, M  Grumet, F  Fernandez-Vina, M  Honda, M  Risch, N 
Citation: Mignot E, etal., Am J Hum Genet. 2001 Mar;68(3):686-99. Epub 2001 Feb 13.
RGD ID: 5147861
Pubmed: PMID:11179016   (View Abstract at PubMed)
PMCID: PMC1274481   (View Article at PubMed Central)

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 lambda 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
narcolepsy susceptibilityISOHLA-DQA1 (Homo sapiens)5147861; 5147861DNA:polymorphisms:cds:multipleRGD 
narcolepsy susceptibilityISOHLA-DQB1 (Homo sapiens)5147861; 5147861DNA:polymorphisms:cds:multipleRGD 
narcolepsy susceptibilityISOHLA-DRB1 (Homo sapiens)5147861; 5147861DNA:polymorphisms:cds:multiple (human)RGD 
narcolepsy susceptibilityIAGP 5147861; 5147861DNA:polymorphisms:cds:multipleRGD 
narcolepsy susceptibilityIAGP 5147861DNA:polymorphisms:cds:multiple (human)RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Cataplexy susceptibilityIAGP 5147861; 5147861; 5147861DNA:polymorphisms:cds:multipleRGD 
Narcolepsy susceptibilityIAGP 5147861; 5147861DNA:polymorphisms:cds:multipleRGD 
Objects Annotated

Genes (Rattus norvegicus)
RT1-Ba  (RT1 class II, locus Ba)
RT1-Bb  (RT1 class II, locus Bb)
RT1-Db1  (RT1 class II, locus Db1)

Genes (Mus musculus)
H2-Aa  (histocompatibility 2, class II antigen A, alpha)
H2-Ab1  (histocompatibility 2, class II antigen A, beta 1)
H2-Eb1  (histocompatibility 2, class II antigen E beta)

Genes (Homo sapiens)
HLA-DQA1  (major histocompatibility complex, class II, DQ alpha 1)
HLA-DQB1  (major histocompatibility complex, class II, DQ beta 1)
HLA-DRB1  (major histocompatibility complex, class II, DR beta 1)


Additional Information