DQB1*06:02 allele-specific expression varies by allelic dosage, not narcolepsy status.
The association of narcolepsy-cataplexy, a sleep disorder caused by the loss of hypocretin/orexin neurons in the hypothalamus, with DQA1*01:02-DQB1*06:02 is one of the tightest known single-allele human leukocyte antigen (HLA) associations. In this study, we explored genome-wide expression in peripheral white blood cells of 50 narcolepsy versus 47 controls (half of whom were DQB1*06:02 positive) and observed the largest differences between the groups in the signal from HLA probes. Further studies of HLA-DQ expression (mRNA and protein in a subset) in 125 controls and 147 narcolepsy cases did not reveal any difference, a result we explain by the lack of proper control of allelic diversity in Affymetrix HLA probes. Rather, a clear effect of DQB1*06:02 allelic dosage on DQB1*06:02 mRNA levels (1.65-fold) and protein (1.59-fold) could be demonstrated independent of disease status. These results indicate that allelic dosage is transmitted into changes in heterodimer availability, a phenomenon that may explain the increased risk for narcolepsy in DQB1*06:02 homozygotes versus heterozygotes.
Center for Sleep Sciences, Stanford University, Palo Alto, CA 94304-5592, USA.
Karin
K
Weiner Lachmi
Ling
L
Lin
Birgitte Rahbek
BR
Kornum
Tom
T
Rico
Betty
B
Lo
Adi
A
Aran
Emmanuel
E
Mignot
D000328:Adult; D000483:Alleles; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression; D020869:Gene Expression Profiling; D005838:Genotype; D059866:HLA-DQ beta-Chains / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008297:Male; D009290:Narcolepsy / Q000235:genetics* / Q000276:immunology / Q000378:metabolism
D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen