DQB1*06:02 allele-specific expression varies by allelic dosage, not narcolepsy status

TY - JOUR

T1 - DQB1*06:02 allele-specific expression varies by allelic dosage, not narcolepsy status

AU - Weiner Lachmi, Karin

AU - Lin, Ling

AU - Kornum, Birgitte Rahbek

AU - Rico, Tom

AU - Lo, Betty

AU - Aran, Adi

AU - Mignot, Emmanuel

N1 - Copyright © 2012 American Society for Histocompatibility and Immunogenetics. All rights reserved.

PY - 2012/4

Y1 - 2012/4

N2 - 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.

AB - 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.

KW - Adult

KW - Alleles

KW - B-Lymphocytes/immunology

KW - Case-Control Studies

KW - Female

KW - Gene Dosage

KW - Gene Expression

KW - Gene Expression Profiling

KW - Genotype

KW - HLA-DQ beta-Chains/genetics

KW - Humans

KW - Male

KW - Narcolepsy/genetics

U2 - 10.1016/j.humimm.2012.01.004

DO - 10.1016/j.humimm.2012.01.004

M3 - Journal article

C2 - 22326585

SN - 0198-8859

VL - 73

SP - 405

EP - 410

JO - Human Immunology

JF - Human Immunology

IS - 4

ER -