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

Abstract

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 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 found the largest differences between the groups to be 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 the disease status. These results indicate that allelic dosage is transmitted into changes in heterodimer availability, a phenomenon that may explain increased risk for narcolepsy in DQB1*06:02 homozygotes versus heterozygotes.

HLA‐DQ association and allele competition in Chinese narcolepsy

“…On the basis of these findings, we propose a model involving competition between DQ1 compatible alleles with DQα1*01:02 / DQβ1*06:02 predisposing to narcolepsy, explaining the protective effects of the other DQ1 subtypes. This result is also compatible with a recent finding showing that the expression of the DQB1*06:02 mRNA and DQβ1*06:02 protein is 1.54‐fold higher in DQA1*01:02‐DQB1*06:02 homozygotes versus heterozygotes , a finding that could explain why homozygotes are at increased risk for narcolepsy.…”

“…As in other HLA‐associated diseases, the genetic association is not simply a dominant effect of DQA1*01:02‐DQB1*06:02 . First and foremost, association is highest with subjects homozygous for DQB1*06:02 (about twofold to threefold higher risk than in heterozygotes) a result likely explained by increased availability of the DQβ*06:02 protein in immune cells of homozygous versus heterozygous patients . Furthermore, strong protective effects are noted with DQA1*01:03‐DQB1*06:01 , DQA1*01:01‐DQB1*05:01 and DQA1*01:03‐DQB1*06:03 .…”

Narcolepsie : une maladie auto-immune affectant un peptide de l’éveil liée à un mimétisme moléculaire avec des épitopes du virus de la grippe

“…Des études de séquençage de la région HLA-DQ, ainsi que des études de marqueurs microsatellites dans la région, ont montré qu'aucun autre gène n'était présent dans l'intervalle de susceptibilité, et que l'association concernait en réalité le HLA-DQ (Ellis et al, 1997 ;Mignot et al, 1997 ;Kadotani et al, 1998). La poursuite des travaux sur plusieurs groupes ethniques a permis de montrer que non seulement DQ0602 (la combinaison de DQA1*01:02 et DQB1*06:02) est une condition préalable au développement de la narcolepsie, mais aussi que les individus homozygotes pour DQ0602 ont un risque 1,5 à 2 fois plus élevé de développer la narcolepsie (Pelin et al, 1998 ;Mignot et al, 2001 ;Hong et al, 2007 ;Han et al, 2012a), suggérant que la quantité d'hétérodimère DQ0602 augmente également le risque (Weiner Lachmi et al, 2012). Curieusement, nous avons également constaté que les sujets DQ0602/DQB1*03:01 présentent un risque accru par rapport aux autres combinaisons HLA Hong et al, 2007 ;Han et al, 2012a).…”

The association of HLA-DQB1*0602 but not HLA-DRB1*15 with obstructive sleep apnea

“…Family clustering was observed in narcolepsy [6], which is a sleep disorder that is characterized by excessive daytime somnolence, sleep paralysis, hypnagogic hallucinations and cataplexy [7]. Narcolepsy has been reported to be associated with human leukocyte antigens (HLA) [5,[8][9][10][11].…”