HLA and sleep parameter associations in post-H1N1 narcolepsy type 1 patients and first-degree relatives

Abstract

Study Objectives To explore HLA (human leukocyte antigen) in post-H1N1 narcolepsy type 1 patients (NT1), first-degree relatives and healthy controls, and assess HLA associations with clinical and sleep parameters in patients and first-degree relatives. Methods Ninety post-H1N1 NT1 patients and 202 of their first-degree relatives were HLA-genotyped (next generation sequencing) and phenotyped (semistructured interviews, Stanford Sleep Questionnaire, polysomnography, and multiple sleep latency test). HLA allele distributions were compared between DQB1*06:02-heterozygous individuals (77 patients, 59 parents, 1230 controls). A subsample (74 patients, 114 relatives) was investigated for associations between HLA-loci and continuous sleep variables using logistic regression. Identified candidate HLA-loci were explored for HLA allele associations with hypnagogic hallucinations and sleep paralysis in 90 patients, and patient allele findings were checked for similar associations in 202 relatives. Results DQB1*06:02 heterozygous post-H1N1 NT1 patients (84.4% H1N1-vaccinated) showed several significant HLA associations similar to those reported previously in samples of mainly sporadic NT1, i.e. DQB1*03:01, DRB1*04:01, DRB1*04:02, DRB1*04:07, DRB1*11:04, A*25:01, B*35:03, and B*51:01, and novel associations, i.e. B*14:02, C*01:02, and C*07:01. Parents HLA alleles did not deviate significantly from controls. The HLA-C locus was associated with sleep parameters in patients and relatives. In patients C*02:02 seems to be associated with protective effects against sleep paralysis and hypnagogic hallucinations. Conclusions Our findings of similar risk/protective HLA-alleles in post-H1N1 as in previous studies of mainly sporadic narcolepsy support similar disease mechanisms. We also report novel allelic associations. Associations between HLA-C and sleep parameters were seen independent of NT1 diagnosis, supporting involvement of HLA-C in sleep subphenotypes.

HLA associations in narcolepsy type 1 persist after the 2009 H1N1 pandemic

“…These findings are in line with those of two recent reports describing these associations in small numbers of post-H1N1 NT1 patients that report positive associations of post-H1N1 with HLA-DQ7 and negative associations with HLA-DQ2 (Lind et al, 2019;Juvodden et al, 2019). Both these and other studies in NT1 patients before and after the H1N1 pandemic also describe the same associations that we found (Mignot et al, 2001;van der Heide et al, 2015;Hong et al, 2007;Tafti et al, 2014;Bomfim et al, 2017;Tafti et al, 2016;Han et al, 2013).…”

“…Following these epidemiological and laboratory reports, a discussion on the existence of a post-H1N1 NT1 variant has arisen, with specifically Scandinavian countries making the distinction between sporadic and post-H1N1 NT1. Several recent Scandinavian studies report HLA-DQ-haplotypes associated specifically with post-H1N1 NT1 (HLA-DQ2, HLA-DQ7) (Juvodden et al, 2019;Lind et al, 2019). These reports started a discussion about whether different immunological mechanisms may be involved in post-H1N1 NT1.…”

Influence of Disease Severity and Gender on HLA-C Methylation in COVID-19 Patients

“…It is also demonstrated that the other related respiratory viral infections, including influenza and MERS-CoV, lead to various responses in infected patients through epigenetic modulation (Menachery et al 2018 ). In addition, it is indicated that the HLA-C locus is linked to hypnagogic hallucinations and sleep paralysis in post-H1N1 narcolepsy type 1 individuals (NT1) (Juvodden et al 2020 ). Despite its long and close relationship with HLA-A and B, HLA-C expression on the cell surface is significantly lower than HLA-A and B (Apps et al 2015 ).…”

Narcolepsy type 1: what have we learned from genetics?

“…In both instances, all cases are DQB1*06:02 positive and share the other major HLA risk factors. In addition, the only consistently associating non-HLA association in vaccination-related NT1 is TRA [ 36 , 39 ]. This association is most likely also the only one with large enough effect size to be detectable in the relatively small studies.…”