Abstract
The incidence of narcolepsy type 1 (NT1) increased in Sweden following the 2009–2010 mass-vaccination with the influenza Pandemrix-vaccine. NT1 has been associated with Human leukocyte antigen (HLA) DQB1*06:02 but full high-resolution HLA-typing of all loci in vaccine-induced NT1 remains to be done. Therefore, here we performed HLA typing by sequencing HLA-DRB3, DRB4, DRB5, DRB1, DQA1, DQB1, DPA1 and DPB1 in 31 vaccine-associated NT1 patients and 66 of their first-degree relatives (FDR), and compared these data to 636 Swedish general population controls (GP). Previously reported disease-related alleles in the HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02:01-DQB1*06:02:01 extended haplotype were increased in NT1 patients (34/62 haplotypes, 54.8%) compared to GP (194/1272 haplotypes, 15.3%, p = 6.17E-16). Indeed, this extended haplotype was found in 30/31 patients (96.8%) and 178/636 GP (28.0%). In total, 15 alleles, four extended haplotypes, and six genotypes were found to be increased or decreased in frequency among NT1 patients compared to GP. Among subjects with the HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02-DQB1*06:02 haplotype, a second DRB4*01:03:01-DRB1*04:01:01-DQA1*03:02//*03:03:01-DQB1*03:01:01 haplotype (p = 2.02E-2), but not homozygosity for DRB1*15:01:01-DQB1*06:02:01 (p = 7.49E-1) conferred association to NT1. Alleles with increased frequency in DQA1*01:02:01 (p = 1.07E-2) and DQA1*03:02//*03:03:01 (p = 3.26E-2), as well as with decreased frequency in DRB3*01:01:02 (p = 8.09E-3), DRB1*03:01:01 (p = 1.40E-2), and DQB1*02:01:01 (p = 1.40E-2) were found among patients compared to their FDR. High-resolution HLA sequencing in Pandemrix-associated NT1 confirmed the strong association with the DQB1*06:02:01-containing haplotype but also revealed an increased association to the not previously reported extended HLA-DRB4*01:03:01-DRB1*04:01:01-DQA1*03:02//*03:03:01-DQB1*03:01:01 haplotype. High-resolution HLA typing should prove useful in dissecting the immunological mechanisms of vaccination-associated NT1.
Highlights
Narcolepsy type 1 (NT1) is a chronic disease characterized by excessive daytime sleepiness and disturbed nocturnal sleep [1, 2]
Relative predispositional effects (RPEs) showed that DRB5 01:01:01, DRB4 01:03:01 and DRB3 03:01:01 were associated to NT1 compared to general population controls (GP) (Table 1 and S4 Table)
High-resolution Human leukocyte antigen (HLA) sequencing was used to dissect the association between HLA and NT1 that developed in subjects vaccinated with Pandemrix
Summary
Narcolepsy type 1 (NT1) is a chronic disease characterized by excessive daytime sleepiness and disturbed nocturnal sleep [1, 2]. The cell loss, together with the near-complete association to Human leukocyte antigen (HLA) DQB1 06:02 [5], suggests an autoimmune etiology. It has been difficult to fulfill criteria for autoimmunity in narcolepsy through the identification of autoantigens or disease-specific autoantibodies [6] as well as a disease-related appearance of hypothalamic immune-cell infiltration [2]. The HLA-DQB1 06:02 allele is present in about 20% of the general European population; it is more common in northern than in southern countries [5]. HLADQB1 06:02 has been considered as a necessary but not sufficient genetic factor for NT1, since this allele is common in the population, and the incidence of the disease is low.
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