HLA high-resolution typing by next-generation sequencing in Pandemrix-induced narcolepsy

PLoS One. 2019 Oct 2;14(10):e0222882. doi: 10.1371/journal.pone.0222882. eCollection 2019.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Genetic Predisposition to Disease
  • HLA Antigens / genetics
  • Haplotypes / genetics
  • High-Throughput Nucleotide Sequencing*
  • Histocompatibility Testing / methods*
  • Humans
  • Influenza Vaccines / adverse effects*
  • Narcolepsy / chemically induced*
  • Narcolepsy / genetics*

Substances

  • HLA Antigens
  • Influenza Vaccines
  • pandemrix

Grants and funding

Our investigation was supported by Alfred Österlunds stiftelse, Anna och Edvin Bergers Stiftelse, Magnus Bergvalls Stiftelse, Crafoord Foundation, Filip Lundbergs stiftelse, Fredrik och Ingrid Thurings Stiftelse, the Royal Physiographic Society of Lund- Hedda and John Forssmans foundation, Gunvor och Josef Anérs stiftelse, Jerringfonden, Kronprinsessan Lovisas Förening För Barnasjukvård/Stiftelsen Axel Tielmans Minnesfond, Linnéa och Josef Carlssons Stiftelse, Neuro Sweden, Rune Ljungdahls Stiftelse, Stiftelsen Samariten, Stiftelsen till minne av Personalföreningarna i Holmia Försäkring AB, The Gun and Bertil Stohne’s foundation, the Segerfalk Foundation, Svenska Läkaresällskapet, Region Skane FoU, Tage Blüchers stiftelse, Gyllenstiernska Krapperupsstiftelsen, and ALF grants. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.