Open AccessHLA high-resolution typing by next-generation sequencing in Pandemrix-induced narcolepsy
Author(s) -
A. R. Lind,
Omar Akel,
Madeleine Wallenius,
Anita Ramelius,
Marlena Maziarz,
Lue Ping Zhao,
Daniel E. Geraghty,
Lars Palm,
Åke Lernmark,
Helena Elding Larsson
Publication year - 2019
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0222882
Subject(s) - haplotype , human leukocyte antigen , allele , typing , biology , genotype , genetics , population , narcolepsy , immunology , medicine , antigen , gene , environmental health , neurology , neuroscience
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.