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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.
Pubmed ID: 31577807
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View all literature mentionsSwedish study to get a better understanding of how genes, environment and way of life affect health that will enable access to the longitudinal data on 500,000 participants after ethical approval. Half a million people in Sweden between the ages of 0 and 45 will be recruited as volunteers for 6 to 8 years. People between 18 and 45 will be invited and they may, in turn, bring children and other people that they live with into the project. Participants will be followed for many years with regular online surveys and health checks. Their blood and urine samples will also be stored in a biobank. All the data will form a very large information base, where researchers can follow what happens with people''''s health. The LifeGene test center will measure height, hip, waist and chest measurements. A so-called spirometry test will be conducted which measures lung function, a hearing test and bioimpedance measurement (includes weight, BMI and distribution of body fat and muscle mass). They also take blood and urine samples and measure blood pressure and pulse. LifeGene foresees a lot of different research cooperation. Everything from simple withdrawal of longitudinal data, leverage of LifeGene infrastructure and cooperation between LifeGene and complementing scientific projects covering specific areas in more depth. LifeGene will enable access to unique longitudinal data on 500,000 participants available for researchers after ethical approval. LifeGene is also an infrastructure with Test Centers covering most of Sweden, logistics for sample management from arm-to-freezer and state-of-the-art large scale automatic biobanking enabling low cost, high quality, fast withdrawal of biological samples.
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