Abstract
Previous studies in narcolepsy, an autoimmune disorder affecting hypocretin (orexin) neurons and recently associated with H1N1 influenza, have demonstrated significant associations with five loci. Using a well-characterized Chinese cohort, we refined known associations in TRA@ and P2RY11-DNMT1 and identified new associations in the TCR beta (TRB@; rs9648789 max P = 3.7×10−9 OR 0.77), ZNF365 (rs10995245 max P = 1.2×10−11 OR 1.23), and IL10RB-IFNAR1 loci (rs2252931 max P = 2.2×10−9 OR 0.75). Variants in the Human Leukocyte Antigen (HLA)- DQ region were associated with age of onset (rs7744020 P = 7.9×10−9 beta −1.9 years) and varied significantly among cases with onset after the 2009 H1N1 influenza pandemic compared to previous years (rs9271117 P = 7.8×10−10 OR 0.57). These reflected an association of DQB1*03:01 with earlier onset and decreased DQB1*06:02 homozygosity following 2009. Our results illustrate how genetic association can change in the presence of new environmental challenges and suggest that the monitoring of genetic architecture over time may help reveal the appearance of novel triggers for autoimmune diseases.
Highlights
A remarkable feature of narcolepsy is its strong Human Leukocyte Antigen (HLA) association, with similar effects across different ethnicities and countries [1,2,3,4]
We found that one HLA variant, (DQB1*03:01), is associated with dramatically earlier disease onset
We identified differences in HLA haplotype frequencies among cases with onset following the 2009 H1N1 influenza pandemic as compared to before the outbreak, with fewer HLA DQB1*06:02 homozygotes
Summary
A remarkable feature of narcolepsy is its strong HLA association, with similar effects across different ethnicities and countries [1,2,3,4]. Susceptibility is further increased in DQB1*06:02 homozygotes [5], and DQB1*06:02/DQB1*03:01 heterozygotes [1,2,3]. It is lower in subjects with HLA DQA1*01:02-DQB1*06:02 and other, nonDQA1*01:02 and DQB1*06:02 DQ1 alleles [1,2,3,4], an effect likely due to trans-dimerization and reduction of DQ0602 availability [3]. Associations between group A Streptococcus Pyogenes and narcolepsy have been found in several studies [10,11,12]
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