Genome wide analysis of narcolepsy in China implicates novel immune loci and reveals changes in association prior to versus after the 2009 H1N1 influenza pandemic

• Published in: PLoS genetics 2013-10, Vol.9 (10), p.e1003880
• Main Authors: Han, Fang, Faraco, Juliette, Dong, Xiao Song, Ollila, Hanna M, Lin, Ling, Li, Jing, An, Pei, Wang, Shan, Jiang, Ke Wei, Gao, Zhan Cheng, Zhao, Long, Yan, Han, Liu, Ya Nan, Li, Qing Hua, Zhang, Xiao Zhe, Hu, Yan, Wang, Jing Yu, Lu, Yun Hui, Lu, Chang Jun, Zhou, Wei, Hallmayer, Joachim, Huang, Yu Shu, Strohl, Kingman P, Pollmächer, Thomas, Mignot, Emmanuel
• Format: Article
• Language: English
• Subjects: Age of Onset; Autoimmune diseases; Avian influenza; China; DNA-Binding Proteins - genetics; Genetic aspects; Genome-wide association studies; Genome-Wide Association Study; HLA-DQ Antigens - genetics; HLA-DQ beta-Chains - genetics; Host-parasite relationships; Humans; Immunogenetics; Immunology; Influenza A Virus, H1N1 Subtype - genetics; Influenza A Virus, H1N1 Subtype - pathogenicity; Influenza, Human - complications; Influenza, Human - genetics; Influenza, Human - pathology; Interleukin-10 Receptor beta Subunit - genetics; Intracellular Signaling Peptides and Proteins - genetics; Narcolepsy - complications; Narcolepsy - genetics; Narcolepsy - pathology; Neurons - pathology; Neuropeptides - genetics; Orexins; Physiological aspects; Receptor, Interferon alpha-beta - genetics; Receptors, Antigen, T-Cell, alpha-beta - genetics; Studies; T cell receptors; Transcription Factors - genetics; Viral genetics
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1003880

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.