HLA-DPB1 and HLA Class I Confer Risk of and Protection from Narcolepsy

摘要

Type 1 narcolepsy, a disorder caused by a lack of hypocretin (orexin), is so strongly associated with human leukocyte antigen (HLA) class II HLA-DQA1*01:02-DQB1*06:02 (DQ0602) that very few non-DQ0602 cases have been reported. A known triggering factor for narcolepsy is pandemic 2009 influenza H1N1, suggesting autoimmunity triggered by upper-airway infections. Additional effects of other HLA-DQ alleles have been reported consistently across multiple ethnic groups. Using over 3,000 case and 10,000 control individuals of European and Chinese background, we examined the effects of other HLA loci. After careful matching of HLA-DR and HLA-DQ in case and control individuals, we found strong protective effects of HLA-DPA1*01:03-DPB1*04:02 (DP0402; odds ratio [OR] = 0.51 [0.38-0.67], p = 1.01 x 10(-6)) and HLA-DPA1*01:03-DPB1*04:01 (DP0401; OR = 0.61 [0.47-0.80], p = 2.07 x 10(-4)) and predisposing effects of HLA-DPB1*05:01 in Asians (OR = 1.76 [1.34-2.31], p = 4.71 x 10(-05)). Similar effects were found by conditional analysis controlling for HLA-DR and HLA-DQ with DP0402 (OR = 0.45 [0.38-0.55] p = 8.99 x 10(-17)) and DP0501 (OR = 1.38 [1.18-1.61], p = 7.11 x 10(-5)). HLA-class-II-independent associations with HLA-A*11:01 (OR = 1.32 [1.13-1.54], p = 4.92 x 10(-4)), HLA-B*35:03 (OR similar to 1.96 [1.41-2.70], p = 5.14 x 10(-5)), and HLA-B*51:01 (OR = 1.49 [1.25-1.78], p = 1.09 x 10(-5)) were also seen across ethnic groups in the HLA class I region. These effects might reflect modulation of autoimmunity or indirect effects of HLA class I and HLA-DP alleles on response to viral infections such as that of influenza.