No abstract

Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. Using genome-wide association (GWA) in narcolepsy patients versus controls, with replication and fine mapping across three ethnic groups (3406 individuals of European ancestry, 2414 Asians, and 302 African Americans), we found a novel association between SNP rs2305795 in the 3′UTR of the purinergic receptor subtype 2Y11 (P2RY11) gene and narcolepsy (p(Mantel Haenszel)=6.1×10-10; odds ratio 1.28; n=5689). The disease-associated allele is correlated with a 3-fold lower expression of P2RY11 in CD8+ T lymphocytes (p=0.003) and natural killer (NK) cells (p=0.031) but not in other peripheral blood mononuclear cell (PBMC) types. The low expression variant is also associated with decreased P2RY11 mediated resistance to adenosine triphosphate (ATP) induced cell death in T lymphocytes (p=0.0007) and NK cells (p=0.001). These results identify P2RY11 as an important regulator of immune cell survival, with possible implications in narcolepsy and other autoimmune diseases.

Narcolepsy (hypocretin deficiency), a sleep disorder characterized by sleepiness, cataplexy and rapid eye movement (REM) sleep abnormalities, is tightly associated with HLA-DRB1*1501 (M17378) and HLA-DQB1*0602 (M20432). Susceptibility genes other than those in the HLA region are also likely involved. We conducted a genome-wide association study using 500K SNP microarrays in 222 Japanese individuals with narcolepsy and 389 Japanese controls, with replication of top hits in 159 Japanese individuals with narcolepsy and 190 Japanese controls, followed by the testing of 424 Koreans, 785 individuals of European descent and 184 African Americans. rs5770917, a SNP located between CPT1B and CHKB, was associated with narcolepsy in Japanese (rs5770917[C], odds ratio (OR) = 1.79, combined P = 4.4 x 10(-7)) and other ancestry groups (OR = 1.40, P = 0.02). Real-time quantitative PCR assays in white blood cells indicated decreased CPT1B and CHKB expression in subjects with the C allele, suggesting that a genetic variant regulating CPT1B or CHKB expression is associated with narcolepsy. Either of these genes is a plausible candidate, as CPT1B regulates beta-oxidation, a pathway involved in regulating theta frequency during REM sleep, and CHKB is an enzyme involved in the metabolism of choline, a precursor of the REM- and wake-regulating neurotransmitter acetylcholine.

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 × 10(-6)) and HLA-DPA1(∗)01:03-DPB1(∗)04:01 (DP0401; OR = 0.61 [0.47-0.80], p = 2.07 × 10(-4)) and predisposing effects of HLA-DPB1(∗)05:01 in Asians (OR = 1.76 [1.34-2.31], p = 4.71 × 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 × 10(-17)) and DP0501 (OR = 1.38 [1.18-1.61], p = 7.11 × 10(-5)). HLA-class-II-independent associations with HLA-A(∗)11:01 (OR = 1.32 [1.13-1.54], p = 4.92 × 10(-4)), HLA-B(∗)35:03 (OR = 1.96 [1.41-2.70], p = 5.14 × 10(-5)), and HLA-B(∗)51:01 (OR = 1.49 [1.25-1.78], p = 1.09 × 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.

No abstract

The ICSD-2 was easily applicable in cases with typical cataplexy. In these cases, the MSLT and further evaluations were almost always positive and may thus not always be needed. Many patients without cataplexy were difficult to classify because of difficulties in interpreting the MSLT in the presence of sleep apnea or reduced sleep.

Tonsil/adenoid size did not predict the severity of AHI. Nevertheless, adenoid size might be related to lowest oxygen saturation, which is thought to be related to subjective symptoms. Although flow limitation was related to tonsil size but not to QOL in the control group, further research will be needed to understand the importance of flow limitation and upper airway resistance syndrome in the pediatric population.

. CC-BY 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/373555 doi: bioRxiv preprint first posted online Jul. 22, 2018; Main Text 1 Type 1 narcolepsy (T1N) is a sleep disorder that affects 1/3,000 individuals across ethnic 2 groups 1-3 . Onset is typically in childhood through early adulthood. Symptoms are caused by the 3 destruction of hypocretin/orexin neurons, a small neuronal subpopulation of the hypothalamus 4 . 4Although the disease is considered autoimmune, the exact mechanism leading to hypocretin cell 5 death is still unclear. Indeed, T1N is strongly associated with alleles encoding the heterodimer 6 DQ0602 haplotype (HLA-DQA1*01:02~DQB1*06:02, 97% vs. 25%) across ethnic groups 5,6 . 7Other loci previously associated with the disease include T cell receptor (TCR) loci alpha (TRA) 8 and beta (TRB), receptors of HLA-peptide presentations, and other autoimmune associated 9 genes (CTSH, P2RY11, ZNF365, IFNAR1 and TNFSF4) [7][8][9][10] . 11Triggers of T1N point to the immune system, including influenza and Streptococcus Pyogenes 12 infections 9,11,12 , as well as immunization with Pandemrix®, an influenza-A vaccine developed 13 specifically against the H1N1 "swine flu" strain 13-20 suggest a strong environmental modifier of 14 disease risk for narcolepsy. Increased T1N incidence following the Pandemrix® vaccination was 15 first seen in Northern Europe [13][14][15][16][17][18][19][20] with 8-fold increase in incidence in (0.79/100,000 to 16 6.3/100,000) in children. The specificity was striking, as increased T1N was later detected in all 17 countries where Pandemrix® was used, whereas countries using other pH1N1 vaccine brands 18 did not detect vaccination-associated increases in incidence [13][14][15][16][17][18][19][20][21][22] . is defined by antigen presentation, mediated through specific T cell receptor chains, and 27 modulated by influenza-A as a critical trigger. 28. CC-BY 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/373555 doi: bioRxiv preprint first posted online Jul. 22, 2018; examined using LD Score Regression 33 , the shared heritability was largest with type-1 diabetes Genetics of vaccination-triggered narcolepsy. We have previously shown that both influenza 21 infections and, in rare cases, immunization with Pandemrix® can trigger narcolepsy 13,18,19,42,43 . 22The baseline for narcolepsy in unvaccinated vs. Pandemrix® vaccinated individuals was 23 0.7/100,000 vs. 9/100,000 person years with on average 10-fold increase in risk 13,18,19,[42][43][44] was not peer-reviewed) is t...