TCRA, P2RY11, and CPT1B/CHKB associations in Chinese narcolepsy

Abstract

Objectives Polymorphisms in the TCRA and P2RY11, two immune related genes, are associated with narcolepsy in Caucasians and Asians. In contrast, CPT1B/CHKB polymorphisms have only been shown to be associated with narcolepsy in Japanese, with replication in a small group of Koreans. Our aim was to study whether these polymorphisms are associated with narcolepsy and its clinical characteristics in Chinese patients with narcolepsy. Methods We collected clinical data on 510 Chinese patients presenting with narcolepsy/hypocretin deficiency. Patients were included either when hypocretin deficiency was documented (CSF hypocretin-1 ≤110 pg/ml, n=91) or on the basis of the presence of clear cataplexy and HLA-DQB1*0602 positivity (n=419). Genetic data was compared to typing obtained in 452 controls matched for geographic origin within China. Clinical evaluations included demographics, the Stanford Sleep Inventory (presence and age of onset of each symptom), and Multiple Sleep Latency Test (MSLT) data. Results Chinese narcolepsy was strongly and dose dependently associated with TCRA (rs1154155C) and P2RY11 (rs2305795A) but not CPT1B/CHKB (rs5770917C) polymorphisms. CPT1B/CHKB polymorphisms were not associated with any specific clinical characteristics. TCRA rs1154155A homozygotes (58 subjects) had a later disease onset, but this was not significant when corrected for multiple comparisons, thus replication is needed. CPT1B/CHKB or P2RY11 polymorphisms were not associated with any specific clinical characteristics. Conclusion The study extends on the observation of a strong multiethnic association of polymorphisms in the TCRA and P2RY11 with narcolepsy, but does not confirm the association of CPT1B/CHKB (rs5770917) in the Chinese population.

Increased Incidence and Clinical Picture of Childhood Narcolepsy following the 2009 H1N1 Pandemic Vaccination Campaign in Finland

“…Genetic associations [10], [11], [12], [13], [14], [15], [16], presence of anti-tribbles 2 antibodies [17], [18], [19] and other recent observations [20], [21] suggest that autoimmune mechanisms are involved in the etiopathogenesis of narcolepsy [22], [23], [24]. Seasonality of onset [25] and reports of an association to preceding streptococcal infections [26], [27] have suggested a link with upper respiratory tract infections.…”

Identification of the Variations in the CPT1B and CHKB Genes Along with the HLA-DQB1*06:02 Allele in Turkish Narcolepsy Patients and Healthy Persons

“…These researchers suggested that variations in the CPT1B/CHKB susceptibility genes are thought to play a role in sleep regulation and were a common genetic susceptibility factor to narcolepsy in the East Asian population. However, this finding was not replicated in Chinese narcolepsy samples (Han et al, 2012), indicating that the association of SNP harboring between CPT1B and CHKB with narcolepsy susceptibility is still speculative. They also reported that rs5770917 has strong linkage disequilibrium with rs5770911, rs2269381, rs2269382 SNPs according to the HapMap data for individuals of Japanese ancestry (Miyagawa et al, 2008).…”

“…However, the susceptibility found in the Japanese and Korean samples was not replicated in Chinese narcolepsy samples (Han et al, 2012). A protein encoded by the CPT1B gene is the rate-controlling enzyme of the longchain fatty acid (-oxidation pathway in muscle mitochondria (McGarry and Brown, 1997).…”

Autoimmunity in narcolepsy

“…TCR alpha and beta loci are strongly associated with narcolepsy [9, 11, 67, 75]. Furthermore, variants in Cathepsin H ( CTSH ), an enzyme that process peptides for presentation by HLA on dendritic cells, and TNFSF4 a molecule regulating immune cell fate, are associated with narcolepsy [9].…”

“…Furthermore, variants in Cathepsin H ( CTSH ), an enzyme that process peptides for presentation by HLA on dendritic cells, and TNFSF4 a molecule regulating immune cell fate, are associated with narcolepsy [9]. Finally, variants located within the interferon receptor region ( IL10RB-IFNAR1 ), the purinergic receptor ( P2RY11 ), the ZNF365 transcription factor as well as chemokine receptor CCR1-CCR3 regions are associated with narcolepsy [9, 75, 76]. As all these genetic loci have been associated with immune function or other autoimmune disorders, pathway analysis clearly demonstrate narcolepsy is likely autoimmune.…”