Variant between CPT1B and CHKB associated with susceptibility to narcolepsy

Abstract

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.

Polymorphism of the genes encoding for the carnitine acyltransferases in native populations of Siberia

“…Так, в отношении присутствующего у эскимо-сов гаплотипа, основанного на вариантах полиморфизма в локусах rs470117, rs8142477 и rs3213445 гена CPT1B, было высказано предположение о его причастности к ре-гуляции сна в условиях полярной ночи [6]. Эта гипотеза возникла вследствие того, что у японцев была выявлена ассоциация варианта полиморфизма в локусе rs5770917, расположенном на указанном выше гаплотипе, и ассоци-ация варианта полиморфизма и нарколепсии [13]. В от-ношении несинонимичных замен в локусах rs2229291 (F352C) и rs1799821 (V368I) гена CPT2 высказывалось предположение об их связи с энергетическим метабо-лизмом [6,14].…”

Overview of orexin/hypocretin system

“…Recently, Tribbles homolog 2 (Trib2) was reported as a possible antigen involved in the autoimmune destruction of orexin neurons (Cvetkovic-Lopes et al, 2010). Recent studies also showed that susceptibility to narcolepsy is associated with SNPs in the T-cell receptor alpha locus (Hallmayer et al, 2009) and between the carnitine palmitoyl-transferase 1B and choline kinase  loci (Miyagawa et al, 2008).…”

Genome-Wide Association Studies of Sleep Disorders

“…In 2008, Miyagawa et al 56 reported a GWAS on 222 Japanese patients with narcolepsy with clear cataplexy and 389 healthy Japanese control subjects. Narcolepsy is known to be tightly associated with human leukocyte antigen HLA-DQB1 * 0602, 18 , 57 and www.chestpubs.org indeed, the investigators found the expected strong association with the HLA region on chromosome 6 ( P , 10 2 46 ).…”