New Risk Variant for Narcolepsy Identified in Asian Populations

Jacquelyn K .Beals, PhD

September 29, 2008

September 29, 2008 — A genetic variant on chromosome 22 is strongly associated with narcolepsy susceptibility in Asian populations, according to a study published online yesterday in Nature Genetics. This association, established in Japanese populations, was also significant in Korean subjects but not in populations of European or African American heritage.

Narcolepsy is a sleep disorder in which patients demonstrate abnormal rapid eye movement (REM) sleep, cataplexy, and extreme daytime sleepiness. First appearing in adolescence, narcolepsy occurs in .16% to .18% of the Japanese population but in only .02% to .06% of individuals in Europe or the United States. Its genetic basis is also demonstrated by the 10 to 40 times greater risk among first-degree relatives of affected individuals.

"It is still unknown how and why narcolepsy usually begins in adolescence," senior author Katsushi Tokunaga, PhD, professor, Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Japan, told Medscape Pathology & Lab Medicine via email. "However, we consider that a variety of stress in adolescence might trigger narcolepsy."

Patients with narcolepsy have little or no hypocretin in their cerebrospinal fluid and fewer hypocretin-secreting neurons in their hypothalamus. Almost 25 years ago, Japanese researchers discovered that narcolepsy is linked to HLA-DR2 — nearly all Japanese patients with narcolepsy are DR2-positive. However, 10% of all Japanese are DR2-positive, so this characteristic was a necessary but insufficient cause of narcolepsy.

"Other hormonal or neural changes may also contribute to the hypocretin deficiency," said Dr. Tokunaga, "since human narcolepsy is clearly a multifactorial disease."

The present genome-wide association study enrolled 222 Japanese patients with narcolepsy and 389 Japanese control patients. Single nucleotide polymorphisms (SNPs) in the HLA region were significantly associated with narcolepsy (strongest association, P = 4.7 × 10−47) but were excluded from follow-up.

Investigators identified 30 SNPs for a replication study using Japanese subjects: 159 patients with narcolepsy and 190 control patients. With a criterion for replication of P < 1.7 × 10−3, only 1 of the 30 SNPs was found to be significantly associated with narcolepsy (P = 5.2 × 10−4; odds ratio [OR], 1.97; 95% confidence interval [CI], 1.34 – 2.90). The minor allele (C allele) of this SNP (rs5770917) on chromosome 22 is associated with narcolepsy susceptibility.

"We are...interested in a possible correlation of the genotypes of the SNP (rs5770917) with clinical characteristics of narcolepsy," said Dr. Tokunaga. "We have measured Epworth Sleepiness Scale (ESS) [scores]...for narcoleptic patients. However, since ESS was measured during medical treatment, the values could be affected by the treatment. Thus, we have to be careful about the interpretation of the results," Dr. Tokunaga cautioned.

rs5770917 lies between 2 genes known to affect sleep behavior: CPT1B (carnitine palmitoyl-transferase 1B) and CHKB (choline kinase beta). This study showed that individuals heterozygous for the risk allele had "significantly lower mRNA expression" of both these genes (P = .003 and .01, respectively) compared with people homozygous for the nonrisk allele.

CPT1B codes for an enzyme involved in fatty-acid beta-oxidation in muscle mitochondria. Animal studies suggest that reduced CPT1B expression in individuals with the susceptibility allele (C allele) of rs5770917 results in decreased beta-oxidation and that animals with reduced beta-oxidation show a slower electroencephalogram frequency during REM sleep. The second gene, CHKB (choline kinase beta), codes for an enzyme important for phosphatidylcholine synthesis and affects the release of acetylcholine — a neurotransmitter associated with REM- and wake-promotion.

The final section of the study investigated rs5770917 in non-Japanese populations. A significant association was found between rs5770917 and narcolepsy in the Korean test population (P = .03; OR, 1.40; 95% CI, .97 – 2.00), but no significant association was present in individuals of European or African American heritage.

David Rye, MD, PhD, professor of neurology at Emory University School of Medicine, Atlanta, Georgia, commented to Medscape Pathology & Lab Medicine: "This is the first — and therefore seminal — paper identifying susceptibility genes for narcolepsy (beyond HLA, which has been known for some 20 years)."

He further noted, "[H]ypocretin reductions in human narcolepsy...are due to cell death of hypocretin neurons, not simply reductions in their production mediated by genes. As these genes have an apparently smaller effect (if not statistically insignificant) in Europeans and African Americans, it raises the possibility that narcolepsy has a different etiology in different ethnic groups."

Medscape Pathology & Lab Medicine also contacted Juliane Winkelmann, MD, about clinical applications of the present study. Dr. Winkelmann is assistant professor of neurology and neurogenetics, Ludwig Maximilians University, and assistant medical director, Department of Neurology, Max Planck Institute of Psychiatry, Munich, Germany. "This article is fantastic," said Dr. Winkelmann.

"So far, we have treated the cataplexy and daytime sleepiness with drugs modulating the monoaminergic system. The new discoveries now pave the way for the development of new innovative treatment strategies, which are important not only for narcolepsy but also for other sleep disorders," Dr. Winkelmann said. She considers the new information important for understanding the pathology of the pathways involved in hypocretinergic neurotransmission, as well as for sleep-wake regulation.

Dr. Tokunaga noted that "[C]ompounds which can restore and improve beta-oxidation are considered to be candidates from our study (decreased CPT1B) and other studies." However, "In regard to CHKB, it may be difficult to get opportunities for clinical intervention at present, because the effect of decreased CHKB level may be very complicated."

Dr. Tokunaga and Dr. Winkelmann have disclosed no relevant financial relationships. Dr. Rye consults or is in speakers' bureaus for several pharmaceutical companies (GSK, Boehringer Ingelheim, and UCB).

Nat Genet. Published online September 28, 2008.

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