在亞洲人種身上發現新的昏睡症風險變異


  September 29, 2008 — 根據一項線上發表於自然基因學期刊的研究,第22對染色體上的基因變異與亞洲人種罹患昏睡症感受性強烈有關。這項於日本族群上確認的關聯性,在韓國族群中也可以發現,但並未在歐洲或是亞裔美人身上發現。
  
  昏睡症是一種睡眠異常,罹患這種疾病的病患會有不正常的快速動眼期(REM)睡眠,也可能會有猝倒的現象發生,以及強烈的日間睡眠傾向。這最早發生於青少年時期,0.16%至0.18%的日本人有這樣的問題,但在歐洲或是美國僅有0.02%到0.06%的病患有此問題。這項基因變異同樣會使受影響個體的一等親發生昏睡症的風險高出10~40倍。
  
  資深作者日本東京大學醫學研究所人類基因部門的Katsushi Tokunaga博士向Medscape病理學與實驗醫學表示,為什麼昏睡症經常於青少年時期發生目前仍不清楚,然而,我們認為青少年時期所遭遇到的許多壓力可能誘發昏睡症。
  
  在患有昏睡症個體的腦脊髓液中,hypocretin這個物質的濃度很低、甚至是測不到的,這些病患分泌hypocretin這個物質的神經元也比較少;大約在25年前,日本研究者們發現昏睡症與HLA-DR2這個基因有關,幾乎所有罹患昏睡症的日本人,這個基因都是呈陽性的。然而,有近10%的日本人這個基因同樣呈現陽性,因此這個特性對於昏睡症的發生是必須但不足夠的。
  
  Tokunaga博士表示,其他荷爾蒙或是神經變化也可能與hypocretin缺乏有關,因為人類昏睡症很明顯是一種多重因素的疾病。
  
  目前這項基因體關聯性研究收納了222位罹患昏睡症的日本病患,與389位控制組日本人。HLA區段的單一核苷酸多形性(SNPs)強烈地與昏睡症有關(最強烈關聯,P值達4.7x10-47),但是從後續追蹤中排除。
  
  研究團隊在一項收納日本族群的研究中確認出30種SNPs,這項研究包括159位罹患昏睡症的病患,與190位控制組病患;以P<1.7x10-3為複製的條件,30個SNPs中僅有一個被發現強烈地與昏睡症有關(P=5.2x10-4;勝算比為1.97[1.34-2.90]);第22對染色體上這個SNP(rs5770917)的對偶基因(C對偶基因)與昏睡症感受性有關。
  
  Tokunaga博士表示,我們對於SNP(rs5770917)這個基因表現型與昏睡症臨床表徵之間的相關性感到興趣,我們已經測量罹患昏睡症病患的Epworth睡眠分數(ESS);然而,因為ESS是在病患接受藥物治療時監測的,其價值會受到治療影響,因此,我們在解釋這項研究結果時必須特別小心。
  
  Rs5770917處在兩個已知會影響睡眠的基因之間,這兩個基因分別為CPT1B(肉鹼棕梠酸轉化脢1B)與CHKB(膽酸磷酸酶貝他)。這項研究顯示,有這個具風險對偶基因異源子的個體,相較於有非風險對偶基因的同源子,這兩個基因的mRNA表現顯著較低(P值分別為0.003與0.01)。
  
  CPT1B基因解碼牽涉到肌肉粒線體脂肪酸貝他氧化作用的一種酵素;動物實驗顯示有具感受性對偶基因(C對偶基因)rs5770917的個體,其CPT1B基因表現下降,這會使得貝他氧化作用減少,且貝他氧化作用減少的動物,其REM睡眠時期的腦電波頻率較慢。第二個基因,CHKB(膽酸磷酸酶貝他),負責解碼一個對磷酸膽酸製造與影響乙醯膽鹼釋放的酵素,這是一個與REM及促使覺醒有關的神經傳導物質。
  
  這項研究的最後一個部分是針對非日本族群的rs5770917進行研究;在韓國測試族群中,rs5770917顯著地與昏睡症有關(P = .03; OR, 1.40; 95% CI, .97 – 2.00),但在歐洲或是非裔美人族群身上,並沒有顯著的關聯。
  
  喬治亞州亞特蘭大Emory大學醫學院的神經學教授David Rye博士對Medscape病理學與實驗醫學提供評論,這是第一個且也是一個種子性的文獻,找出昏睡症的感受性基因(除了HLA之外,這已經被發現超過20年了)。
  
  他進一步表示,人類昏睡症中觀察到Hypocretin的降低,可能是肇因於hypocretin神經元的細胞死亡,非僅僅只是他們受到基因調控而減少分泌;在歐洲人種與非裔美人身上,這些基因顯然作用不大,這提出了一種昏睡症在不同族群上有不同病因學的可能性。
  
  Medscape病理學與實驗醫學也連絡了Juliane Winkelmann醫師,有關於目前這項研究的臨床應用。Winkelmann醫師是Ludwig Maximilians大學神經學與神經基因學的助理教授,也是德國慕尼黑Max Planck精神學機構神經部門的醫療主任。Winkelmann醫師表示,這篇文章是很了不起的。
  
  Winkelmann醫師指出,目前為止,他已經以調控單胺激性系統的藥物來治療猝倒與日間睡眠症,這些新的發現可以引領日後創新的治療策略,這不僅僅對於昏睡症是重要的,對於其他睡眠異常來說也是很關鍵的。她理解這些新資訊對於了解牽涉到hypocretin激性神經傳導路徑的病理學是很重要的,除此之外,還有睡眠與覺醒的調控。
  
  Tokunaga博士表示,回復與改善貝他氧化作用的化合物,被認為是我們(CPT1B減少)與其他研究中的一個候選物質。然而,以CHKB而言,目前要做出臨床介入可能很難,因為CHKB減少所帶來的效應是非常複雜的。
  
  Tokunaga博士與Winkelmann醫師表示沒有相關資金上的往來。Rye博士是許多藥廠的顧問與發言人(包括GSK、伯明罕百靈佳與UCB藥廠)。

New Risk Variant for Narcolepsy Identified in Asian Populations

By Jacquelyn K. Beals, PhD
Medscape Medical News

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 and 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 and 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 and 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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