肌萎縮側(cè)索硬化癥(ALS)是一種可怕的疾病，許多病人會(huì)因?yàn)闊o(wú)法忍受病痛的折磨而尋求安樂(lè)死,。而最近一國(guó)際研究小組的研究發(fā)現(xiàn)，位于9號(hào)染色體的兩個(gè)基因變異與ALS密切相關(guān),，該發(fā)現(xiàn)為診治該疾病帶來(lái)了希望,，相關(guān)結(jié)果發(fā)表在最近一期的《柳葉刀·神經(jīng)病學(xué)》網(wǎng)絡(luò)版上。
ALS是一種運(yùn)動(dòng)神經(jīng)元疾病,，俗稱(chēng)“漸凍人癥”,，又因美國(guó)著名棒球明星盧奧·葛雷克死于此病而稱(chēng)“葛雷克氏病”,。該病通常以四肢肌無(wú)力和萎縮為首發(fā)癥狀，有時(shí)病況也會(huì)出現(xiàn)在嘴與喉嚨處,，患者的肌肉會(huì)逐漸無(wú)力以至癱瘓,，其說(shuō)話、吞咽和呼吸功能也會(huì)減退,，直至呼吸衰竭而死亡,。
這種疾病發(fā)展十分迅速，病患通常在3年內(nèi)就會(huì)死亡,。一般認(rèn)為,，該疾病有多種致病因素，其中約5%至10%的患者屬于遺傳,，但對(duì)于散發(fā)性病人的致病原因,，目前尚不十分清楚。
英國(guó)倫敦國(guó)王大學(xué)9月6日發(fā)布的新聞公報(bào)稱(chēng),，為找到與散發(fā)性ALS有關(guān)的基因變異,，由英美等8個(gè)國(guó)家的研究人員組成的國(guó)際研究小組進(jìn)行了大規(guī)模二級(jí)全基因組相關(guān)性研究。
他們檢測(cè)了英國(guó)599名散發(fā)性ALS病人的DNA(脫氧核糖核酸)樣本,，而作為對(duì)照組的非ALS病患DNA樣本則高達(dá)4144個(gè),。分析結(jié)果顯示，9號(hào)染色體中的兩個(gè)基因變異與ALS密切相關(guān),。
為了確認(rèn)其發(fā)現(xiàn),，研究人員還將英國(guó)的樣本與采自另外7個(gè)國(guó)家的4312名ALS病患的DNA樣本及8425個(gè)非ALS病患的DNA樣本進(jìn)行了比較，結(jié)果同樣證實(shí),，位于9號(hào)染色體的基因變異與ALS密切相關(guān),。
該研究項(xiàng)目的領(lǐng)導(dǎo)者、英國(guó)倫敦國(guó)王大學(xué)的阿瑪爾·阿爾沙拉比博士指出,，ALS是一種令人恐懼的疾病,，關(guān)于該種疾病的任何線索都極具價(jià)值，因此,，證實(shí)9號(hào)染色體中存在與ALS密切相關(guān)的危險(xiǎn)基因極為重要,，有助于科學(xué)家更好地了解該疾病的發(fā)病機(jī)理并最終找到有價(jià)值的治療手段。（生物谷Bioon.com）
生物谷推薦英文摘要：
The Lancet Neurology doi:10.1016/S1474-4422(10)70197-6
Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study
Aleksey Shatunov PhD a, Kin Mok MSc e, Stephen Newhouse PhD a, Michael E Weale PhD b, Bradley Smith PhD a, Caroline Vance PhD a, Lauren Johnson PhD a, Jan H Veldink MD f, Michael A van Es MD f, Prof Leonard H van den Berg MD f, Prof Wim Robberecht MD g, Philip Van Damme MD g, Prof Orla Hardiman MD h, Prof Anne E Farmer FRCPsych c, Prof Cathryn M Lewis PhD b c, Amy W Butler PhD c, Olubunmi Abel MSc a, Prof Peter M Andersen MD i, Isabella Fogh PhD a, Prof Vincenzo Silani MD j, Adriano Chiò MD k, Bryan J Traynor MD l, Prof Judith Melki MD m, Prof Vincent Meininger MD n, John E Landers PhD o, Prof Peter McGuffin FRCPsych c, Jonathan D Glass MD p, Hardev Pall MD q, Prof P Nigel Leigh FMedSci a, Prof John Hardy PhD e, Prof Robert H Brown DPhil o, John F Powell DPhil d, Richard W Orrell MD e, Prof Karen E Morrison DPhil q, Prof Pamela J Shaw MD r, Prof Christopher E Shaw MD a, Prof Ammar Al-Chalabi PhD a
Background
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons that results in progressive weakness and death from respiratory failure, commonly within about 3 years. Previous studies have shown association of a locus on chromosome 9p with ALS and linkage with ALS—frontotemporal dementia. We aimed to test whether this genomic region is also associated with ALS in an independent set of UK samples, and to identify risk factors associated with ALS in a further genome-wide association study that combined data from the independent analysis with those from other countries.
Methods
We collected samples from patients with sporadic ALS from 20 UK hospitals and obtained UK control samples from the control groups of the Depression Case Control study, the Bipolar Affective Case Control Study, and the British 1958 birth cohort DNA collection. Genotyping of DNA in this independent analysis was done with Illumina HumanHap550 BeadChips. We then undertook a joint genome-wide analysis that combined data from the independent set with published data from the UK, USA, Netherlands, Ireland, Italy, France, Sweden, and Belgium. The threshold for significance was p=0·05 in the independent analysis, because we were interested in replicating a small number of previously reported associations, whereas the Bonferroni-corrected threshold for significance in the joint analysis was p=2·20×10?7
Findings
After quality control, samples were available from 599 patients and 4144 control individuals in the independent set. In this analysis, two single nucleotide polymorphisms in a locus on chromosome 9p21.2 were associated with ALS: rs3849942 (p=2·22×10?6; odds ratio [OR] 1·39, 95% CI 1·21—1·59) and rs2814707 (p=3·32×10?6; 1·38, 1·20—1·58). In the joint analysis, which included samples from 4312 patients with ALS and 8425 control individuals, rs3849942 (p=4·64×10?10; OR 1·22, 95% CI 1·15—1·30) and rs2814707 (p=4·72×10?10; 1·22, 1·15—1·30) were associated with ALS.
Interpretation
We have found strong evidence of a genetic association of two single nucleotide polymorphisms on chromosome 9 with sporadic ALS, in line with findings from previous independent GWAS of ALS and linkage studies of ALS—frontotemporal dementia. Our findings together with these earlier findings suggest that genetic variation at this locus on chromosome 9 causes sporadic ALS and familial ALS—frontotemporal dementia. Resequencing studies and then functional analysis should be done to identify the defective gene.
Funding
ALS Therapy Alliance, the Angel Fund, the Medical Research Council, the Motor Neurone Disease Association of Great Britain and Northern Ireland, the Wellcome Trust, and the National Institute for Health Research Dementias and Neurodegenerative Diseases Research Network (DeNDRoN).
