肌萎缩侧索硬化症(ALS)是一种可怕的疾病，许多病人会因为无法忍受病痛的折磨而寻求安乐死。而最近一国际研究小组的研究发现，位于9号染色体的两个基因变异与ALS密切相关，该发现为诊治该疾病带来了希望，相关结果发表在最近一期的《柳叶刀·神经病学》网络版上。
ALS是一种运动神经元疾病，俗称“渐冻人症”，又因美国著名棒球明星卢奥·葛雷克死于此病而称“葛雷克氏病”。该病通常以四肢肌无力和萎缩为首发症状，有时病况也会出现在嘴与喉咙处，患者的肌肉会逐渐无力以至瘫痪，其说话、吞咽和呼吸功能也会减退，直至呼吸衰竭而死亡。
这种疾病发展十分迅速，病患通常在3年内就会死亡。一般认为，该疾病有多种致病因素，其中约5%至10%的患者属于遗传，但对于散发性病人的致病原因，目前尚不十分清楚。
英国伦敦国王大学9月6日发布的新闻公报称，为找到与散发性ALS有关的基因变异，由英美等8个国家的研究人员组成的国际研究小组进行了大规模二级全基因组相关性研究。
他们检测了英国599名散发性ALS病人的DNA(脱氧核糖核酸)样本，而作为对照组的非ALS病患DNA样本则高达4144个。分析结果显示，9号染色体中的两个基因变异与ALS密切相关。
为了确认其发现，研究人员还将英国的样本与采自另外7个国家的4312名ALS病患的DNA样本及8425个非ALS病患的DNA样本进行了比较，结果同样证实，位于9号染色体的基因变异与ALS密切相关。
该研究项目的领导者、英国伦敦国王大学的阿玛尔·阿尔沙拉比博士指出，ALS是一种令人恐惧的疾病，关于该种疾病的任何线索都极具价值，因此，证实9号染色体中存在与ALS密切相关的危险基因极为重要，有助于科学家更好地了解该疾病的发病机理并最终找到有价值的治疗手段。（生物谷Bioon.com）
生物谷推荐英文摘要：
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).
