肌萎缩性侧索硬化最新研究成果（肌萎缩侧索硬化）

导读

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一

双语资讯

今日分享1个小研究~

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肌萎缩侧索硬化(ALS)的遗传度及终生患病风险

[1] Lifetime Risk and Heritability of Amyotrophic Lateral Sclerosis

➤ 肌萎缩侧索硬化（ALS）的遗传度及终生患病风险

[2] Importance : Heritability describes theproportion of variance in the risk of developing a condition that is explainedby genetic factors. Although amyotrophic lateral sclerosis (ALS) is known to have a complex genetic origin, disease heritability remains unclear.

➤ 重要性：遗传度（heritability )用来描述一些受遗传因素影响的疾病的发病风险变异程度。尽管ALS发病的复杂遗传机理广为人知，但其遗传度的规律仍不清楚。 [3]Objectives : To determine the extent of ALS heritability and assess the association of sex with disease transmission.

➤ 研究目的：估测ALS的遗传度以及其遗传过程与性别的相关性。

[4] Design, Setting, and Participants : Aprospective population-based parent-offspring heritability study was conductedfrom January 1, 2008, to December 31, 2017 to assess ALS heritability, and was the first study to assess heritability in the context of known gene mutations of large effect.

➤ 研究方案、设置及纳入试验者：本研究开展于2008年1月1日至2017年12月31日之间，应用父母-子代遗传度研究方法，是迄今首个基于已知的ALS相关突变基因的大规模遗传度评估研究。

[5] A total of 1123 incident cases of ALS,diagnosed according to the El Escorial criteria and recorded on the Irish ALSregister, were identified. Ninety-two individuals were excluded (non-Irishparental origin [n = 86] and familial ALS [n = 6]), and 1117 patients were included in the final analysis.

➤ 基于EI Escorial诊断标准，总计有1123位在爱尔兰ALS登记中心记录的新发ALS患者被初次识别。92名患者被排除出本研究，包括86名父母为非爱尔兰族裔者和6名诊断为家族性ALS者。最终1117位患者被纳入最终数据分析。

[6] Main Outcomes and Measures : Annualage-specific and sex-specific standardized ALS incidence and mortality-adjusted lifetime risk were determined. Sex-specific heritability estimates were calculated for the overall study cohort, for those known to carry theC9orf72(OMIM 614260) variant, and for those with no known genetic risk.

➤ 主要结果、指标：本研究计算年龄标准化年发病率、性别标准化年发病率以及校正死亡率后的终生患病风险。区分2种情况，携带C9orf72(OMIM 614260) 变异基因型者和不具有任何已知遗传风险者，对整个ALS队列计算性别特异性遗传度。

[7] Results : A total of 32 parent-child ALS dyads were identified during the study period. Affected offspring were younger at the onset of disease (mean age, 52.0 years; 95% CI, 48.8-55.3 years)compared with their parents (mean age, 69.6 years; 95% CI, 62.4-76.9 years;P = .008). Lifetime risk of developing ALS in first-degree relatives ofindividuals with ALS was increased compared with the general population (1.4%[32 of 2234] vs 0.3% [2.6 of 1000]; P < .001).

➤ 结果：在研究期间，总计识别出32对ALS父母-子代共病者。与父代发病年龄（平均69.6岁，95% CI：62.4-76.9岁）相比，ALS后代的发病年龄更早 (平均52.0岁，95% CI：48.8-55.3岁，P=0.08）。与普通人群相比，ALS的一级亲属有更高的ALS发病风险 (1.4% [32 of 2234] vs 0.3% [2.6 of 1000]; P < .001)。

[8] Mean lifetime heritability of ALS forthe overall study cohort was 52.3% (95% CI, 42.9%-61.7%) and 36.9% (95% CI,19.8%-53.9%) for those with no known genetic risk. Heritability estimates were highest in mother-daughter pairings (66.2%; 95% CI, 58.5%-73.9%).

➤ 整个ALS研究队列的终生遗传度为52.3% (95% CI：42.9%-61.7%) ，无任何已知遗传风险者遗传度为36.9% (95% CI：19.8%-53.9%) 。母-女配对的ALS具有最高的遗传度 (66.2%; 95% CI:58.5%-73.9%).

[9] Conclusions and Relevance : This population-basedstudy confirms that up to 50% of variance in ALS has a genetic basis, and that the presence of theC9orf72variant is an important determinant ofheritability.

➤ 结论与意义：本人群研究证实，高达50%的ALS具有遗传背景，是否存在C9orf72 基因变异是其遗传度的重要决定因子。

[10] First-degree relatives of individualswith ALS without a known genetic basis remain at increased risk of developingALS compared with the general population. A higher heritability estimate inmother-daughter pairings points to a sex-mediated effect that has beenpreviously unrecognized.

➤ 即使是无任何已知基因背景的ALS患者的一级亲属，其ALS发病风险也高于普通人群。母-女配对ALS患者具有更高的遗传度，说明其中存在以往未认识到的性别调节效应。

——译者：长沙市第一医院神经医学中心湛韬

参考文献：Ryan M, Heverin M, McLaughlin RL, Hardiman O. Lifetime Risk and Heritability of Amyotrophic Lateral Sclerosis.JAMA Neurol.Published online July 22, 2019. doi:10.1001/jamaneurol.2019.2044.

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