From the Department of Neurology (S.B.G., K.P.F., M.B.B., S.-M.P.) and Department of Medicine, Division of Genetic Epidemiology (L.C.-A.), University of Utah School of Medicine; and George E. Wahlen Department of Veterans Affairs Medical Center (L.C.-A.), Salt Lake City, UT.
Neurology. 2014 Jan 7;82(1):17-22. doi: 10.1212/01.wnl.0000438219.39061.da. Epub 2013 Dec 4.
To determine the extent of an inherited contribution to amyotrophic lateral sclerosis (ALS) mortality.
Death certificates (DCs) from 1904 to 2009 were analyzed from patients with at least 3 generations recorded in the Utah Population Database, a genealogic and medical database of more than 2 million Utah residents. Among probands whose DCs listed ALS, the relative risk (RR) of death with ALS was determined among spouses and first- through fifth-degree relatives, using birth year-, sex-, and birthplace-matched cohorts.
Eight hundred seventy-three patients with ALS met the inclusion criteria. Among 3,531 deceased first-degree relatives of probands, the RR of dying with ALS was increased compared with control cohorts (RR = 4.91, 95% confidence interval 3.36, 6.94). The RR of dying with ALS was also increased among 9,386 deceased second-degree relatives (RR = 2.85, 95% confidence interval 2.06, 3.84). The RR of dying with ALS was not increased among third- through fifth-degree relatives. More affected first-degree relatives were male (p = 0.014). No cases of conjugal ALS were observed.
This study is suggestive of familial clustering in excess of expected for ALS. Our results confirm the results of prior studies of familial ALS, suggesting applicability of our findings to other mixed European populations. Furthermore, this work expands on previous studies by quantifying the RR of ALS among more distant relatives. The use of mortality data obtained from DCs reduces the ascertainment and recall bias of many previous studies. Finally, the excess of ALS among second-degree relatives and lack of conjugal ALS are strongly supportive of a genetic contribution.
确定遗传性对肌萎缩侧索硬化症（ALS）死亡率的影响程度。
从犹他州人口数据库中分析了 1904 年至 2009 年的死亡证明（DC），该数据库是一个拥有超过 200 万犹他州居民的家谱和医疗数据库，其中至少有 3 代人被记录在案。在所分析的 DC 中列出 ALS 的先证者中，使用按出生年份、性别和出生地匹配的队列，确定 ALS 死亡的相对风险（RR）与配偶和 1 至 5 级亲属。
873 名符合纳入标准的 ALS 患者。在 3531 名先证者的已故一级亲属中，ALS 死亡的 RR 高于对照组（RR=4.91，95%置信区间 3.36，6.94）。在 9386 名已故二级亲属中，ALS 死亡的 RR 也增加（RR=2.85，95%置信区间 2.06，3.84）。在 3 至 5 级亲属中，ALS 死亡的 RR 没有增加。受影响更多的一级亲属为男性（p=0.014）。未观察到夫妻 ALS 病例。
本研究提示 ALS 存在家族聚集性，超出预期。我们的结果证实了先前关于家族性 ALS 的研究结果，表明我们的发现适用于其他混合欧洲人群。此外，这项工作通过量化 ALS 在更远的亲属中的 RR，扩展了先前的研究。使用从 DC 获得的死亡率数据减少了许多先前研究的检出和回忆偏倚。最后，二级亲属中 ALS 的过多和夫妻 ALS 的缺乏强烈支持遗传贡献。
