To test the hypothesis that rs573116164 will have disease-modifying effects in patients with superoxide dismutase 1 (SOD1) familial amyotrophic lateral sclerosis (fALS), we characterized rs573116164 within a cohort of 190 patients with fALS and 560 healthy age-matched controls to assess the variant for association with various measures of disease.

Using a previously described bioinformatics evaluation algorithm, a polymorphic short structural variant associated with SOD1 was identified according to its theoretical effect on gene expression. An 12–18 poly-T repeat (rs573116164) within the 3' untranslated region of serine and arginine rich proteins-related carboxy terminal domain associated factor 4 (SCAF4), a gene that is adjacent to SOD1, was assessed for disease association and influence on survival and age at onset in an fALS cohort using PCR, Sanger sequencing, and capillary separation techniques for allele detection.

In a North American cohort of predominantly SOD1 fALS patients (n =190) and age-matched healthy controls (n = 560), we showed that carriage of an 18T SCAF4 allele was associated with disease within this cohort (odds ratio [OR] 6.6; 95% confidence interval [CI] 3.9–11.2; p = 4.0e-11), but also within non-SOD1 cases (n = 27; OR 5.3; 95% CI 1.9–14.5; p = 0.0014). This finding suggests genetically SOD1-independent effects of SCAF4 on fALS susceptibility. Furthermore, carriage of an 18T allele was associated with a 26-month reduction in survival time (95% CI 6.6–40.8; p = 0.014), but did not affect age at onset of disease.

The findings in this fALS cohort suggest that rs573116164 could have SOD1-independent and broader relevance in ALS, warranting further investigation in other fALS and sporadic ALS cohorts, as well as studies of functional effects of the 18T variant on gene expression.

为了验证 rs573116164 对超氧化物歧化酶 1 ( SOD1 ) 家族性肌萎缩性侧索硬化症 (fALS) 患者的疾病改善作用这一假设，我们在 190 名 fALS 患者和 560 名健康年龄匹配的对照组中对 rs573116164 进行了表征，以评估与各种疾病测量相关的变体。

使用先前描述的生物信息学评估算法，根据其对基因表达的理论影响，鉴定了与SOD1相关的多态性短结构变体。对与SOD1相邻的基因，在富含丝氨酸和精氨酸的蛋白质相关羧基末端结构域相关因子 4 ( SCAF4 ) 的 3' 非翻译区域内的 12-18 个多 T 重复序列 (rs573116164)进行了疾病关联和影响评估使用 PCR、Sanger 测序和毛细管分离技术进行等位基因检测的 fALS 队列中的存活率和发病年龄。

在主要由SOD1 fALS 患者 (n = 190) 和年龄匹配的健康对照 (n = 560) 组成的北美队列中，我们发现携带 18T SCAF4等位基因与该队列中的疾病相关（优势比 [OR] 6.6 ; 95% 置信区间 [CI] 3.9–11.2；p = 4.0e-11），但也适用于非SOD1病例（n = 27；OR 5.3；95% CI 1.9–14.5；p = 0.0014）。这一发现表明SCAF4 对 fALS 易感性的遗传SOD1独立影响。此外，携带 18T 等位基因与 26 个月的生存时间减少相关（95% CI 6.6-40.8；p = 0.014），但不影响发病年龄。

该 fALS 队列中的研究结果表明 rs573116164 可能在 ALS 中具有SOD1独立和更广泛的相关性，值得在其他 fALS 和散发性 ALS 队列中进行进一步研究，以及研究 18T 变体对基因表达的功能影响。