Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Laboratório de Identificação Genética, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
J Neurol Neurosurg Psychiatry. 2019 Feb;90(2):203-210. doi: 10.1136/jnnp-2018-319200. Epub 2018 Oct 18.
To perform a systematic review and meta-analysis of genetic risk factors for age at onset (AO) in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD).
Two authors independently reviewed reports on the mathematical relationship between CAG length at the expanded allele (CAGexp), and other genetic variants if available, and AO. Publications from January 1994 to September 2017 in English, Portuguese or Spanish and indexed in MEDLINE (PubMed), LILACS or EMBASE were considered. Inclusion criteria were reports with >20 SCA3/MJD carriers with molecular diagnosis performed by capillary electrophoresis. Non-overlapping cohorts were determined on contact with corresponding authors. A detailed analysis protocol was registered at the PROSPERO database prior to data extraction (CRD42017073071).
Eleven studies were eligible for meta-analysis, comprising 10 individual-participant (n=2099 subjects) and two aggregated data cohorts. On average, CAGexp explained 55.2% (95% CI 50.8 to 59.0; p<0.001) of AO variability. Population-specific factors accounted for 8.3% of AO variance. Cohorts clustered into distinct geographic groups, evidencing significantly earlier AO in non-Portuguese Europeans than in Portuguese/South Brazilians with similar CAGexp lengths. Presence of intermediate alleles (27-33 CAG repeats) significantly correlated with earlier AO. Familial factors accounted for ~10% of AO variability. CAGexp, origin, family effects and CAG length at together explained 73.5% of AO variance.
Current evidence supports genetic modulation of AO in SCA3/MJD by CAGexp, and family-specific and population-specific factors. Future studies should take these into account in the search for new genetic modifiers of AO, which could be of therapeutic relevance.
对脊髓小脑共济失调 3 型/马查多-约瑟夫病（SCA3/MJD）发病年龄（AO）的遗传风险因素进行系统评价和荟萃分析。
两名作者独立查阅了关于扩展等位基因（CAGexp）的 CAG 长度与其他遗传变异之间数学关系的报告，如果有其他遗传变异的报告，则查阅。纳入标准为 1994 年 1 月至 2017 年 9 月以英文、葡萄牙文或西班牙文发表并在 MEDLINE（PubMed）、LILACS 或 EMBASE 索引的报告，且进行分子诊断时使用毛细管电泳法检测 SCA3/MJD 携带者>20 例。通过与相应作者联系确定非重叠队列。在提取数据之前，将详细的分析方案在 PROSPERO 数据库中进行了注册（CRD42017073071）。
有 11 项研究符合荟萃分析的条件，包括 10 项个体参与者（n=2099 名受试者）和 2 项汇总数据队列。平均而言，CAGexp 解释了 AO 变异性的 55.2%（95%CI 50.8 至 59.0；p<0.001）。特定人群的因素占 AO 方差的 8.3%。队列聚类为不同的地理群体，表明非葡萄牙裔欧洲人的 AO 出现得更早，而葡萄牙裔/南巴西裔的 CAGexp 长度相似，但 AO 出现得更晚。存在中间等位基因（27-33 CAG 重复）与 AO 出现较早显著相关。家族因素占 AO 变异性的~10%。CAGexp、起源、家族效应和 共同解释了 AO 变异性的 73.5%。
目前的证据支持 CAGexp、和家族特异性和人群特异性因素对 SCA3/MJD 中 AO 的遗传调节。未来的研究应在寻找新的 AO 遗传修饰因子时考虑到这些因素，这可能具有治疗意义。
