i3S Instituto de Investigação e Inovação em Saúde Universidade do Porto Porto Portugal.
UnIGENe IBMC - Instituto de Biologia Molecular e Celular Universidade do Porto Porto Portugal.
Ann Clin Transl Neurol. 2019 Mar 7;6(4):748-754. doi: 10.1002/acn3.748. eCollection 2019 Apr.
Transthyretin (TTR) familial amyloid polyneuropathy (FAP) (OMIM 176300) shows a variable age-at-onset (AO), including within families. We hypothesized that variants in and genes, might also act as genetic modifiers of AO in TTR-FAP Val30Met Portuguese patients.
We analyzed DNA samples of 267 patients (117 families). To search for variants, all exons and flanking regions were genotyped by automated sequencing. We used generalized estimating equations (GEEs) to take into account the non-independency of AO among relatives. Intensive in silico analyses were performed, using various software to assess miRNAs target sites, splicing sites, transcription factor binding sites alterations, and gene-gene interactions.
Two variants for gene, GA genotype of rs201693493 ( < 0.001) and CT genotype of rs149050968 ( < 0.001), were significantly associated with later AO. In silico analysis demonstrated, that rs201693493 may alter splicing activity. Regarding , we found three statistically significant results: GA genotype of rs2935537 ( = 0.003), GA genotype of rs201241346 ( < 0.001) and GA genotype of rs200952686 ( < 0.001). The first two were associated with earlier AO, whereas the third was associated with later-onset.
was associated with later onset, whereas may have a double role: variants may confer earlier or later AO. As found in a study in Cyprus, we confirmed the role of complement genes (and thus of inflammation) as modulator of AO in Portuguese patients with TTR-FAP Val30Met.
转甲状腺素蛋白（TTR）家族性淀粉样多神经病（FAP）（OMIM 176300）表现出可变的发病年龄（AO），包括在家族内。我们假设 和 基因中的变体也可能作为 TTR-FAP Val30Met 葡萄牙患者 AO 的遗传修饰因子。
我们分析了 267 名患者（117 个家族）的 DNA 样本。为了寻找变体，我们通过自动测序对所有外显子和侧翼区域进行了基因分型。我们使用广义估计方程（GEE）来考虑亲属间 AO 的非独立性。我们使用各种软件进行了密集的计算机分析，以评估 miRNA 靶位点、剪接位点、转录因子结合位点改变和基因-基因相互作用。
基因的 rs201693493GA 基因型（<0.001）和 rs149050968CT 基因型（<0.001）与较晚的 AO 显著相关。计算机分析表明，rs201693493 可能改变剪接活性。关于 ，我们发现了三个具有统计学意义的结果：rs2935537GA 基因型（=0.003）、rs201241346GA 基因型（<0.001）和 rs200952686GA 基因型（<0.001）。前两个与较早的 AO 相关，而第三个与较晚的发病相关。
与较晚发病相关，而 可能具有双重作用：变体可能导致较早或较晚的发病。正如在塞浦路斯的一项研究中发现的那样，我们证实了补体 基因（因此炎症）作为葡萄牙 TTR-FAP Val30Met 患者 AO 调节剂的作用。
