Hereditary transthyretin (TTR) amyloidosis (hATTR) is a rare life-threatening disorder caused by amyloidogenic coding mutations located in TTR gene. To understand the high phenotypic variability observed among carriers of TTR disease-causing mutations, we conducted an epigenome-wide association study (EWAS) assessing more than 700,000 methylation sites and testing epigenetic difference of TTR coding mutation carriers vs. non-carriers. We observed a significant methylation change at cg09097335 site located in Beta-secretase 2 (BACE2) gene (standardized regression coefficient = −0.60, p = 6.26 × 10–8). This gene is involved in a protein interaction network enriched for biological processes and molecular pathways related to amyloid-beta metabolism (Gene Ontology: 0050435, q = 0.007), amyloid fiber formation (Reactome HSA-977225, q = 0.008), and Alzheimer’s disease (KEGG hsa05010, q = 2.2 × 10–4). Additionally, TTR and BACE2 share APP (amyloid-beta precursor protein) as a validated protein interactor. Within TTR gene region, we observed that Val30Met disrupts a methylation site, cg13139646, causing a drastic hypomethylation in carriers of this amyloidogenic mutation (standardized regression coefficient = −2.18, p = 3.34 × 10–11). Cg13139646 showed co-methylation with cg19203115 (Pearson’s r2 = 0.32), which showed significant epigenetic differences between symptomatic and asymptomatic carriers of amyloidogenic mutations (standardized regression coefficient = −0.56, p = 8.6 × 10–4). In conclusion, we provide novel insights related to the molecular mechanisms involved in the complex heterogeneity of hATTR, highlighting the role of epigenetic regulation in this rare disorder.

中文翻译：

---

意大利患者的表观遗传分析确定了与遗传性转甲状腺素蛋白淀粉样变性相关的甲基化位点


遗传性转甲状腺素蛋白（TTR）淀粉样变性（hATTR）是一种罕见的危及生命的疾病，由位于 TTR 基因的淀粉样蛋白生成编码突变引起。为了了解 TTR 致病突变携带者中观察到的高表型变异性，我们进行了一项全表观基因组关联研究 (EWAS)，评估了超过 700,000 个甲基化位点，并测试了 TTR 编码突变携带者与非携带者的表观遗传差异。我们观察到位于 Beta 分泌酶 2 (BACE2) 基因的 cg09097335 位点存在显着的甲基化变化（标准化回归系数 = -0.60，p = 6.26 × 10–8）。该基因参与蛋白质相互作用网络，该网络富含与淀粉样蛋白代谢相关的生物过程和分子途径（基因本体：0050435，q = 0.007）、淀粉样蛋白纤维形成（Reactome HSA-977225，q = 0.008）和阿尔茨海默病（KEGG hsa05010，q = 2.2 × 10–4）。此外，TTR 和 BACE2 共享 APP（β 淀粉样蛋白前体蛋白）作为经过验证的蛋白质相互作用因子。在 TTR 基因区域内，我们观察到 Val30Met 破坏了甲基化位点 cg13139646，导致该淀粉样蛋白突变携带者的甲基化严重降低（标准化回归系数 = -2.18，p = 3.34 × 10–11）。 Cg13139646 显示与 cg19203115 共甲基化（Pearson r2 = 0.32），这表明有症状和无症状的淀粉样蛋白突变携带者之间存在显着的表观遗传差异（标准化回归系数 = -0.56，p = 8.6 × 10–4）。总之，我们提供了与 hATTR 复杂异质性所涉及的分子机制相关的新见解，强调了表观遗传调控在这种罕见疾病中的作用。