Background:The Val122Ile mutation in Transthyretin (TTR) gene causes a rare, difficult to diagnose hereditary form of cardiac amyloidosis. This mutation is most common in the United States and mainly present in people of African descent. The carriers have an increased risk of congestive heart failure, peripheral edema, and several other noncardiac phenotypes such as carpal tunnel syndrome, and arthroplasty which are top reasons for ambulatory/outpatient surgeries (OSs) in the country.Methods:We conducted first-ever epigenome-wide association study using the Illumina’s EPIC array, in Val122Ile carriers of African descent for heart disease and multiple OSs—an early disease indicator. Differential methylation across genome wide cytosine-phosphate guanine (CpG) sites was tested between carriers with and without heart disease and OS. Significant CpG sites were investigated for cis-mQTLs loci, followed by gene ontology and protein-protein interaction network. We also investigated the significant CpG sites in a secondary cohort of carriers for replication.Results:Five differentially methylated sites (P≤2.1×10⁻⁸) in genes—FAM129B, SKI, WDR27, GLS, and an intergenic site near RP11-550A5.2, and one differentially methylated region containing KCNA6 and GALNT3 (P=1.1×10⁻¹²) were associated with heart disease. For OS, we observe 4 sites—2 sites in UBE2E3 and SEC14L5, and other 2 in intergenic regions (P≤1.8×10⁻⁷) and 3 regions overlapping SH3D21, EVA1B, LTB4R2, and CIDEB (P≤3.9×10⁻⁷). Functional protein-interaction module analysis identified ABCA1 (P=0.001) for heart disease. Six cis-mQTLs were associated with one of the significant CpG sites (FAM129B; P=4.1×10⁻²⁴). We replicated 2 CpG sites (cg18546846 and cg06641417; P<0.05) in an external cohort of biopsy-confirmed cases of TTR (transthyretin) amyloidosis. The genes identified are involved in transport and clearance of amyloid deposits (GLS, ABCA1, FAM129B); cardiac fibrosis (SKI); and muscle tissue regulation (SKI, FAM129B).Conclusions:These findings highlight the link between a complex amyloid circuit and diverse symptoms of Val122Ile.

中文翻译：

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非裔美国人转甲状腺素蛋白 Val122Ile 携带者的表观基因组学特征揭示了假定失调的淀粉样蛋白机制

背景：甲状腺素运载蛋白( TTR ) 中的 Val122Ile 突变) 基因导致一种罕见的、难以诊断的遗传性心脏淀粉样变性。这种突变在美国最为常见，主要存在于非洲人后裔中。携带者患充血性心力衰竭、外周水肿和其他几种非心脏表型的风险增加，如腕管综合征和关节成形术，这些是该国门诊/门诊手术 (OS) 的主要原因。方法：我们进行了第一次使用 Illumina 的 EPIC 阵列进行的表观基因组范围关联研究，在 Val122Ile 非洲裔携带者的心脏病和多种 OS（早期疾病指标）中进行。在患有和不患有心脏病和 OS 的携带者之间测试了全基因组范围内的胞嘧啶-磷酸鸟嘌呤 (CpG) 位点的差异甲基化。研究了 cis-mQTLs 基因座的重要 CpG 位点，其次是基因本体和蛋白质-蛋白质相互作用网络。我们还研究了第二组携带者中重要的 CpG 位点进行复制。结果：五个差异甲基化位点（P ≤2.1×10 ^-8）基因——FAM129B、SKI、WDR27、GLS和RP11-550A5.2附近的一个基因间位点和一个含有KCNA6和GALNT3的差异甲基化区域（P =1.1×10 ^-12）相关患有心脏病。对于 OS，我们观察到 4 个位点 — UBE2E3和SEC14L5中的 2 个位点，其他 2 个位于基因间区域 ( P ≤1.8×10 ^-7 ) 和 3 个与SH3D21、EVA1B、LTB4R2和CIDEB重叠的区域( P≤3.9×10 ^-7 )。功能性蛋白质相互作用模块分析确定了心脏病的ABCA1（P = 0.001）。六个 cis-mQTL 与一个重要的 CpG 位点 ( FAM129B ; P =4.1×10 ^-24 ) 之一相关。我们在活检证实的 TTR（转甲状腺素蛋白）淀粉样变性病例的外部队列中复制了 2 个 CpG 位点（cg18546846 和 cg06641417；P <0.05）。鉴定的基因参与淀粉样沉积物的运输和清除（GLS、ABCA1、FAM129B）；心脏纤维化（SKI）；和肌肉组织调节 ( SKI , FAM129B). 结论：这些发现强调了复杂的淀粉样蛋白回路与 Val122Ile 的不同症状之间的联系。