Department of Psychiatry, Yale School of Medicine, Yale University, New Haven (G.A.P., F.R.W., Y.Z.N., A.G., F.D.A., J.G., R.P.).
Veteran Affairs Connecticut Healthcare System, West Haven, CT (G.A.P., F.R.W., Y.Z.N., A.G., F.D.A., J.G., R.P.).
Circ Genom Precis Med. 2021 Feb;14(1):e003011. doi: 10.1161/CIRCGEN.120.003011. Epub 2021 Jan 11.
The Val122Ile mutation in () 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.
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.
Five differentially methylated sites (≤2.1×10) in genes-, , , , and an intergenic site near RP11-550A5.2, and one differentially methylated region containing and (=1.1×10) were associated with heart disease. For OS, we observe 4 sites-2 sites in and , and other 2 in intergenic regions (≤1.8×10) and 3 regions overlapping , , , and (≤3.9×10). Functional protein-interaction module analysis identified (=0.001) for heart disease. Six cis-mQTLs were associated with one of the significant CpG sites (; =4.1×10). We replicated 2 CpG sites (cg18546846 and cg06641417; <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 (, , ); cardiac fibrosis (); and muscle tissue regulation (, ).
These findings highlight the link between a complex amyloid circuit and diverse symptoms of Val122Ile.
载脂蛋白 AI（）基因中的 Val122Ile 突变导致一种罕见的、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，主要存在于非洲裔人群中。该突变携带者心力衰竭、外周水肿以及腕管综合征和关节置换术等几种其他非心脏表型的风险增加，这些是该国门诊/门诊手术（OS）的主要原因。
我们首次使用 Illumina 的 EPIC 阵列对非洲裔 Val122Ile 携带者进行了全基因组范围内的表观基因组关联研究，用于心脏病和多种 OS（早期疾病指标）。在有心脏病和无心脏病的携带者之间测试了全基因组范围内胞嘧啶-磷酸-鸟嘌呤（CpG）位点的差异甲基化。对顺式-甲基化 QTLs 基因座进行了显著的 CpG 位点调查，随后进行了基因本体论和蛋白质-蛋白质相互作用网络分析。我们还在携带者的二级队列中对显著的 CpG 位点进行了复制。
在基因、、、和 RP11-550A5.2 附近的一个内含子中发现了 5 个差异甲基化位点（≤2.1×10），在与心脏病相关的基因中发现了一个差异甲基化区域，包含和（=1.1×10）。对于 OS，我们观察到 2 个位于和中的位点、2 个位于内含子区域的其他位点（≤1.8×10）以及 3 个重叠、、和（≤3.9×10）的区域。功能蛋白质相互作用模块分析确定了与心脏病相关的（=0.001）。与一个显著的 CpG 位点（cg18546846 和 cg06641417；<0.05）相关的 6 个顺式甲基化 QTLs 存在于外部 TTR（转甲状腺素蛋白）淀粉样变性活检确认病例的队列中。鉴定的基因参与淀粉样沉积物的转运和清除（、、）；心脏纤维化（）；和肌肉组织调节（、）。
这些发现强调了复杂淀粉样蛋白电路与 Val122Ile 多种症状之间的联系。
