V30M和V122I转甲状腺蛋白淀粉样变的病理生理特征与症状发展的回顾性分析

IF 2.5 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS

IJC Heart and Vasculature Pub Date : 2025-04-15 DOI:10.1016/j.ijcha.2025.101663

Sameer U. Kini , Ha My Thi Vy , Madhav Subramanian , Parasuram M. Krishnamoorthy , Son Q. Duong , Ghislain Rocheleau , Jagat Narula , Ron Do , Girish N. Nadkarni

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引用次数: 0

摘要

背景Val30Met （V30M）和Val122Ile （V122I）转甲状腺素（TTR）突变常引起遗传性淀粉样转甲状腺素淀粉样变性（hATTR）。由于症状逐渐使人衰弱，如果不治疗可能致命，因此hATTR患者的晚期诊断导致生存率低。这项对微阵列和生物库数据的回顾性分析有助于建立早期hatr检测的临床生物标志物。方法对183名葡萄牙V30M携带者进行基因分析，发现免疫标记异常。在西奈山BioMe生物库的非洲裔美国人（AA）和西班牙裔/拉丁裔美国人（HA）中（n = 28,718），一项病例对照式全现象关联研究(PheWAS；表型和超声心动图性状（β系数[95% CI]）的比值比（95%置信区间）决定了基因多效性。结果96例（52.4%）有症状，表达中性粒细胞活性上调(p <；10-16)， IL-6/JAK/STAT3信号通路(p <；10-3)，与无症状患者相比，CD4+T细胞表达下调（p = 0.009）。在BioMe中，562例（2.0%）为V122I携带者，与心力衰竭相关(1.71 [1.23-2.39]；P = 0.0014)，淀粉样变性(20.79 [8.42-51.31]；P = 4.67 × 10−11)，继发性/外源性心肌病(17.73 [7.25-43.37]；P = 2.97 × 10−10)，周围神经紊乱(4.14 [2.42-7.09]；P = 2.26 × 10−7)，原发性闭角型青光眼(8.03 [3.15-20.46]；P = 1.27 × 10−5)，女性乳腺恶性肿瘤(4.48 [2.23-9.00]；P = 2.48 × 10−5)，胫骨和腓骨骨折(8.42 [3.25-21.89]；p = 1.19 × 10−5)，腕管综合征(2.62 [1.68-4.11]；p = 2.44 × 10−5)。超声心动图表现为LVEDV升高(15.87 [9.63-22.10]；p = 6.04×10−7)和洛杉矶长度(1.52 [0.69 - -2.35];p = 3.31 × 10−4)。种族分层关联表明AA比HA表现出更严重的心脏异常。本研究确定了症状性V30M携带者的炎症生物标志物上调，以及与V122I相关的表型/超声心动图特征，代表了hATTR病理的合并症。这些标记物可以为将来改进诊断制度提供早期治疗提供基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Associations between pathophysiological traits and symptom development in retrospective analysis of V30M and V122I transthyretin amyloidosis

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Associations between pathophysiological traits and symptom development in retrospective analysis of V30M and V122I transthyretin amyloidosis

Background

The Val30Met (V30M) and Val122Ile (V122I) transthyretin (TTR) mutations often beget hereditary amyloid transthyretin amyloidosis (hATTR). Since symptoms are progressively debilitating and potentially fatal if untreated, low survival rates result from late diagnoses of hATTR patients. This retrospective analysis of microarray and biobank data helped establish clinical biomarkers for early hATTR detection.

Methods

In a Portuguese sample of V30M carriers (n = 183), gene profiling identified dysregulated immune markers. Among African Americans (AA) and Hispanic/Latinx Americans (HA) from the Mount Sinai BioMe Biobank (n = 28,718), a case-control style Phenome-Wide Association Study (PheWAS; odds ratio [95% confidence interval]) of V122I for phenotypic and echocardiogram traits (β coefficients [95 % CI]) determined gene pleiotropy.

Results

Among V30M profiles, 96 (52.4%) were symptomatic, expressing upregulated neutrophil activity (p < 10^-16), IL-6/JAK/STAT3 signaling (p < 10^-3), and downregulated CD4⁺T cell expression (p = 0.009), compared to their asymptomatic counterparts. In BioMe, 562 (2.0%) were V122I carriers, demonstrating associations with heart failure (1.71 [1.23–2.39]; p = 0.0014), amyloidosis (20.79 [8.42–51.31]; p = 4.67 × 10⁻¹¹), secondary/extrinsic cardiomyopathies (17.73 [7.25–43.37]; p = 2.97 × 10⁻¹⁰), peripheral nerve disorders (4.14 [2.42–7.09]; p = 2.26 × 10⁻⁷), primary angle-closure glaucoma (8.03 [3.15–20.46]; p = 1.27 × 10⁻⁵), malignant neoplasm of the female breast (4.48 [2.23–9.00]; p = 2.48 × 10⁻⁵), fracture of tibia and fibula (8.42 [3.25–21.89]; p = 1.19 × 10⁻⁵), and Carpal tunnel syndrome (2.62 [1.68–4.11]; p = 2.44 × 10⁻⁵). Echocardiographic presentations included higher LVEDV (15.87 [9.63–22.10]; p = 6.04 × 10⁻⁷) and LA length (1.52 [0.69–2.35]; p = 3.31 × 10⁻⁴). Race-stratified associations identified that AA presented more severe cardiac abnormalities than HA.

Conclusions

This study identified inflammatory biomarkers upregulated in symptomatic V30M carriers and phenotypic/echocardiographic traits associated with V122I, representing comorbidities of hATTR pathology. Such markers can provide the basis for future improvements in diagnostic regimes to deliver early therapies.

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来源期刊

IJC Heart and Vasculature Medicine-Cardiology and Cardiovascular Medicine

CiteScore

4.90

自引率

10.30%

发文量

216

审稿时长

56 days

期刊介绍： IJC Heart & Vasculature is an online-only, open-access journal dedicated to publishing original articles and reviews (also Editorials and Letters to the Editor) which report on structural and functional cardiovascular pathology, with an emphasis on imaging and disease pathophysiology. Articles must be authentic, educational, clinically relevant, and original in their content and scientific approach. IJC Heart & Vasculature requires the highest standards of scientific integrity in order to promote reliable, reproducible and verifiable research findings. All authors are advised to consult the Principles of Ethical Publishing in the International Journal of Cardiology before submitting a manuscript. Submission of a manuscript to this journal gives the publisher the right to publish that paper if it is accepted. Manuscripts may be edited to improve clarity and expression.