ImportanceIndividual cohort studies concur that the amyloidogenic V142I variant of the transthyretin (TTR) gene, present in 3% to 4% of US Black individuals, increases heart failure (HF) and mortality risk. Precisely defining carrier risk across relevant clinical outcomes and estimating population burden of disease are important given established and emerging targeted treatments.ObjectivesTo better define the natural history of disease in carriers across mid to late life, assess variant modifiers, and estimate cardiovascular burden to the US population.Design, Setting, and ParticipantsA total of 23 338 self-reported Black participants initially free from HF were included in 4 large observational studies across the US (mean [SD], 15.5 [8.2] years of follow-up). Data analysis was performed between May 2023 and February 2024.ExposureV142I carrier status (n = 754, 3.2%).Main Outcomes and MeasuresHospitalizations for HF (including subtypes of reduced and preserved ejection fraction) and all-cause mortality. Outcomes were analyzed by generating 10-year hazard ratios for each age between 50 and 90 years. Using actuarial methods, mean survival by carrier status was estimated and applied to the 2022 US population using US Census data.ResultsAmong the 23 338 participants, the mean (SD) age at baseline was 62 (9) years and 76.7% were women. Ten-year carrier risk increased for HF hospitalization by age 63 years, predominantly driven by HF with reduced ejection fraction, and 10-year all-cause mortality risk increased by age 72 years. Only age (but not sex or other select variables) modified risk with the variant, with estimated reductions in longevity ranging from 1.9 years (95% CI, 0.6-3.1) at age 50 to 2.8 years (95% CI, 2.0-3.6) at age 81. Based on these data, 435 851 estimated US Black carriers between ages 50 and 95 years are projected to cumulatively lose 957 505 years of life (95% CI, 534 475-1 380 535) due to the variant.Conclusions and RelevanceAmong self-reported Black individuals, male and female V142I carriers faced similar and substantial risk for HF hospitalization, predominantly with reduced ejection fraction, and death, with steep age-dependent penetrance. Delineating the individual contributions of, and complex interplay among, the V142I variant, ancestry, the social construct of race, and biological or social determinants of health to cardiovascular disease merits further investigation.

中文翻译：

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V142I 运甲状腺素蛋白变体的心血管负担

重要性 个体队列研究一致认为转甲状腺素蛋白的淀粉样变 V142I 变体（总温度) 基因存在于 3% 至 4% 的美国黑人中，会增加心力衰竭 (HF) 和死亡风险。考虑到已建立的和新兴的靶向治疗，准确定义相关临床结果的携带者风险并估计人群疾病负担非常重要。目标更好地定义中晚年携带者疾病的自然史，评估变异修饰因素并估计美国的心血管负担人群.设计、环境和参与者美国各地的 4 项大型观察性研究纳入了总共 23 338 名自我报告的最初没有心力衰竭的黑人参与者（平均 [SD]，15.5 [8.2] 年随访）。数据分析于 2023 年 5 月至 2024 年 2 月期间进行。暴露 V142I 携带者状态（n = 754，3.2%）。主要结果和措施心衰住院（包括射血分数降低和保留的亚型）和全因死亡率。通过生成 50 至 90 岁之间每个年龄的 10 年风险比来分析结果。使用精算方法，根据携带者状态估计平均生存率，并使用美国人口普查数据应用于 2022 年美国人口。结果在 23 338 名参与者中，基线平均 (SD) 年龄为 62 (9) 岁，其中 76.7% 为女性。 63 岁时，因心力衰竭住院的 10 年携带者风险增加，主要是由射血分数降低的心力衰竭驱动，而 72 岁时，10 年全因死亡风险增加。只有年龄（而不是性别或其他选择变量）改变了该变异的风险，估计寿命缩短范围为 50 岁时的 1.9 年（95% CI，0.6-3.1）至 2.8 岁（95% CI，2.0-3.6） 81 岁。根据这些数据，预计 435 851 名年龄在 50 岁至 95 岁之间的美国黑人携带者预计将因该变异而累计损失 957 505 岁（95% CI，534 475-1 380 535）。结论和相关性在自我报告的黑人个体中，男性和女性 V142I 携带者面临相似且巨大的心力衰竭住院风险，主要表现为射血分数降低和死亡，且外显率与年龄相关。描述 V142I 变体、血统、种族社会结构以及健康的生物或社会决定因素对心血管疾病的个体贡献以及它们之间复杂的相互作用值得进一步研究。