ImportanceTransthyretin tetramer destabilization is the rate-limiting step in the development of transthyretin cardiac amyloidosis, an underrecognized contributor to mortality in older adults.ObjectiveTo test the hypothesis that transthyretin tetramer destabilization is associated with all-cause and cardiovascular mortality in the general population.Design, Setting, and ParticipantsIn this cohort study including individuals aged 20 to 80 years, genetic data were analyzed from 2 similar prospective studies of the Danish general population, the Copenhagen City Heart Study (CCHS) and the Copenhagen General Population Study (CGPS). Observational data from a subsample of the same studies where transthyretin was measured consecutively were also analyzed. In both studies, individuals were followed up from the examination date (1991-1994 in CCHS and 2003-2015 in CGPS) until death or the end of follow-up in December 2018. Data were analyzed from November 1, 2023, to August 15, 2024.ExposuresMissense variants in TTR associated with increasing transthyretin tetramer destabilization in primary genetic analyses, and plasma transthyretin level in secondary observational analyses.Main Outcomes and MeasuresAll-cause and cardiovascular mortality identified from the national Danish Civil Registration System and the national Danish Register of Causes of Death.ResultsA total of 102 204 individuals (median [IQR] age, 57 [47-66] years; 56 445 [55%] female) were included. Median follow-up was 10 years (range, <1-27 years). In genetic analyses, p.T139M, a transthyretin tetramer stabilizing variant that is more stable than noncarriers’ tetramer stability, was used as the reference. For noncarriers who have intermediate tetramer stability and for heterozygotes for amyloidogenic variants (p.V142I, p.H110N, and p.D119N) who have the lowest tetramer stability, respective hazard ratios (HRs) were 1.37 (95% CI, 1.06-1.77) and 1.65 (95% CI, 0.95-2.88) for all-cause mortality (P for trend = .01), and 1.63 (95% CI, 0.92-2.89) and 2.23 (95% CI, 0.78-6.34) for cardiovascular mortality (P for trend = .06). Furthermore, compared with p.T139M, plasma transthyretin decreased stepwise by TTR genotype: −18% for noncarriers and −29% for heterozygotes for amyloidogenic variants (p.V142I, p.H110N, p.D119N; P for trend < .001). Therefore, genetically determined, increasingly lower plasma transthyretin could be considered a surrogate marker for transthyretin tetramer destabilization. Observationally, among 19 619 individuals, noncarriers with plasma transthyretin concentrations less than 20 mg/dL vs 20 to 40 mg/dL had HRs of 1.12 (95% CI, 1.02-1.23) for all-cause mortality and 1.16 (95% CI, 0.97-1.39) for cardiovascular mortality.Conclusions and RelevanceTransthyretin tetramer destabilization was associated with all-cause and cardiovascular mortality in the Danish general population. These findings may suggest a need for large-scale assays to measure transthyretin destabilization for detection of transthyretin amyloidosis before clinical manifestations emerge, since early treatment improves the prognosis.

中文翻译：

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转甲状腺素蛋白四聚体不稳定和普通人群死亡率增加


重要性转甲状腺素蛋白四聚体不稳定是转甲状腺素蛋白心脏淀粉样变性发展的限速步骤，转甲状腺素蛋白心脏淀粉样变性是导致老年人死亡的一个未被充分认识的原因。目的检验转甲状腺素蛋白四聚体不稳定与普通人群全因死亡率和心血管死亡率相关的假设。设计、设置和参与者在这项包括 20 至 80 岁个体的队列研究中，分析了来自丹麦普通人群的 2 项类似的前瞻性研究的遗传数据，即哥本哈根城市心脏研究 （CCHS） 和哥本哈根一般人群研究 （CGPS）。还分析了连续测量甲状腺素运载蛋白的相同研究的子样本的观察数据。在这两项研究中，个体从检查日期 （CCHS 为 1991-1994 年，CGPS 为 2003-2015） 开始随访，直至死亡或 2018 年 12 月随访结束。数据分析时间为 2023 年 11 月 1 日至 2024 年 8 月 15 日。主要结局和措施从丹麦国家民事登记系统和丹麦国家死因登记处确定的全因死亡率和心血管死亡率结果共纳入 102 204 人 （中位 [IQR] 年龄，57 [47-66] 岁;56 445 [55%] 女性）。中位随访时间为 10 年（范围，<1-27 岁）。在遗传分析中，p.T139M 是一种转甲状腺素蛋白四聚体稳定变体，比非载体的四聚体稳定性更稳定，被用作参考。 对于具有中等四聚体稳定性的非携带者和具有最低四聚体稳定性的淀粉样蛋白生成变异（p.V142I、p.H110N 和 p.D119N）的杂合子，全因死亡率（趋势 P = .01）的风险比 （HR） 分别为 1.37（95% CI，1.06-1.77）和 1.65（95% CI，0.95-2.88），以及 1.63（95% CI，0.92-2.89）和 2.23（95% CI， 0.78-6.34） 的心血管死亡率 （P 趋势 = .06）。此外，与 p.T139M 相比，血浆转甲状腺素蛋白通过 TTR 基因型逐步降低：淀粉样蛋白生成变体的非携带者为 -18%，杂合子为 -29%（p.V142I、p.H110N、p.D119N;P 代表趋势 < .001）。因此，遗传决定的、越来越低的血浆转甲状腺素蛋白可被视为转甲状腺素蛋白四聚体不稳定的替代标志物。据观察，在 19 619 名个体中，血浆转甲状腺素蛋白浓度低于 20 mg/dL 与 20 至 40 mg/dL 的非携带者全因死亡率的 HR 为 1.12 （95% CI，1.02-1.23），心血管死亡率为 1.16 （95% CI，0.97-1.39）。结论和相关性转甲状腺素蛋白四聚体不稳定与丹麦普通人群的全因死亡率和心血管死亡率相关。这些发现可能表明需要进行大规模检测来测量转甲状腺素蛋白不稳定，以便在临床表现出现之前检测转甲状腺素蛋白淀粉样变性，因为早期治疗可改善预后。