Division of Cardiovascular Disease, University of Alabama, Birmingham.
Department of Epidemiology, University of Alabama, Birmingham.
JAMA. 2022 Apr 12;327(14):1368-1378. doi: 10.1001/jama.2022.2896.
A genetic variant in the TTR gene (rs76992529; Val122Ile), present more commonly in individuals with African ancestry (population frequency: 3%-4%), causes misfolding of the tetrameric transthyretin protein complex that accumulates as extracellular amyloid fibrils and results in hereditary transthyretin amyloidosis.
To estimate the association of the amyloidogenic Val122Ile TTR variant with the risk of heart failure and mortality in a large, geographically diverse cohort of Black individuals.
DESIGN, SETTING, AND PARTICIPANTS: Retrospective population-based cohort study of 7514 self-identified Black individuals living in the US participating in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study with genetic data available and without heart failure at baseline. The participants were enrolled at the baseline visit (2003-2007). The end of follow-up for the majority of outcomes was on December 31, 2018. All-cause mortality data were available through December 31, 2020.
TTR Val122Ile (rs76992529) genotype.
The primary outcome was incident heart failure (first hospitalization for heart failure or death due to heart failure). The secondary outcomes were heart failure mortality, cardiovascular mortality, and all-cause mortality. The multivariable Cox proportional hazards regression analyses were adjusted for genetic ancestry and demographic, clinical, and social factors.
Among 7514 Black participants (median age, 64 years [IQR, 57-70 years]; 61% women), the population frequency of the TTR Val122Ile variant was 3.1% (232 variant carriers and 7282 noncarriers). During a median follow-up of 11.1 years (IQR, 5.9-13.5 years), incident heart failure occurred in 535 individuals (34 variant carriers and 501 noncarriers) and the incidence of heart failure was 15.64 per 1000 person-years among variant carriers vs 7.16 per 1000 person-years among noncarriers (adjusted hazard ratio [HR], 2.43 [95% CI, 1.71-3.46]; P < .001). Deaths due to heart failure occurred in 141 individuals (13 variant carriers and 128 noncarriers) and the incidence of heart failure mortality was 6.11 per 1000 person-years among variant carriers vs 1.85 per 1000 person-years among noncarriers (adjusted HR, 4.19 [95% CI, 2.33-7.54]; P < .001). Deaths due to cardiovascular causes occurred in 793 individuals (34 variant carriers and 759 noncarriers) and the incidence of cardiovascular death was 15.18 per 1000 person-years among variant carriers vs 10.61 per 1000 person-years among noncarriers (adjusted HR, 1.69 [95% CI, 1.19-2.39]; P = .003). Deaths due to any cause occurred in 2715 individuals (100 variant carriers and 2615 noncarriers) and the incidence of all-cause mortality was 41.46 per 1000 person-years among variant carriers vs 33.94 per 1000 person-years among noncarriers (adjusted HR, 1.46 [95% CI, 1.19-1.78]; P < .001). There was no significant interaction between TTR variant carrier status and sex on incident heart failure and the secondary outcomes.
Among a cohort of Black individuals living in the US, being a carrier of the TTR Val122Ile variant was significantly associated with an increased risk of heart failure.
TTR 基因（rs76992529；Val122Ile）中的一个遗传变异体在具有非洲血统的个体中更为常见（人群频率：3%-4%），导致四聚体转甲状腺素蛋白复合物的错误折叠，复合物积累为细胞外淀粉样纤维，导致遗传性转甲状腺素蛋白淀粉样变性。
在一个大型、地理上多样化的美国黑人个体队列中，评估淀粉样变性 Val122Ile TTR 变体与心力衰竭和死亡率的风险之间的关联。
设计、地点和参与者：这是一项回顾性基于人群的队列研究，纳入了 7514 名自认为是黑人的个体，他们居住在美国，参加了 REGARDS（地理和种族差异中风研究）研究，并且有可用的遗传数据，在基线时没有心力衰竭。参与者在基线访视（2003-2007 年）时入组。大多数结局的随访终点是 2018 年 12 月 31 日。所有原因死亡率数据可获得至 2020 年 12 月 31 日。
TTR Val122Ile（rs76992529）基因型。
主要结局是心力衰竭事件（心力衰竭首次住院或心力衰竭死亡）。次要结局是心力衰竭死亡率、心血管死亡率和全因死亡率。多变量 Cox 比例风险回归分析调整了遗传祖先和人口统计学、临床和社会因素。
在 7514 名黑人参与者中（中位年龄 64 岁[IQR，57-70 岁]；61%为女性），TTR Val122Ile 变体的人群频率为 3.1%（232 名变体携带者和 7282 名非携带者）。在中位随访 11.1 年（IQR，5.9-13.5 年）期间，34 名变体携带者中有 535 人发生心力衰竭事件（34 名变体携带者和 501 名非携带者），变体携带者的心力衰竭发生率为每 1000 人年 15.64 例，而非携带者为每 1000 人年 7.16 例（调整后的危险比[HR]，2.43[95%CI，1.71-3.46]；P<0.001）。141 名个体因心力衰竭死亡（13 名变体携带者和 128 名非携带者），变体携带者的心力衰竭死亡率为每 1000 人年 6.11 例，而非携带者为每 1000 人年 1.85 例（调整后的 HR，4.19[95%CI，2.33-7.54]；P<0.001）。793 名个体因心血管原因死亡（34 名变体携带者和 759 名非携带者），变体携带者的心血管死亡率为每 1000 人年 15.18 例，而非携带者为每 1000 人年 10.61 例（调整后的 HR，1.69[95%CI，1.19-2.39]；P=0.003）。2715 名个体因任何原因死亡（100 名变体携带者和 2615 名非携带者），变体携带者的全因死亡率为每 1000 人年 41.46 例，而非携带者为每 1000 人年 33.94 例（调整后的 HR，1.46[95%CI，1.19-1.78]；P<0.001）。TTR 变体携带者状态和性别之间没有显著的交互作用，影响心力衰竭和次要结局的发生。
在美国黑人个体队列中，TTR Val122Ile 变体的携带者与心力衰竭风险增加显著相关。
