BACKGROUND Nearly 3% to 4% of Black individuals in the United States carry the transthyretin V142I variant, which increases their risk of heart failure. However, the role of cardiovascular (CV) risk factors (RFs) in influencing the risk of clinical outcomes among V142I variant carriers is unknown. OBJECTIVES This study aimed to assess the impact of CV RFs on the risk of heart failure in V142I carriers. METHODS This study included self-identified Black individuals without prevalent heart failure from 6 TOPMed (Trans-Omics for Precision Medicine) cohorts, the REGARDS (Reasons for Geographic And Racial Differences in Stroke) study, and the All of Us Research Program. The cohort was stratified based on the V142I genotype and the number of CV RFs (hypertension, diabetes, obesity, and hypercholesterolemia). Adjusted Cox models were used to assess the association of heart failure with the V142I genotype and CV RF profile, taking noncarriers with a favorable CV RF profile as reference. RESULTS The cross-sectional analysis, including 1,625 V142I carriers among 48,365 Black individuals, found that the prevalence of CV RFs did not vary by V142I carrier status. In the longitudinal analysis, there were 587 (3.2%) V142I carriers among 18,407 Black individuals (median age: 60 years [Q1-Q3: 52-68 years], 63.0% female). Among carriers, the heart failure risk was attenuated with a favorable (0 or 1 RF) CV RF profile (adjusted HR: 2.26; 95% CI: 1.58-3.23) compared with an unfavorable (3 or 4 RFs) CV RF profile (adjusted HR: 4.14; 95% CI: 2.79-6.14). CONCLUSIONS A favorable CV RF profile lowers but does not abrogate V142I variant-associated heart failure risk. This study highlights the importance of having a favorable CV RF profile among V142I carriers for risk reduction of heart failure.

中文翻译：

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转甲状腺素蛋白 V142I 携带者的心血管危险因素和遗传风险。


背景 在美国，近 3% 至 4% 的黑人携带转甲状腺素蛋白 V142I 变体，这增加了他们患心力衰竭的风险。然而，心血管 （CV） 危险因素 （RFs） 在影响 V142I 变异携带者临床结局风险中的作用尚不清楚。目的 本研究旨在评估 CV RFs 对 V142I 携带者心力衰竭风险的影响。方法 本研究包括来自 6 个 TOPMed（精准医学跨组学）队列、REGARDS（中风地理和种族差异的原因）研究和 All of Us 研究计划的自我认同的无普遍心力衰竭的黑人个体。根据 V142I 基因型和 CV RF（高血压、糖尿病、肥胖和高胆固醇血症）的数量对队列进行分层。调整后的 Cox 模型用于评估心力衰竭与 V142I 基因型和 CV RF 谱的关联，以具有良好 CV RF 谱的非载波为参考。结果 横断面分析包括 1,625 名黑人个体中的 1422 名 V48,365I 携带者，发现 CV RF 的患病率不因 V142I 携带者状态而异。在纵向分析中，18,407 名黑人中有 587 名 （3.2%） V142I 携带者 （中位年龄： 60 岁 [Q1-Q3： 52-68 岁]，63.0% 为女性）。在携带者中，与不利的（3 或 4 个 RF）CV RF 曲线（调整后的 HR：4.14;95% CI：2.79-6.14）相比，良好的 （0 或 1 RF） CV RF 曲线 （调整后的 HR： 2.26;95% CI： 1.58-3.23） 降低了心力衰竭风险。结论良好的 CV RF 曲线可降低但不能消除 V142I 变异相关的心力衰竭风险。本研究强调了 V142I 携带者具有良好的 CV RF 谱对降低心力衰竭风险的重要性。