Abstract

Background: Destabilised transthyretin (TTR) can result in the progressive, fatal disease transthyretin-mediated (ATTR) amyloidosis. A stabilising TTR mutation, T119M, is the basis for a therapeutic strategy to reduce destabilised TTR. Recently, T119M was associated with extended lifespan and lower risk of cerebrovascular disease in a Danish cohort. We aimed to determine whether this finding could be replicated in the UK Biobank.

Methods: TTR T119M carriers were identified in the UK Biobank, a large prospective cohort of ∼500,000 individuals. Association between T119M genotype and inpatient diagnosis of vascular disease, cardiovascular disease, cerebrovascular disease, and mortality was analysed.

Results: Frequency of T119M within the white UK Biobank population (n = 337,148) was 0.4%. Logistic regression comparing T119M carriers to non-carriers found no association between T119M and vascular disease (odds ratio [OR] = 1.08; p = .27), cardiovascular disease (OR = 1.08; p = .31), cerebrovascular disease (OR = 1.1; p = .42), or death (OR = 1.2; p = .06). Cox proportional hazards regression showed similar results (hazard ratio >1, p>.05). Age at death and vascular disease diagnosis were similar between T119M carriers and non-carriers (p = .12 and p = .38, respectively).

Conclusions: There was no association between the TTR T119M genotype and risk of vascular disease or death in a large prospective cohort study, indicating that TTR tetramer stabilisation through T119M is not protective in this setting.

摘要

背景：不稳定的运甲状腺素蛋白（TTR）可能导致进行性致命疾病，运甲状腺素蛋白介导的（ATTR）淀粉样变性。稳定的TTR突变T119M是减少不稳定的TTR的治疗策略的基础。最近，在丹麦人群中，T119M与延长寿命和降低脑血管疾病的风险有关。我们旨在确定这一发现是否可以在UK Biobank中复制。

方法： 在英国生物库中鉴定出TTR T119M携带者，这是一个约500,000人的大型前瞻性队列。分析了T119M基因型与血管疾病，心血管疾病，脑血管疾病和死亡率的住院诊断之间的关联。

结果：英国生物库中的白人人群（n  = 337,148）中T119M的发生率为0.4％。通过逻辑回归比较T119M携带者和非携带者，发现T119M与血管疾病（优势比[OR] = 1.08；p =  .27），心血管疾病（OR = 1.08；p =  .31），脑血管疾病（OR = 1.1；p =  0.42）或死亡（OR = 1.2；p =  .06）。Cox比例风险回归显示相似的结果（风险比> 1，p > .05）。T119M携带者和非携带者的死亡年龄和血管疾病诊断相似（分别为p =  0.12和p =  0.38）。

结论：在一项大型前瞻性队列研究中，TTR T119M基因型与血管疾病或死亡风险之间没有关联，表明通过T119M稳定TTR四聚体在这种情况下没有保护作用。