• Margaret M Parker, Simina Ticau, James Butler, David Erbe, Madeline Merkel, Emre Aldinc, Gregory Hinkle, and Paul Nioi.
• Alnylam Pharmaceuticals, Cambridge, MA, USA.
• Amyloid. 2020 Sep 1; 27 (3): 184-190.

AbstractBackground: 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.

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