Transthyretin-stabilizing mutation T119M is not associated with protection against vascular disease or death in the UK Biobank

Background Destabilized transthyretin (TTR) can result in the progressive, fatal disease transthyretin-mediated (ATTR) amyloidosis. A stabilizing TTR mutation, T119M, is the basis for a therapeutic strategy to reduce destabilized 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 analyzed. 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 stabilization through T119M is not protective in this setting.