;

:e

NHLBI Exome Sequencing Project (ESP) Exome Variant Server. evs.gs.washington.edu/EVS/. Accessed November

Significance

Transthyretin can cause amyloidosis attributable to destabilization of transthyretin tetramers in plasma. We tested the hypothesis that genetic stabilization of transthyretin associates with reduced risk of vascular disease and increased life expectancy. Our novel findings include the following: (1) One in 200 individuals (0.47%) is heterozygous for TTR T119M, a variant known to stabilize transthyretin tetramers; (2) T119M is associated with increases in transthyretin and total thyroxine levels in heterozygotes versus noncarriers, providing direct evidence for the stabilizing function of this variant in vivo; (3) T119M heterozygotes have reduced risk of vascular disease, mainly cerebrovascular disease; (4) T119M heterozygotes have increased life expectancy overall and after diagnosis of vascular disease. These results have potential clinical implications, because they suggest that current drugs, which inhibit the amyloid cascade by mimicking the stabilizing effect of T119M on transthyretin, may slow the progression of vascular deposits leading to cerebrovascular disease in the general population.