Genetic Stabilization of Transthyretin, Cerebrovascular Disease, and Life Expectancy

Abstract

Objective-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. Approach and Results-We included 68 602 participants from 2 prospective studies of the general population. We genotyped for 2 stabilizing genetic variants in the transthyretin gene (TTR), R104H and T119M, and determined the association of genotypes with plasma levels of transthyretin, measures of thyroid function, risk of vascular disease, and life expectancy. During a mean follow-up of 32 years, 10 636 participants developed vascular disease. We identified 321 heterozygotes for T119M (frequency, 0.47%); R104H was not detected. First, mean plasma transthyretin and thyroxine levels were increased by 17% (26 µg/mL) and 20% (19 nmol/L), respectively, in heterozygotes versus noncarriers (P=0.007 and P<0.0001), demonstrating functionality of this variant in the general population. Second, corresponding hazard ratios were 0.70 (95% confidence interval, 0.51-0.97) for all vascular diseases, 0.85 (0.59-1.23) for cardiovascular disease, 0.45 (0.25-0.81) for cerebrovascular disease, 0.47 (0.25-0.88) for ischemic cerebrovascular disease, and 0.31 (0.04-2.22) for hemorrhagic stroke. The cumulative incidence of cerebrovascular disease as a function of age was decreased in heterozygotes versus noncarriers (P=0.005). Third, median age at death from all causes, from vascular and cerebrovascular diseases, and after diagnosis of vascular disease, and median age at diagnosis of vascular disease, was increased by 5 to 10 years in heterozygotes versus noncarriers (P=0.002-0.05). Conclusions-These results are compatible with an association between genetic stabilization of transthyretin and decreased risk of cerebrovascular disease, and with increased life expectancy in the general population.

Targeting protein aggregation for the treatment of degenerative diseases

“…The recently renamed WT TTR Amyloidosis—formally called senile systemic amyloidosis (SSA)—results in a cardiomyopathy that affects as much as 15% of the population exceeding 80 years of age 288, 289, 293, 294 . It was recently reported that WT TTR aggregation in and around the vasculature may be a more prominent cause of vascular diseases than previously thought 295 .…”

Transthyretin: a multifaceted protein

“…An epidemiologic study revealed that the population heterozygous for T119M (a TTR mutant with increased tetrameric stability) have decreased risk of cerebrovascular disease and increased life expectancy when compared with noncarriers individuals (101).…”

Quantification of Transthyretin Kinetic Stability in Human Plasma Using Subunit Exchange

“…8 WT TTR aggregation on blood vessels also appears to play a central role in a variety of vascular diseases. 37 The autosomal dominant familial TTR amyloidoses present as a polyneuropathy [familial amyloid polyneuropathy (FAP) 38 ] and/or a cardiomyopathy (familial amyloid cardiomyopathy 7,39 ), depending on the identity of the TTR mutation the patient has inherited of the >100 disease-linked variants. 40,41 …”