Genetic stabilization of transthyretin, cerebrovascular disease, and life expectancy

Louise S Hornstrup; Ruth Frikke-Schmidt; Børge G Nordestgaard; Anne Tybjærg-Hansen

doi:10.1161/ATVBAHA.113.301273

Genetic stabilization of transthyretin, cerebrovascular disease, and life expectancy

Louise S Hornstrup, Ruth Frikke-Schmidt, Børge G Nordestgaard, Anne Tybjærg-Hansen

32 Citations (Scopus)

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.

Original language	English
Journal	Arteriosclerosis, Thrombosis, and Vascular Biology
Volume	33
Issue number	6
Pages (from-to)	1441-7
Number of pages	7
ISSN	1079-5642
DOIs	https://doi.org/10.1161/ATVBAHA.113.301273
Publication status	Published - Jun 2013

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10.1161/ATVBAHA.113.301273

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title = "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.",

author = "Hornstrup, {Louise S} and Ruth Frikke-Schmidt and Nordestgaard, {B{\o}rge G} and Anne Tybj{\ae}rg-Hansen",

year = "2013",

month = jun,

doi = "10.1161/ATVBAHA.113.301273",

language = "English",

volume = "33",

pages = "1441--7",

journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",

issn = "1079-5642",

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TY - JOUR

T1 - Genetic stabilization of transthyretin, cerebrovascular disease, and life expectancy

AU - Hornstrup, Louise S

AU - Frikke-Schmidt, Ruth

AU - Nordestgaard, Børge G

AU - Tybjærg-Hansen, Anne

PY - 2013/6

Y1 - 2013/6

N2 - 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.

AB - 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.

U2 - 10.1161/ATVBAHA.113.301273

DO - 10.1161/ATVBAHA.113.301273

M3 - Journal article

C2 - 23580146

SN - 1079-5642

VL - 33

SP - 1441

EP - 1447

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

IS - 6

ER -

Genetic stabilization of transthyretin, cerebrovascular disease, and life expectancy

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