Abstract 15977: A Stabilizing Variant in Transthyretin, T119M, and Risk of Ischemic Vascular Disease
Background: Senile systemic amyloidosis, which clinically may present as ischemic vascular disease, is a common aging phenomenon caused by deposition of wildtype transthyretin (TTR) fibrils mainly in the heart. A common mutation in TTR, T119M, results in a more stable, less amyloidogenic protein. T119M mimics the effect of Tafamidis; a drug that has been approved recently for the treatment of hereditary TTR-amyloid disease, and Tafamidis is currently in a clinical trial for the senile TTR amyloidosis. We tested the hypothesis that TTR T119M protects against ischemic vascular events in the general population.
Methods: We genotyped T119M in two large cohorts of the general population, the Copenhagen City Heart Study and the Copenhagen General Population Study, totalling app. 70.000 participants, of which 7,146 had ischemic heart disease (IHD) and 4,174 had ischemic cerebrovascular disease (ICVD).
Results: In heterozygotes versus noncarriers, the T119M mutation (present in 1:200), predicted odds ratios (OR) for risk of IHD, ICVD and any ischemic event of 0.88 (95% confidence interval (CI): 0.60-1.30), 0.50 (0.26-0.95), and 0.77 (0.54-1.10), respectively. When stratified by age (<70 or ≥70 years of age), the risk reduction was largest in individuals <70 years (IHD: OR 0.52 (0.27-0.98); ICVD: OR 0.29 (0.09-0.91); any ischemic event: OR 0.48 (0.27-0.83). Furthermore, mean age at event in heterozygotes versus noncarriers was increased by 8, 7, and 7 years, respectively, for IHD (P=0.04), ICVD (P=0.21) and any ischemic event (P=0.02). Finally, age at death and age at death after any ischemic event was increased by 5 and 6 years, respectively (P-values: 0.04 and 0.002).
Conclusion: Compared with noncarriers, TTR T119M associated with reduced risk of ischemic vascular events, with later age at onset of events, with increased age at death, and with increased age at death after any ischemic event. This suggests a potential beneficial effect of stabilizing transthyretin in the general population.
- © 2012 by American Heart Association, Inc.