Abstract 12017: Genetically Determined Transthyretin Levels, Transthyretin Stability, and Risk of Vascular Disease
Introduction: Transthyretin can cause amyloidosis due to destabilization of transthyretin(TTR) tetramers in plasma.
Objective: We tested the hypothesis that genetic destabilization of TTR associates inversely with plasma levels of TTR and risk of vascular disease in the general population.
Methods: We resequenced TTR in 10,396 participants in a general population study, the Copenhagen City Heart Study, and genotyped all identified nonsynonymous variants in the Copenhagen General Population Study(n=58,206). We determined the association of TTR genotypes with plasma levels of TTR, TTR stability score, and with risk of vascular disease.
Results: During a median follow-up of 32 years, 10,636 participants developed vascular disease. We identified 8 functional variants (S8F, V30M, T59I, H90N, D99N, I107T, T119M and V122I) in TTR in a total of 68,602 participants (6:1000). Genotype was associated with plasma levels of TTR and with the combined stability score: Compared to wildtype, carriers of destabilizing variants had lower plasma TTR levels(mean reduction: 37%), whereas carriers of the stabilizing variant, T119M, had higher TTR levels(mean increase: 26%) (P for trend≤0.0001for unstable variants versus wildtype versus stable variants). The cumulative incidence of vascular disease as a function of age and TTR genotype increased inversely with plasma levels of TTR and with stability score(stable versus wildtype versus unstable; log-rank P=0.004). The corresponding risk of vascular disease compared to wildtype was increased by 78% in carriers of unstable variants[hazard ratio: 1.78(1.09-2.91)], and decreased by 29%[0.71(95% CI:0.51-0.98)] in carriers of stable variants, implying a more than 100% increase in risk of vascular disease from stable to unstable variants.
Conclusion: Genetic variation in TTR identified in 6 per 1000 individuals in the general population associates with TTR levels, TTR stability, and inversely with risk of vascular disease, suggesting a role for vascular amyloid deposition in the general population. This is clinically important, because TTR stabilizing drugs are currently under development for the treatment of TTR amyloidosis.
- © 2013 by American Heart Association, Inc.