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Transthyretin-stabilizing mutation T119M is not associated with protection against vascular disease or death in the UK Biobank

Margaret M. Parker, Simina Ticau, James Butler, David Erbe, Madeline Merkel, Emre Aldinc, Gregory Hinkle, Paul Nioi
doi: https://doi.org/10.1101/771626
Margaret M. Parker
Alnylam Pharmaceuticals, Cambridge, MA, USA
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Simina Ticau
Alnylam Pharmaceuticals, Cambridge, MA, USA
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James Butler
Alnylam Pharmaceuticals, Cambridge, MA, USA
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David Erbe
Alnylam Pharmaceuticals, Cambridge, MA, USA
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Madeline Merkel
Alnylam Pharmaceuticals, Cambridge, MA, USA
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Emre Aldinc
Alnylam Pharmaceuticals, Cambridge, MA, USA
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Gregory Hinkle
Alnylam Pharmaceuticals, Cambridge, MA, USA
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Paul Nioi
Alnylam Pharmaceuticals, Cambridge, MA, USA
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  • For correspondence: pnioi@alnylam.com
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Abstract

Background Destabilized transthyretin (TTR) can result in the progressive, fatal disease transthyretin-mediated (ATTR) amyloidosis. A stabilizing TTR mutation, T119M, is the basis for a therapeutic strategy to reduce destabilized TTR. Recently, T119M was associated with extended lifespan and lower risk of cerebrovascular disease in a Danish cohort. We aimed to determine whether this finding could be replicated in the UK Biobank.

Methods TTR T119M carriers were identified in the UK Biobank, a large prospective cohort of ∼500,000 individuals. Association between T119M genotype and inpatient diagnosis of vascular disease, cardiovascular disease, cerebrovascular disease, and mortality was analyzed.

Results Frequency of T119M within the white UK Biobank population (n=337,148) was 0.4%. Logistic regression comparing T119M carriers to non-carriers found no association between T119M and vascular disease (odds ratio [OR]=1.08; p=.27), cardiovascular disease (OR=1.08; p=.31), cerebrovascular disease (OR=1.1; p=.42), or death (OR=1.2; p=.06). Cox proportional hazards regression showed similar results (hazard ratio>1, p>.05). Age at death and vascular disease diagnosis were similar between T119M carriers and non-carriers (p=.12 and p=.38, respectively).

Conclusions There was no association between the TTR T119M genotype and risk of vascular disease or death in a large prospective cohort study, indicating that TTR tetramer stabilization through T119M is not protective in this setting.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted September 21, 2019.
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Transthyretin-stabilizing mutation T119M is not associated with protection against vascular disease or death in the UK Biobank
Margaret M. Parker, Simina Ticau, James Butler, David Erbe, Madeline Merkel, Emre Aldinc, Gregory Hinkle, Paul Nioi
bioRxiv 771626; doi: https://doi.org/10.1101/771626
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Transthyretin-stabilizing mutation T119M is not associated with protection against vascular disease or death in the UK Biobank
Margaret M. Parker, Simina Ticau, James Butler, David Erbe, Madeline Merkel, Emre Aldinc, Gregory Hinkle, Paul Nioi
bioRxiv 771626; doi: https://doi.org/10.1101/771626

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