Molecular Neurobiology

, Volume 55, Issue 5, pp 3676–3683 | Cite as

A Trans-acting Factor May Modify Age at Onset in Familial Amyloid Polyneuropathy ATTRV30M in Portugal

  • Miguel Alves-Ferreira
  • Teresa Coelho
  • Diana Santos
  • Jorge Sequeiros
  • Isabel Alonso
  • Alda Sousa
  • Carolina Lemos


Although all familial amyloid polyneuropathy (FAP) ATTRV30M patients carry the same causative mutation, early (<40) and late-onset forms (≥50 years) of FAP may coexist in the same family. However, this variability in age at onset is still unexplained. To identify modifiers closely linked to the TTR locus that may in part be associated with age at onset of FAP ATTRV30M, in particular in a group of very early-onset patients (≤30 years) when compared with late-onset individuals. A clinical genetic study at a referral center comprising a sample of 910 Portuguese individuals includes 589 Val30Met carriers, 102 spouses, and 189 controls from the general population. Haplotype analysis was performed, using eight intragenic single nucleotide polymorphisms (SNPs) at the TTR locus. We compared haplotypes frequency in FAP samples and controls and in parent-offspring pairs using appropriated statistical analysis. Haplotype A was the most common in the general population. Noteworthy, haplotype C was more frequent in early-onset (<40) than in late-onset patients (≥50 years) (p = 0.012). When comparing allelic frequencies of each SNP within haplotype C between “very early” (≤30 years) and late-onset (≥50 years) cases, the A allele of rs72922947 was associated with an earlier onset (p = 0.009); this remained significant after a permutation-based correction. Also, the heterozygous genotype (GA) for this SNP was associated with a decrease in mean age at onset of 8.6 years (p = 0.014). We found a more common haplotype (A) linked to the Val30Met variant and a possible modulatory trans effect on age at onset. These findings may lead to potential therapeutical targets.


Familial amyloid polyneuropathy (FAP) Transthyretin-related amyloidosis Trans effect Transthyretin (TTR) Age at onset Haplotype 



The authors thank all the patients and families for participating in this study and Vanessa Costa (from Unidade Corino de Andrade (UCA), Centro Hospitalar do Porto (CHP)) for all the help in data collection. This work was supported by grants of Fundação para a Ciência e Tecnologia, FCT [PTDC/SAU-GMG/100240/2008 and PEsT], cofunded by ERDF and COMPETE; and by Financiamento Plurianual de Unidades de Investigação (FCT).

Compliance with Ethical Standards

Conflict of Interest

M.A.F. and D. S. have received research support from a FCT fellowship (SFRH/BD/101352/2014 and SFRH/BD/91160/2012, respectively). T. C.’s institution has received support from FoldRx Pharmaceuticals, which was acquired by Pfizer Inc. in October 2010; T. C. has served on the scientific advisory board of Pfizer Inc. and received funding from Pfizer Inc. for scientific meeting expenses (travel, accommodations, and registration). She currently serves on the THAOS (natural history disease registry) scientific advisory board. J. S., I. A., A. S., and C. L. report no disclosures.


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.UnIGENe, IBMC—Institute for Molecular and Cell Biology; Institute for Research and Innovation in Health Sciences (i3S)University of PortoPortoPortugal
  2. 2.ICBAS—Instituto Ciências Biomédicas Abel SalazarUniversidade do PortoPortoPortugal
  3. 3.Unidade Corino de Andrade (UCA), Centro Hospitalar do Porto (CHP)PortoPortugal
  4. 4.UnIGENe, IBMC-i3SPortoPortugal

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