Familial amyloid polyneuropathy in Portugal: New genes modulating age-at-onset.
Familial amyloid polyneuropathy (FAP ATTRV30M) shows a wide variation in age-at-onset (AO) between clusters, families, and among generations. We will now explore some candidate genes involved in altered disease pathways in order to assess their role as genetic modifiers of AO, using a family-centered approach.



We analyzed 62 tagging SNPs from nine genes-NGAL,MMP-9,BGN,MEK1,MEK2,ERK1,ERK2,HSP27, andYWHAZ- in a sample of 318 V30M Portuguese patients (106 families), currently under follow-up. A generalized estimating equation analysis was used to take into account nonindependency of AO between relatives. Also, anin silicoanalysis was performed in order to assess the functional impact of significant variants associated with AO.



We found for the first time variants from six genes (NGAL,BGN(in the female group),MEK1,MEK2,HSP27, andYWHAZ) that were significantly associated with early- and/or late-onset. Then, we confirmed a strong synergistic interaction betweenNGALandMMP-9genes. Additionally, by anin silicoanalysis, we found some variants forMEK1gene that may alter binding of the transcription factors and that influence the regulation of gene expression regarding microRNA binding sites and splicing regulatory factors.



These findings showed that different genetic factors can modulate differently the onset of disease's symptoms and revealed new mechanisms with clinical implications in the genetic counseling and follow-up of mutation carriers and could contribute for development of potential therapeutical targets.
i3S Instituto de Investigação e Inovação em Saúde Universidade do Porto Porto Portugal; UnIGENeIBMC - Institute for Molecular and Cell Biology Universidade do Porto Porto Portugal; ICBAS Instituto Ciências Biomédicas Abel Salazar Universidade do Porto Porto Portugal.
Diana
D
Santos
UCA Unidade Corino de Andrade Centro Hospitalar do Porto (CHP) Porto Portugal.
Teresa
T
Coelho
i3S Instituto de Investigação e Inovação em Saúde Universidade do Porto Porto Portugal; UnIGENeIBMC - Institute for Molecular and Cell Biology Universidade do Porto Porto Portugal; ICBAS Instituto Ciências Biomédicas Abel Salazar Universidade do Porto Porto Portugal.
Miguel
M
Alves-Ferreira
i3S Instituto de Investigação e Inovação em Saúde Universidade do Porto Porto Portugal; UnIGENeIBMC - Institute for Molecular and Cell Biology Universidade do Porto Porto Portugal; ICBAS Instituto Ciências Biomédicas Abel Salazar Universidade do Porto Porto Portugal.
Jorge
J
Sequeiros
ICBA SInstituto Ciências Biomédicas Abel Salazar Universidade do Porto Porto Portugal; ISPUP Instituto de Saúde Pública Universidade do Porto Porto Portugal.
Denisa
D
Mendonça
i3S Instituto de Investigação e Inovação em Saúde Universidade do Porto Porto Portugal; UnIGENeIBMC - Institute for Molecular and Cell Biology Universidade do Porto Porto Portugal; ICBAS Instituto Ciências Biomédicas Abel Salazar Universidade do Porto Porto Portugal.
Isabel
I
Alonso
i3S Instituto de Investigação e Inovação em Saúde Universidade do Porto Porto Portugal; UnIGENeIBMC - Institute for Molecular and Cell Biology Universidade do Porto Porto Portugal; ICBAS Instituto Ciências Biomédicas Abel Salazar Universidade do Porto Porto Portugal.
Carolina
C
Lemos
i3S Instituto de Investigação e Inovação em Saúde Universidade do Porto Porto Portugal; UnIGENeIBMC - Institute for Molecular and Cell Biology Universidade do Porto Porto Portugal; ICBAS Instituto Ciências Biomédicas Abel Salazar Universidade do Porto Porto Portugal.
Alda
A
Sousa