Open AccessFamilial amyloid polyneuropathy in Portugal: New genes modulating age‐at‐onset
Author(s) -
Santos Diana,
Coelho Teresa,
AlvesFerreira Miguel,
Sequeiros Jorge,
Mendonça Denisa,
Alonso Isabel,
Lemos Carolina,
Sousa Alda
Publication year - 2017
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.380
Subject(s) - in silico , gene , medicine , genetics , single nucleotide polymorphism , disease , amyloid polyneuropathy , candidate gene , genetic variation , biology , genotype , bioinformatics , age of onset
Objectives Familial amyloid polyneuropathy ( FAP ATTRV 30M) 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. Methods We analyzed 62 tagging SNP s from nine genes‐ NGAL , MMP ‐9 , BGN , MEK 1 , MEK 2 , ERK 1 , ERK 2 , HSP 27 , and YWHAZ – 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, an in silico analysis was performed in order to assess the functional impact of significant variants associated with AO . Results We found for the first time variants from six genes ( NGAL , BGN (in the female group), MEK 1 , MEK 2 , HSP 27 , and YWHAZ ) that were significantly associated with early‐ and/or late‐onset. Then, we confirmed a strong synergistic interaction between NGAL and MMP ‐9 genes. Additionally, by an in silico analysis, we found some variants for MEK 1 gene that may alter binding of the transcription factors and that influence the regulation of gene expression regarding micro RNA binding sites and splicing regulatory factors. Interpretation 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.