Familial amyloid polyneuropathy in Portugal: New genes modulating age-at-onset

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Familial Amyloid Polyneuropathy (FAP ATTRV30M) exhibits considerable variability in age-at-onset (AO) across different populations, families, and generations.
• Understanding the genetic underpinnings of this variability is crucial for predicting disease course and developing targeted interventions.

Purpose of the Study:

• To investigate candidate genes as potential genetic modifiers of AO in FAP ATTRV30M.
• To employ a family-centered approach to analyze the influence of genetic variants on disease onset.

Main Methods:

• Analysis of 62 tagging SNPs from nine candidate genes (NGAL, MMP-9, BGN, MEK1, MEK2, ERK1, ERK2, HSP27, YWHAZ) in 318 Portuguese FAP ATTRV30M patients from 106 families.
• Utilized generalized estimating equation analysis to account for non-independent AO data within families.
• Performed in silico analysis to assess the functional impact of significant genetic variants on AO.

Main Results:

• Identified significant associations between variants in six genes (NGAL, BGN, MEK1, MEK2, HSP27, YWHAZ) and early/late onset of FAP ATTRV30M.
• Confirmed a strong synergistic interaction between NGAL and MMP-9 genes in modulating disease onset.
• In silico analysis revealed potential functional impacts of MEK1 variants on gene expression regulation, including transcription factor binding, microRNA sites, and splicing factors.

Conclusions:

• Genetic factors play a significant role in modulating the age of symptom onset in FAP ATTRV30M.
• The identified genetic modifiers and interactions provide new insights into disease mechanisms.
• Findings have clinical implications for genetic counseling, patient follow-up, and the development of novel therapeutic targets for FAP ATTRV30M.