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Complement C1Q polymorphisms modulate onset in familial amyloidotic polyneuropathy TTR Val30Met

Efthimios Dardiotis1, Pantelitsa Koutsou, Eleni Zamba-Papanicolaou

  • 1The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683 Nicosia, Cyprus.

Journal of the Neurological Sciences
|June 5, 2009
PubMed
Abstract

Insights

This study identified specific gene polymorphisms that may influence the age of onset for Familial Amyloidotic Polyneuropathy (FAP) TTR Val30Met. These findings could lead to new therapeutic strategies for this genetic disorder.

Area of Science:

  • Genetics
  • Neurology
  • Molecular Biology

Background:

  • Familial Amyloidotic Polyneuropathy (FAP) TTR Val30Met is a lethal inherited neuropathy caused by a transthyretin (TTR) gene mutation.
  • Amyloid deposits from mutated TTR affect the nervous system, heart, and kidneys, with significant variability in disease onset and penetrance.
  • Environmental and genetic factors are suspected to influence FAP variability, but no specific modifier genes have been identified.

Purpose of the Study:

  • To investigate potential genetic modifiers influencing the age of onset and penetrance of FAP TTR Val30Met.
  • To identify correlations between polymorphisms in chaperone protein genes and the clinical presentation of FAP.
  • To explore the role of complement C1Q and serum amyloid P genes in FAP pathogenesis.

Main Methods:

  • Candidate modifier genes encoding chaperone proteins co-localized with TTR deposits were selected.
  • Genetic sequencing of TTR, APCS, and C1Q genes was performed on 71 TTR Val30Met carriers and 59 controls.
  • APOE genotyping and analysis of single nucleotide polymorphisms (SNPs) were conducted to assess correlations with disease onset.

Main Results:

  • Four novel and four known single nucleotide substitutions were identified in the studied genes.
  • A significant correlation was found between a specific polymorphic site in C1QA (rs172378), a site in C1QC (rs9434), and the TTR Val30Met epsilon2 allele with the age of disease onset (p<0.05).

Conclusions:

  • Specific polymorphisms in complement C1Q genes (C1QA and C1QC) and the APOE epsilon2 allele are associated with the age of onset in FAP TTR Val30Met.
  • Identification of these modifier genes provides insights into the variable phenotype of FAP.
  • Further research into modifier genes and their protein products may pave the way for novel therapeutic interventions for FAP.

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