Complement C1Q polymorphisms modulate onset in familial amyloidotic polyneuropathy TTR Val30Met.
BACKGROUND
Familial amyloidotic polyneuropathy (FAP) TTR Val30Met is a lethal autosomal dominant sensorimotor and autonomic neuropathy due to a substitution of methionine for valine at position 30 of the transthyretin (TTR) gene. Amyloid, composed of mutated TTR, is deposited in the peripheral nervous system, myocardium and kidneys. Considerable variability in the age of onset and penetrance of the disease occurs in different countries. Penetrance in Sweden, Cyprus and Portugal is 2%, 28% and 80% respectively. Environmental and genetic factors are believed to contribute to this variability. So far, no single modifier gene has been unequivocally associated with age of onset or penetrance.


METHODS
Candidate modifier genes were chosen from among those coding for chaperone proteins co-localized with TTR deposits in peripheral nerves. Seventy one TTRVal30Met carriers, 51 affected and 20 asymptomatic, belonging to 22 unrelated Greek-Cypriot families, and 59 normal controls were recruited for this study. Sequencing of the coding regions of TTR, serum amyloid P (APCS) and complement C1Q (A, B and C) genes was performed and APOE genotypes were determined. We searched for correlations between various polymorphisms of chaperone proteins and age of disease onset.


RESULTS
Four new and 4 previously described single nucleotide substitutions were identified. One polymorphic site in C1QA (rs172378) and one in C1QC (rs9434) as well as the epsilon2 allele correlated with age of onset (p<0.05).


CONCLUSIONS
Our study has identified polymorphisms which may influence the FAP-TTR Val30Met phenotype. Identifying modifier genes and their protein products may contribute to therapeutic advances.
Dardiotis
Efthimios
E
The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683 Nicosia, Cyprus.
Koutsou
Pantelitsa
P
Zamba-Papanicolaou
Eleni
E
Vonta
Ilia
I
Hadjivassiliou
Marilena
M
Hadjigeorgiou
Georgios
G
Cariolou
Marios
M
Christodoulou
Kyproula
K
Kyriakides
Theodoros
T
D000328:Adult; D017668:Age of Onset; D000368:Aged; D000682:Amyloid / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D028227:Amyloid Neuropathies, Familial / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics*; D053329:Apolipoprotein E2 / Q000235:genetics / Q000502:physiology; D015922:Complement C1q / Q000235:genetics* / Q000502:physiology; D003535:Cyprus / Q000208:ethnology; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006115:Greece / Q000453:epidemiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011228:Prealbumin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000683:Serum Amyloid P-Component / Q000235:genetics
D000682:Amyloid; D053329:Apolipoprotein E2; D018832:Molecular Chaperones; D011228:Prealbumin; D000683:Serum Amyloid P-Component; D015922:Complement C1q; C041120:amyloid prealbumin