Association of C3 and C4 A Complement Types with Familial Amyloidotic Polyneuropathy

Abstract

A mutant variant of the serum protein transthyretin (TTR-met³⁰) appears to be a necessary but not sufficient condition for the development of familial amyloidotic polyneuropathy (FAP). We have studied a number of serum protein markers (α₁-antitrypsin, properdin factor B, C3, C4A, C4B, haptoglobin, transferrin and group-specific component) in FAP patients and healthy controls in an attempt to identify additional pathogenic factors which may influence the risk for developing FAP in male and female patients as well as the age of onset of the disease. Statistically significant associations were found in the complement systems C3 and C4A. The C3F variant was significantly increased in all FAP patients with a relative risk (RR) of 2.0, more pronounced in female patients (RR = 2.6) and patients with an early onset of the disease (RR = 4.5). In the FAP patients only the variants A3 and A4 were found in the C4A system. C4A3 was found in all patients, which was significantly higher than in the controls. The remaining serum protein systems showed no statistically significant associations with FAP. The results suggest that genetic variants of complement factors C3 and C4A may interact with the mutant TTR-met³⁰ by modifying the expression and onset of FAP.

Epidemiology of ATTRV30M neuropathy in Cyprus and the modifier effect of complement C1q on the age of disease onset

“…Genetic variants of other complement components have previously been shown to act as modifiers of both the onset and the expression of ATTRm amyloidosis, more specifically the C3F and C4A3 variants were found to be significantly higher in early onset patients [35].…”

Familial Amyloidotic Polyneuropathy in Sweden: Geographical Distribution, Age of Onset, and Prevalence

“…There arc indications supporting the hy pothesis that other genetic factors may influence the expressivity of FAP in Swe den [18,19]. Hence, it is important to search for additional factors which may be prevent ing, moderating, or accelerating the expres sion of FAP.…”

Kidney dysfunction in renal amyloidosis: does the complement system play a part in hereditary ATTRV30M and iatrogenic ATTR amyloidosis?

“…Complement has been implicated in clinical manifestations of ATTR amyloidosis: we learn from Nylander and co-workers 23 that genetic variants of complement factors C3 and isotype C4A may interact with the mutant TTR protein, modifying the expression of the disease 24 . In addition, C1q has been implicated in the age of onset in ATTR amyloidosis Cypriot patients 11 .…”