A novel allelic variant of serum amyloid A, SAA1 gamma: genomic evidence, evolution, frequency, and implication as a risk factor for reactive systemic AA-amyloidosis.

Reactive systemic amyloidosis, also called AA-amyloidosis is a rare fatal complication of common chronic inflammatory diseases such as rheumatoid arthritis. It has been proposed that as yet undefined factors other than persistent elevation of serum level of the precursor protein, serum amyloid A (SAA), are also important for the development of AA-amyloidosis. In this work we show genomic evidence for a novel allelic variant of human SAA, SAA1 gamma, which we have recently identified at the protein level. The SAA1 gamma [Ala52(GCC), Ala57(GCG)] differed from SAA1 alpha [Val52(GTC), Ala57(GCG)] only at one base, indicating a single point mutation. On the other hand, SAA1 beta [Ala52(GCC), Val57(GTG)] had not only one, but additional differences in a nearby intron and this portion was identical to the SAA2 gene, suggesting a crossing-over between the SAA1 and SAA2 genes. Furthermore, we report that there was a significant difference in the observed numbers of SAA1 alleles between rheumatoid arthritis patients with AA-amyloidosis and the control population (chi 2(2) = 11.59, p = 0.003) with a higher frequency of gamma-allele in the AA-amyloid group (0.70 vs. 0.37). There was also a notable difference in the distribution of SAA1 genotypes (chi 5(2) = 14.63, p = 0.012) with an increased frequency of gamma/gamma-homozygotes in the AA-amyloid group (0.60 vs. 0.18). Thus our findings indicate that this novel allelic variant may be an important risk factor for the development of AA-amyloidosis.