A novel allelic variant of serum amyloic A, SAA1γ: genomic evidence, evolution, frequency, and implication as a risk factor for reactive systemic AA– amyloidosis

Abstract

Reactive systemic amyloidosis, also called AA-amyl–oidosis 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,, which we have recently identified at the protein level. The SAA1γ [Ala⁵²(GCC), Ala⁵⁷(GCG)] differed from SAA1α [Val⁵²(GIC), Ala⁵⁷(GCG] only at one base, indicating a single point mutation. On the other hand, SAA1β [Ala⁵²(GGC), 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 SAA1and 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 (%2²= 11. 59, P= 0, 003) with a higher frequency of allele in the AA–amyloid group (0. 70 vs. 0. 37). There was also a notable difference in the distribution of SAA1 genotypes (x5²= 14. 63, P= 0. 012) with an increased frequency of γ/γ– 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.