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 fa tal complication of common chronic inflammatory diseases such as rheum atoid arthritis, It has been proposed that as yet undefined factors ot her than persistent elevation of serum level of the precursor protein, serum amyloid A (SAA), are also important for the development of AA-a myloidosis, 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 [Ala(52)(GCC), Ala(57)(GCG)] differ ed from SAA1 alpha [Val(52)(GTC), Ala(57)(GCG)] only at one base, indi cating a single point mutation, On the other hand, SAA1 beta [Ala(52)( GCC), Val(57)(GTG)] had not only one, but additional differences in a nearby intron and this portion was identical to the SAA2 gene, suggest ing a crossing-over between the SAA1 and SAA2 genes, Furthermore, we r eport that there was a significant difference in the observed numbers of SAA1 alleles between rheumatoid arthritis patients with AA-amyloido sis and the control population (chi(2)(2) = 11.59, P = 0.003) with a h igher 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 gen otypes (chi(5)(2) = 14.63, p = 0.012) with an increased frequency of g amma/gamma-homozygotes in the AA-amyloid group (0.60 vs, 0.18), Thus o ur findings indicate that this novel allelic variant may be an importa nt risk factor for the development of AA-amyloidosis,