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-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.

Rapidly Progressed Secondary Amyloidosis in a Patient with Mixed Connective Tissue Disease

“…Several reports show that the presence of the -allele in the serum amyloid A protein (SAA) 1 gene is a risk factor for SA in patients with rheumatoid arthritis (RA) (3)(4)(5). Here, we report a case with MCTD who developed SA in a very short time after the onset of the disease with the -allele in the SAA1 gene.…”

Genetic polymorphisms and alternative splicing of the hOGG1 gene, that is involved in the repair of 8-hydroxyguanine in damaged DNA

“…Detailed information on these cell lines can be obtained upon request. High-molecular-weight DNA was prepared from tumors and adjacent noncancerous tissues of 45 patients with SCLC or NSCLC, and from peripheral blood samples of 42 unrelated healthy indivi-duals as described previously (Shiseki et al, 1994(Shiseki et al, , 1996Baba et al, 1995). Poly(A) RNA was prepared by the Fast Track mRNA isolation kit (Invitrogen Corp.).…”

The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever

“…The presence of 2 single-nucleotide polymorphisms (SNPs) within exon 3 of the SAA1 gene, 2995C/T and 3010C/T, define 3 haplotypes that correspond to the SAA1␣ (2995T-3010C), SAA1␤ (2995C-3010T), and SAA1␥ (2995C-3010C) isoforms. In Japanese patients with rheumatoid arthritis (RA), who frequently develop AA amyloidosis, a positive correlation between the SAA1␥ allele and this complication was found (22)(23)(24). The higher susceptibility to amyloidosis of Japanese compared with Caucasian RA patients was thus attributed to the much higher frequency of the SAA1␥ allele among the Japanese (22)(23)(24).…”