A novel single-nucleotide polymorphism at the 5?-flanking region ofSAA1 associated with risk of type AA amyloidosis secondary to rheumatoid arthritis

Abstract

Objective To address whether the γ haplotype at exon 3 of the SAA1 gene is directly associated with type AA amyloidosis or is merely in linkage with an unknown polymorphism that is primarily associated with disease risk, we examined the SAA1 gene for new polymorphisms. Methods We analyzed DNA samples from 44 rheumatoid arthritis (RA) patients with AA amyloidosis (amyloid group), 55 RA patients without AA amyloidosis (RA group), and 58 non‐RA healthy subjects (non‐RA group). We also examined DNA samples from 50 Caucasians to compare linkage disequilibrium relationships involving SAA1 region polymorphisms between Japanese and Caucasoid populations. Results We observed 3 novel single‐nucleotide polymorphisms (SNPs) in the 5′‐flanking region of SAA1: −61C/G, −13T/C, and −2G/A. Comparison of allele frequencies and ratios of individuals with particular alleles between the study groups revealed statistically significant differences between the amyloid and RA groups and between the amyloid and non‐RA groups. Statistical analysis revealed that the −13T/C SNP was strongly associated with AA amyloidosis. In addition, we found tight linkage between the −13T allele and the α haplotype, rather than the β haplotype, at exon 3 in the Caucasoid population, while −13T was closely linked to the γ and β haplotypes, rather than the α haplotype, in the Japanese population. Since the linkage disequilibrium relationship was reversed between the Japanese and Caucasoid populations, different exon 3 haplotypes of SAA1 are found to be associated with the risk of AA amyloidosis in different ethnic groups. Conclusion Our data suggest that the SAA1 −13T allele, rather than SAA1 exon 3 haplotypes, is primarily associated with AA amyloidosis risk.

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

“…Of note, the sample studied by Moriguchi et al included 50 Caucasian controls, of whom 46 bore the 13C/C alleles and 4 carried the 13C/T genotype. In these controls, the 13C/T genotype was associated with the ␣ allele on one occasion only, and with the ␥ allele in 3 individuals (26). We can thus safely conclude that, in Caucasians, both the ␥ isoform and the 13T allele, which are seemingly always linked, are very rare and do not contribute to renal amyloidosis.…”

“…Recently, Moriguchi et al (26) argued that susceptibility to renal amyloidosis, associated with either the ␣ allele in Caucasians or the ␥ allele in Japanese RA patients, should, rather, be attributed to the presence of yet another polymorphism, the 13C/T polymorphism, in the 5Ј-flanking region of the SAA1 gene. According to their recent study, the 13T allele is often linked to the ␣ isoform in Caucasians and to the ␥ allele in Japanese and is thus presumably associated with susceptibility to amyloidosis in these 2 populations (26).…”

“…These were investigated by restrictionenzyme analysis of PCR products spanning the appropriate sites, as described elsewhere (25). The 13C/T polymorphism was searched by cleavage analysis of PCR products, spanning the appropriate site in the 5Ј-flanking sequence, as described elsewhere (26).…”

“…They found that the 13T/C and the 2995C/T SNPs were strongly associated with amyloidosis (26). They asserted that in Caucasians, contrary to the findings in Japanese subjects in whom the 13T allele is linked to the ␥ allele, the 13T allele was more frequently associated with the ␣ allele, allowing for the discrepant association of either the SAA1␣ or SAA1␥ alleles with AA amyloidosis in RA patients of either Japanese or Caucasian descent, and implicating the 13T allele, rather than the ␥ or ␣ alleles, as a marker of AA amyloidosis (26). Cazeneuve et al (20) investigated relationships between genotypes at the SAA1 and SAA2 loci in patients with FMF and found a significant association between the SAA1␣/␣ genotype and the risk for amyloidosis.…”

Abdominal Fat Aspiration Biopsy and Genotyping of Serum Amyloid A Contribute to Early Diagnosis of Reactive AA Amyloidosis Secondary to Rheumatoid Arthritis

“…According to several recent reports apolipoprotein E4 was positively related to the development of AAamyloidosis in patients with RA (21,22). As another factor contributing to the development of AAamyloidosis, much attention has been paid to SAApolymorphism (23)(24)(25)(26). SAAis a polymorphic protein, for which there are at least four major loci present (SAA1-4) in humans (4).…”