A novel single-nucleotide polymorphism at the 5'-flanking region of SAA1 associated with risk of type AA amyloidosis secondary to rheumatoid arthritis.

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.