An allele of serum amyloid A1 associated with amyloidosis in both Japanese and Caucasians

Abstract

Serum amyloid A1 (SAA1), one of the two isotypes of acute phase SAA, is the predominant precursor to amyloid A (AA) protein, the chief constituent of fibrillar deposits in reactive (AA) amyloidosis. Prolonged hyperexpression of SAA protein accompanying chronic inflammation is critical to, but seems not to be sufficient for, the development of AA amyloidosis. Several previous studies have investigated the possibility of linkage between SAA1 exon 3 polymorphisms and susceptibility to amyloidosis. While the SAA1.1 allele was found to have a negative association with amylodosis in Japanese subjects, it showed a positive association in Caucasians. Moriguchi and colleagues recently showed that a single nucleotide polymorphism (SNP) at position -13 in the SAA1 5' flanking region was more strongly associated with amyloidosis than was the exon 3 polymorphism. To test whether this SNP may be an amyloidogenic factor common to Japanese and Caucasians, we have analyzed the SAA1 gene in amyloid and non-amyloid patients of both ethnic groups for the presence of T or C at position -13 and for exon 3 polymorphisms (SAA1.1, 1.3 or 1.5). The frequency of the -13T allele was 0.708 and 0.521 in Japanese rheumatoid arthritis patients with and patients without AA amyloidosis, respectively, and 0.536 and 0.196 in American Caucasian patients with AA amyloidosis and control subjects, respectively. In Caucasians, the -13T allele had a stronger association with amyloidosis than did the SAA1.1 allele. These findings suggest that -13T is a genetic background for AA amyloidosis in both Japanese and Caucasians and the difference in prevalence of AA amyloidosis in the two ethnic groups may be due, at least in part, to a difference in the frequency of the -13T SAA1 allele.

Susceptibility to AA amyloidosis in rheumatic diseases: A critical overview

“…Interestingly, a polymorphism in the SAA1 promoter (Ϫ13 T/C) was subsequently found to be significantly related to AA amyloid risk in both populations and to be in linkage disequilibrium with SAA1.1 and SAA1.3 in Caucasians and Japanese, respectively, thus apparently explaining the previous discrepancy (27,28). However, this genetic association could not be further confirmed in a series of Finnish patients with RA (29) or in patients with FMF (18).…”

The genetics of the amyloidoses: interactions with immunity and inflammation

“…71,72 One analysis, rather than showing a significant increase in SAA 1.3, showed only a decrease in the 1.1 allele in the amyloid patients (P ¼ 0.002). 69 In that same study, the increase in SAA 1.3 was not quite significant (P ¼ 0.06), suggesting perhaps that the study did not have sufficient power. The difference between the RA patients with amyloidosis and the population controls without RA was statistically more impressive (P ¼ 0.01).…”

“…In Caucasian groups, SAA 1.1 is much more common being significantly higher than in the Japanese controls. 68,69 In Japanese RA patients without a tissue diagnosis of amyloidosis, the allele distributions do not differ from controls without RA (Table 3). 70 However, in several studies of Japanese patients with RA and amyloid SAA 1.3 was significantly overrepresented, particularly in the homozygous state.…”

“…In US patients with RA the frequency of SAA 1.1 is significantly higher in patients with amyloid than in nonrheumatoids without amyloid, not unexpectedly resembling the UK distribution more than that in Japan. 69 Recent findings have suggested that another polymorphism in the SAA 1 gene, at position À13 in the 5 0 regulatory region of the gene is more closely associated with the occurrence of amyloid in both Japanese and Caucasian RA patients than any of the prior exon 3 based allelic associations. 69 The frequency of the TT allele is higher in Japanese than in the Caucasians.…”

“…69 Recent findings have suggested that another polymorphism in the SAA 1 gene, at position À13 in the 5 0 regulatory region of the gene is more closely associated with the occurrence of amyloid in both Japanese and Caucasian RA patients than any of the prior exon 3 based allelic associations. 69 The frequency of the TT allele is higher in Japanese than in the Caucasians. The association of the TT and SAA 1.3 alleles is not significantly greater in the amyloid patients (P ¼ 0.09), but a larger sample size might demonstrate a synergistic effect of the two snp's.…”