Association of fibrillin 1 single-nucleotide polymorphism haplotypes with systemic sclerosis in Choctaw and Japanese populations

Objective. Previously, we demonstrated with the use of microsatellite marke rs that a 2-cM haplotype on chromosome 15q containing the fibrillin 1 gene (FBN1) was strongly associated with systemic sclerosis (SSc) in the Choctaw , a population with high SSc prevalence. In this study, all 69 known FBN1 e xons were sequenced to ascertain the presence of changes that might show as sociations with SSc in the Choctaw and Japanese SSc patients and controls. Methods. Screening of FBN1 exons was accomplished by polymerase chain react ion-based fluorescence sequencing of genomic DNA using single-nucleotide po lymorphism (SNP) haplotypes, and their frequencies were determined with a n ew algorithm that recognizes past recombination events between sites. Haplo type phylogenies were inferred using the median-joining network analysis. Results. Five SNPs were identified in FBN1. They are located in the 5'-untr anslated region (SNP-1), exon 15 (SNP-2), intron 17 (SNP-3), exon 27 (SNP-4 ), and intron 27 (SNP-5). Only SNP-1 (T-C) demonstrated an association with SSc in the Choctaw. Eleven FBN1 SNP haplotypes were ascertained in the Cho ctaw population, 2 of which (SNPs 5 and 6) were found only in the SSc patie nts. These same FBN1 SNP haplotypes were associated with SSc in the Japanes e. Conclusion. A SNP in the 5'-untranslated region of FBN1 (SNP-1, C allele) w as strongly associated with SSc in the Choctaw. Furthermore, this polymorph ism is present on 2 unique FBN1 haplotypes found only in Choctaw SSc patien ts. The same 2 haplotypes demonstrate associations with SSc in the Japanese . These data extend the earlier microsatellite studies and are consistent w ith the hypothesis that FBN1 or a nearby gene on chromosome 15q is involved in SSc susceptibility in the Choctaw and the Japanese.