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 markers 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 exons were sequenced to ascertain the presence of changes that might show associations with SSc in the Choctaw and Japanese SSc patients and controls.


METHODS
Screening of FBN1 exons was accomplished by polymerase chain reaction-based fluorescence sequencing of genomic DNA using single-nucleotide polymorphism (SNP) haplotypes, and their frequencies were determined with a new algorithm that recognizes past recombination events between sites. Haplotype phylogenies were inferred using the median-joining network analysis.


RESULTS
Five SNPs were identified in FBN1. They are located in the 5'-untranslated 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 Choctaw population, 2 of which (SNPs 5 and 6) were found only in the SSc patients. These same FBN1 SNP haplotypes were associated with SSc in the Japanese.


CONCLUSIONS
A SNP in the 5'-untranslated region of FBN1 (SNP-1, C allele) was strongly associated with SSc in the Choctaw. Furthermore, this polymorphism is present on 2 unique FBN1 haplotypes found only in Choctaw SSc patients. The same 2 haplotypes demonstrate associations with SSc in the Japanese. These data extend the earlier microsatellite studies and are consistent with the hypothesis that FBN1 or a nearby gene on chromosome 15q is involved in SSc susceptibility in the Choctaw and the Japanese.
Tan
F K
FK
The University of Texas-Houston Medical School, 77030, USA.
Wang
N
N
Kuwana
M
M
Chakraborty
R
R
Bona
C A
CA
Milewicz
D M
DM
Arnett
F C
FC
D020121:5' Untranslated Regions; D044466:Asian People; D004247:DNA / Q000032:analysis; D017931:DNA Primers / Q000737:chemistry; D005091:Exons / Q000235:genetics; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D007198:Indians, North American; D007564:Japan / Q000453:epidemiology; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D018807:Polymorphism, Single-Stranded Conformational; D012595:Scleroderma, Systemic / Q000208:ethnology / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014481:United States / Q000453:epidemiology; D054392:Adipokines
D020121:5' Untranslated Regions; D004247:DNA; D017931:DNA Primers; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines