Association of microsatellite markers near the fibrillin 1 gene on human chromosome 15q with scleroderma in a Native American population
✍ Scribed by Filemon K. Tan; David N. Stivers; Morris W. Foster; Ranajit Chakraborty; Robert F. Howard; Dianna M. Milewicz; Frank C. Arnett
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- English
- Weight
- 980 KB
- Volume
- 41
- Category
- Article
- ISSN
- 0004-3591
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✦ Synopsis
Objective. To localize disease genes for scleroderma, or systemic sclerosis (SSc), in a population of Choctaw Native Americans with a high prevalence of SSc, in which there is evidence of a possible founder effect.
Methods. A candidate gene approach was used in which microsatellite alleles on human chromosomes 15q and 2q, homologous to the murine tight skin 1 (tskl) and tsk2 loci, respectively, were analyzed in Choctaw SSc cases and race-matched normal controls for possible disease association. Genotyping first-degree relatives of the cases identified potential disease haplotypes, and haplotype frequencies were obtained by expectationmaximization and maximum-likelihood estimation methods. Simultaneously, the ancestral origins of contemporary Choctaw SSc cases were ascertained using census and historical records.
Results. A multilocus 2-cM haplotype was identified on human chromosome 15q homologous to the murine tskl region, which showed a significantly increased frequency in SSc cases compared with controls. This haplotype contains 2 intragenic markers for the fibrillin I (FBNI) gene. Genealogical studies demonstrated that the SSc cases were distantly related, and their ancestry could be traced back to 5 founding families in the mid-eighteenth century. The probability that the SSe cases share this haplotype due to familial aggregation effects alone was calculated and found to be very low. There was no evidence of any microsatellite allele disturbances on chromosome 2q in the region homologous to the tsk2 locus or the region containing the interleukin-l family.
Conclusion.
A 2-cM haplotype on chromosome 15q that contains FBNI is associated with scleroderma in Choctaw Native Americans from Oklahoma. This haplotype may have been inherited from common founders about 10 generations ago and may contribute to the high prevalence of SSc that is now seen.