ASSOCIATION OF MICROSATELLITE MARKERS NEAR THE FIBRILLIN-1 GENE ON HUMAN-CHROMOSOME 15Q WITH SCLERODERMA IN A NATIVE-AMERICAN POPULATION

Objective. To localize disease genes for scleroderma? or systemic scle rosis (SSc), in a population of Choctaw Native Americans with a high p revalence of SSc, in which there is evidence of a possible founder eff ect. Methods. A candidate gene approach was used in which microsatelli te alleles on human chromosomes 15q and 2q, homologous to the murine t ight skin 1 (tsk1) and tsk2 loci, respectively, were analyzed in Choct aw SSc cases and race-matched normal controls for possible disease ass ociation. Genotyping first-degree relatives of the cases identified po tential disease haplotypes, and haplotype frequencies were obtained by expectation-maximization and maximum-likelihood estimation methods. S imultaneously, the ancestral origins of contemporary Choctaw SSc cases were ascertained using census and historical records. Results, A mult ilocus 2-cM haplotype was identified on human chromosome 15q homologou s to the murine tsk1 region, which showed a significantly increased fr equency in SSc cases compared with controls. This haplotype contains 2 intragenic markers for the fibrillin I (FBN1) gene. Genealogical stud ies demonstrated that the SSc cases were distantly related, and their ancestry could be traced back to 5 founding families in the mid-eighte enth century. The probability that the SSc 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 distur bances on chromosome 2q in the region homologous to the tsk2 locus or the region containing the interleukin-1 family. Conclusion. A 2-cM hap lotype on chromosome 15q that contains FBN1 is associated with sclerod erma in Choctaw Native Americans from Oklahoma. This haplotype may hav e been inherited from common founders about 10 generations ago and may contribute to the high prevalence of SSc that is now seen.