ABSTRACTWe have tested a simple procedure, disease association by locus stratification, for identifying breast cancer patients with pathogenetic allelic variants at several candidate loci. The strategy was based on the assumption of epistatic interactions of the candidates. We analyzed 66 independent cases from sib pairs affected with breast cancer that had previously been collected during an investigation of pathogenetic-allele-sharing at theHRAS1mini-satellite locus. An exon 24 polymorphism ofATM, substituting arginine for proline was associated with breast cancer in these cases with an overall odds ratio of 4.5 (95 confidence interval, 1.2–20.5, nominalp= 0.02, 2–tail Fisher exact test). In the presence of a rareHRAS1allele, the odds ratio increased to 6.9 (95 CI, 1.2–38.3,p= 0.03). Thus, our procedure identified at least one allelic variant ofATMassociated with breast cancer, and indicated that theATMlocus may interact with
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