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Distribution of family history of a disease as a function of mode of inheritance, genetic relative hazard, allele frequency and disease status of the proband, with application to female breast cancer
by
Jisheng Cui
The University of Melbourne
Coauthors: Jisheng Cui, John L. Hopper
The aim of this paper is to determine the family history distribution of a particular disease due to it having a specific genetic aetiology, defined by the mode of inheritance (dominant or recessive), allele frequency, and increased risk in carriers of the genetic risk. By family history we mean the number of affected first-degree relatives of a defined index person (proband), who may be either affected or unaffected with the disease in question. We consider a disease that affects one sex only, although the extension to both sexes is straightforward, and consider model parameters relevant for female breast cancer in Australia. Contour plots of the relationships between the family history distribution and the genetic parameters, for both dominant and recessive inheritance, are displayed for the proband being affected or unaffected. Under dominant inheritance and an allele frequency of 0.005 (as may be appropriate for mutations in the genes BRAC1 and BRCA2), the proportion of affected probands diagnosed with breast cancer before age 50 years who have no family history is stable, decreasing from 89% to 85%, as the genetic relative hazard increase from 5 to 20. The probability that a proband has a family history is higher when the proband is affected compared with when she is not. For allele frequency 0.005 and relative hazard 10, the ratio of the probability of i (i=1, 2, 3 or more) affected relatives for an affected proband compared with an unaffected proband is 1.2, 2 and 4.5 respectively, under dominant inheritance. Under recessive inheritance with allele frequency 0.35 and relative hazard 3 (as may be the case for a common polymorphism in the CYP17 gene), the corresponding ratios are 1.1, 1.3 and 1.5, respectively.
Date received: August 31, 2001
Copyright © 2001 by the author(s). The author(s) of this document and the organizers of the conference have granted their consent to include this abstract in Atlas Conferences Inc. Document # cahg-73.