Inference From a Multiplicative Model of Joint Genetic Effects for Ovarian Cancer Risk

Extract

Ramus et al. ( 1 ) in this issue of the Journal report that a genetic marker at 9p22.2 protects against ovarian cancer in a population of BRCA1 or BRCA2 mutation carriers. The hazard ratios (HRs) in BRCA1 mutation carriers (HR = 0.78) and in BRCA2 mutation carriers (HR = 0.80) ( 1 ) are remarkably similar to those from a genome-wide association study in populations with very low frequencies of mutation carriers (HR = 0.82) ( 2 ), given random variation, population differences in linkage disequilibrium patterns affecting the attenuation from use of a marker instead of the causal single-nucleotide polymorphism, challenges of achieving unbiased and consistent case ascertainment and control selection (especially for BRCA1 and/or BRCA2 [BRCA1/2] mutation carriers), and disease diagnosis.

The similarity of the three hazard ratios for the 9p22.2 marker suggests that the joint effects of a BRCA1 or BRCA2 mutation and the marker are multiplicative. In a multiplicative model involving two dichotomous risk factors A and B , the relative risk (or relative hazard) of those exposed to A and B is the product of 1) the relative risk of those exposed to A and not B and 2) the relative risk of those exposed to B but not A , all compared with those exposed to neither. The estimated 30- to 50-fold increase in ovarian cancer risk conferred by carrying either a BRCA1 or a BRCA2 mutation ( 3–5 ) implies that the absolute reduction in risk for those with the genetic variant at 9p22.2 is far greater in BRCA1 and BRCA2 mutation carriers than in noncarriers. Consequently, the observed data are inconsistent with an additive model.