Factors other than BRCA1 or BRCA2 mutations may modify breast cancer risk. These may include genes at other loci involved in the biosynthesis and metabolism of endogenous steroid hormones (e.g., estrogen) and environmental carcinogens. In addition, factors such as family history of breast and ovarian cancer, lifestyle, reproductive factors, and exogenous exposures are also likely to modify breast cancer risk. Variants of metabolism genes, associated with either an increased bio-activation or with a decreased detoxification of estrogen or environmental mammary carcinogens, are associated with breast cancer risk. The purpose of this study was to examine the associations between genes involved in the synthesis and metabolism of steroid hormones particularly estrogens, and environmental carcinogens and breast cancer risk, as well as their interactions with risk factors and assess the statistical associations using different designs. In particular, we used 3 designs; a Case-case design, a population-based case-control design using unrelated controls, and a Kin Cohort analysis using family-based structure. We estimated genetic effects by incorporating the phenotypes of first degree relatives conditional on the genotype of the proband. In the comparison of the family-based and case-control study designs, we included 980 case families and 980 population-based control families. For the family-based design we included all female 1st degree relatives of the probands. Our findings show that both designs yield similar estimates for the odds ratios. However, the family-based design was more efficient (as measured by the ratio of the variances). The efficiency ranged from 16%-155% with the family design being more efficient when the allele frequency was smaller.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]