Genetic models suggest that there are breast cancer-associated genetic variants that remain uncharacterized. Heterogeneity among breast tumors may increase the difficulty of identifying these variants. The intrinsic molecular subtypes of breast cancer are associated with distinct risk factors and survival. Genetic risk factors may also differ by subtype. 312 potentially functional and tag SNPs in candidate genes related to hormone synthesis and signaling (CYP19A1, ESR1, HSD17B2, HSD3B1, PGR, SHBG) and central adiposity (ADIPOQ, LEP, LEPR, IL6, TNF) were genotyped in the Carolina Breast Cancer Study, a population-based study of African-American and white women. Genotype data was available for 1776 of 2022 controls and 1972 of 2311 cases (200 basal-like, 679 luminal A). Data from 144 ancestry informative markers was used to estimate ancestry and adjust for residual population stratification. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between genotypes and breast cancer were estimated using logistic regression. Haplotype ORs and 95% CIs were estimated using HAPSTAT. Genotypes in LEP, LEPR, TNF, CYP19A1, ESR1, HSD3B1, HSD17B2, and PGR were associated with breast cancer overall. Genotypes in ADIPOQ, IL6, LEP, LEPR, ESR1, HSD17B2, HSD3B1, PGR, and SHBG were associated with the luminal A or basal-like subtype. Many associations were stronger when cases were stratified by subtype compared to associations for breast cancer overall. In some cases, such as with the strongest associations in ESR1 and HSD17B2, associations were strong overall and by subtype. Haplotypes in IL6, LEP, LEPR, CYP19A1, ESR1, and PGR were associated with breast cancer overall and by subtype. Waist-hip ratio (WHR) and combined parity and lactation were evaluated as potential effect measure modifiers. Among genotypes and haplotypes displaying evidence of multiplicative or additive interaction, genotype/haplotype associations were weaker among women with higher WHR compared to those with lower WHR. There were no clear patterns of interaction between SNPs and parity and lactation. These results suggest that, for a subset of SNPs, SNP-breast cancer associations differ by intrinsic molecular subtype. Analyzing subtypes as distinct outcomes can increase the likelihood of identifying subtype-specific associations that may have been masked in analyses of breast cancer overall
