Abstract 1585: Genetic variations in progesterone receptor (PGR)-related genes and mammographic density in premenopausal women: Are the associations mediated by circulating progesterone

BACKGROUND: Progesterone is a proliferative hormone in the breast. Combined estrogen plus progestin use in postmenopausal women increases mammographic density; a very strong risk for breast cancer. Circulating progesterone and genetic variations in progesterone receptor (PGR)-related genes are positively associated with mammographic density in postmenopausal women, but there are limited data in premenopausal women, with conflicting results. Notably, besides hormone therapy, genetic variation in PGR genes are known to modulate circulating progesterone levels. We, therefore, investigated the associations of genetic variations in PGR-related genes (PGR and Progesterone Receptor Membrane Component 1 (PGRMC1) with mammographic density in premenopausal women and determine, for the first time, whether these associations are mediated via circulating progesterone. METHODS: We genotyped 179 PGR-related single nucleotide polymorphisms (SNPs) (155 for PGR and 24 for PGRMC1 - 17 of which were synonymous variants and were filtered) in 364 cancer-free premenopausal women who had screening mammography at the Joanne Knight Breast Health Center at Washington University School of Medicine, St. Louis in 2016. We used Volpara to determine volumetric percent density, and dense volume. Variants were coded in dominant mode of inheritance. For causal mediation analysis, multivaraite linear regression models were applied to both the mediator (circulating PGR in logarithm scale) with variants and volumetric percent density, and dense volume with variant, PGR in logarithm scale and their interaction, both adjusting for age, body mass index, family history of breast cancer, and parity. The causal mediation effect, direct effect and total effect, by gentoype and averaged across genotypes were estimated with 95% confidence intervals and p values. Significance was claimed with p-value≤0.05. RESULTS: The mean age of the study participants was 47.5 years. Most participants (42.1%) had volumetric percent density between 3.5-7.5%, equivalent to BI-RADS® category b. Rs2020875 (PGR11) had a positive average direct effect (estimate=0.22, 95% CI, 0.016~0.44, p-value=0.024) and rs645213 (PGR11) had a borderline inverse direct effect (-0.25, -0.48~0.0004, p-value=0.052) on volumetric percent density. Further, rs11224565 (PGR11): 0.19, 0.04~0.34, p-value=0.028 had positive average direct effects on dense volume. None of the mediation effects were statistically signficiant. CONCLUSIONS: SNPs in PGR-related genes are associated with mammographic density in premenopausal women. Circulating progesterone levels did not mediate the associations between variants in PGR-related genes and mammographic density. Larger studies are needed to confirm our findings. Citation Format: Favour A. Akinjiyan, Yunan Han, Jingqin R. Luo, Aldi Kraja, Catherine M. Appleton, Graham A. Colditz, Adetunji T. Toriola. Genetic variations in progesterone receptor (PGR)-related genes and mammographic density in premenopausal women: Are the associations mediated by circulating progesterone [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1585.