Bone mineral density and risk of breast cancer: A cohort study and Mendelian randomization analysis

Abstract

BACKGROUND Estrogen is involved in both bone metabolism and breast cancer proliferation. However, evidence about the risk of breast cancer according to women's bone mineral density (BMD) is scarce, and little is known about their causal associations. METHODS Women participating in the UK Biobank cohort were used to investigate the association between BMD and the risk of breast cancer using Cox regression models. Instrumental variants associated with estimated BMD (eBMD) were extracted from genome‐wide association studies with European ancestry. Logistic regression was used to calculate the genetic association with breast cancer in the UK Biobank and 2‐sample Mendelian randomization (MR) analyses to assess their causal associations with breast cancer. Finally, the pleiotropic conditional false discovery rate (cFDR) method was conducted to further detect common genetic variants between BMD and breast cancer. RESULTS Compared with the general population, postmenopausal women with BMD T scores <−2.5 had a lower risk of breast cancer (hazard ratio [HR], 0.77; 95% CI, 0.59‐1.00), and this effect was stronger in women with fracture (HR, 0.31; 95% CI, 0.12‐0.82). In MR analysis, no causal associations between eBMD and breast cancer were observed. The cFDR method identified 63 pleiotropic loci associated with both BMD and breast cancer, of which CCDC170, ESR1, and FTO might play crucial roles in their pleiotropy. CONCLUSIONS An association between BMD and the risk of postmenopausal breast cancer in the UK Biobank was observed, whereas no evidence supported their causal association. Instead, their association could be explained by pleiotropic genetic variants leading to the pathology of osteoporosis and breast cancer.

A causal relationship between bone mineral density and breast cancer risk: a Mendelian randomization study based on East Asian population

“…A prior MR analysis in European populations revealed no genetic evidence supporting a causal link between BMD and BC risk. The observed association between the two was explained by the pleiotropic effects of genetic variants [45]. This is inconsistent with the results of our MR analysis, and ethnic differences may be the primary reason for the discrepancy between this study and the MR analysis on European populations.…”

Mendelian randomization analyses of associations between breast cancer and bone mineral density

“…The same results are consistent with a recently published Mendelian Randomized study of bone density and breast cancer risk. The results of this study also provide no evidence to support a causal association between BMD and breast cancer, while considering that the association found in observational studies could be explained by polymorphic genetic variants that contribute to the pathology of osteoporosis and breast cancer 41 . Elevated hormone levels, including levels of oestradiol and testosterone, have been found to be associated with BMD and breast cancer in several studies 15 , 42 .…”

Genome-wide association study reveals the candidate genes of humerus quality in laying duck

“…Estrogens are important for bone metabolism via a variety of mechanisms in osteoblasts, osteocytes, osteoclasts, immune cells, and other cells to maintain bone mineral density ( Khalid and Krum, 2016 ). Lots of research reporter that estrogen receptor gene ESR1 polymorphisms are associated with BMD and osteoporosis in humans and mice ( Trajanoska et al, 2018 ; Zhang et al, 2022 ). Faccio et al identified that Vav3 , a Rho family guanine nucleotide exchange factor, as essential for stimulated osteoclast activation and bone density in vivo ( Faccio, et al, 2005 ).…”