Identifying molecular mediators of the relationship between body mass index and endometrial cancer risk: a Mendelian randomization analysis

Abstract

Background: Endometrial cancer is the most common gynaecological cancer in high-income countries. Elevated body mass index (BMI) is an established modifiable risk factor for this condition and is estimated to confer a larger effect on endometrial cancer risk than any other cancer site. However, the molecular mechanisms underpinning this association remain unclear. We used Mendelian randomization (MR) to evaluate the causal role of 14 molecular risk factors (hormonal, metabolic and inflammatory markers) in endometrial cancer risk. We then evaluated and quantified the potential mediating role of these molecular traits in the relationship between BMI and endometrial cancer using multivariable MR.

Methods: Genetic instruments to proxy 14 molecular risk factors and BMI were constructed by identifying single-nucleotide polymorphisms (SNPs) reliably associated (P < 5.0 × 10^-8) with each respective risk factor in previous genome-wide association studies (GWAS). Summary statistics for the association of these SNPs with overall and subtype-specific endometrial cancer risk (12,906 cases and 108,979 controls) were obtained from a GWAS meta-analysis of the Endometrial Cancer Association Consortium (ECAC), Epidemiology of Endometrial Cancer Consortium (E2C2) and UK Biobank. SNPs were combined into multi-allelic models and odds ratios (ORs) and 95% confidence intervals (95% CIs) were generated using inverse-variance weighted random-effects models. The mediating roles of the molecular risk factors in the relationship between BMI and endometrial cancer were then estimated using multivariable MR.

Results: In MR analyses, there was strong evidence that BMI (OR per standard deviation (SD) increase 1.88, 95% CI 1.69 to 2.09, P = 3.87 × 10^-31), total testosterone (OR per inverse-normal transformed nmol/L increase 1.64, 95% CI 1.43 to 1.88, P = 1.71 × 10^-12), bioavailable testosterone (OR per natural log transformed nmol/L increase: 1.46, 95% CI 1.29 to 1.65, P = 3.48 × 10^-9), fasting insulin (OR per natural log transformed pmol/L increase: 3.93, 95% CI 2.29 to 6.74, P = 7.18 × 10^-7) and sex hormone-binding globulin (SHBG, OR per inverse-normal transformed nmol/L increase 0.71, 95% CI 0.59 to 0.85, P = 2.07 × 10^-4) had a causal effect on endometrial cancer risk. Additionally, there was suggestive evidence that total serum cholesterol (OR per mg/dL increase 0.90, 95% CI 0.81 to 1.00, P = 4.01 × 10^-2) had an effect on endometrial cancer risk. In mediation analysis, we found evidence for a mediating role of fasting insulin (19% total effect mediated, 95% CI 5 to 34%, P = 9.17 × 10^-3), bioavailable testosterone (15% mediated, 95% CI 10 to 20%, P = 1.43 × 10^-8) and SHBG (7% mediated, 95% CI 1 to 12%, P = 1.81 × 10^-2) in the relationship between BMI and endometrial cancer risk.

Conclusions: Our comprehensive MR analysis provides insight into potential causal mechanisms linking BMI with endometrial cancer risk and suggests targeting of insulinemic and hormonal traits as a potential strategy for the prevention of endometrial cancer.

Keywords: Bioavailable testosterone; Body mass index; Endometrial cancer; Fasting insulin; Mendelian randomization; Sex hormone-binding globulin.

Fig. 1

Flowchart detailing the process of identifying previously reported risk factors with suitable genetic instruments. TNF-α = tumour necrosis factor-α, IGFBP-1 = insulin-like growth factor-binding protein-1, LDL = low-density lipoprotein, HDL = high-density lipoprotein, IGF-1 = insulin-like growth factor-1, IL-6 = interleukin-6, CRP = C-reactive protein, SHBG = sex hormone-binding globulin

Fig. 2

DAG demonstrating the core assumptions of Mendelian randomization. DAG = directed acyclic diagram, G = genetic instrument, E = exposure, O = outcome, C = confounding factors. Arrows labelled 1, 2 and 3 represent the three core assumptions of MR: (1) the instrument strongly associates with the exposure (“relevance”); (2) there is no confounding of the instrument-outcome relationship (“exchangeability”); and (3) the instrument only affects the outcome through the exposure (“exclusion restriction”). MR uses genetic instruments to proxy exposures in order to strengthen causal inference in observational epidemiological settings. As these genetic instruments are randomly inherited at meiosis, they should not be affected by conventional confounding factors like environmental, lifestyle and behavioural traits. In addition, since germline genetic variants are fixed at conception and cannot be altered by subsequent exposures, they are not susceptible to reverse causation. Finally, germline genotype can be measured relatively precisely using modern genotyping technologies which minimizes measurement error. Collectively, these properties of germline genetic variants (along with technologies that measure them) permit MR analyses to minimize many of the sources of bias which can undermine robust causal inference in conventional observational epidemiological analyses

Fig. 3

DAG demonstrating the proposed causal interactions of BMI, SHBG, fasting insulin and bioavailable testosterone on endometrial cancer (overall and the endometrioid histological subtype). DAG = directed acyclic diagram, BMI = body mass index, SHBG = sex hormone-binding globulin. Red lines indicate a negative causal effect, green lines indicate a positive causal effect

Fig. 4

Mendelian randomization analysis of BMI on overall and subtype-specific endometrial cancer risk. Results of MR analyses examining the effect of adult BMI on risk of overall and subtype-specific endometrial cancer risk

Fig. 5

Mendelian randomization analysis of total serum cholesterol, fasting insulin, total testosterone, bioavailable testosterone and sex hormone-binding globulin (SHBG) on overall and endometrioid endometrial cancer risk. LDL = low-density lipoprotein, HDL = high-density lipoprotein, IGF-1 = insulin-like growth factor-1, IL-6 = interleukin-6, CRP = C-reactive protein, SHBG = sex hormone-binding globulin. A Results of MR analyses examining the effects of previously reported molecular risk factors on risk of overall endometrial cancer risk. B Results of MR analyses examining the effects of previously reported molecular risk factors on risk of endometrioid subtype endometrial cancer risk

Fig. 6

Mendelian randomization analysis of adult BMI on previously reported endometrial cancer risk factors. SHBG = sex hormone-binding globulin, LDL = low-density lipoprotein, CRP = C-reactive protein