Causal impact of obesity class stratification and endometrial cancer subtypes: an integrated Mendelian randomization and Global Burden of Disease Study 2021 analysis

BACKGROUND: An elevated body mass index (BMI) is recognized as a significant risk factor for uterine cancer. This is especially true for endometrial cancer, which accounts for over 90% of uterine cancer cases. However, establishing a causal relationship and accurately measuring its impact on a population scale requires comprehensive epidemiological validation. METHODS: We investigated the influence of increased BMI (≥25 kg/m 2 ) on the burden of uterine cancer by utilizing the Global Burden of Disease (GBD) 2021 data covering the period from 1990 to 2021, with a particular emphasis on mortality and disability-adjusted life years (DALYs). Age-standardized morbidity rates were evaluated to compute the estimated annual percentage change (EAPC) through linear regression analyses. Demographic decomposition techniques were employed to analyze the contributions of population growth, aging, and the accumulation of risk factors. A comparison of national performance was made against sociodemographically-adjusted theoretical minimum risk levels using frontier analysis. Additionally, Bayesian age-period-cohort (BAPC) modeling was utilized to project trends in disease burden through 2036. To establish causality between obesity classifications (BMI 30-34.9, 35-39.9, and ≥40 kg/m 2 ) and the subtypes of endometrial cancer (endometrioid versus non-endometrioid), we performed a two-sample Mendelian randomization (MR) analysis with multivariable adjustments, leveraging data from IEU OpenGWAS. The analysis was further fortified by inverse variance-weighted (IVW) methods and pleiotropy-resistant MR strategies, complemented by sensitivity assessments to verify robustness. RESULTS: The GBD analysis revealed a consistent global rise in the burden of uterine cancer attributable to elevated BMI (≥25 kg/m 2 ) over the last three decades. Age-standardized DALYs rates (ASDR) and mortality rates (ASMR) exhibited a strong correlation with the Socio-Demographic Index (SDI). The morbidity was notably highest among individuals aged 60-74 years, who accounted for the largest number of deaths and DALYs, while those aged ≥90 years had the highest age-specific mortality rates. The burden was most pronounced in high-income regions of North America and areas with elevated SDI. Projections suggested an increase in global mortality, DALYs, age-standardized mortality rates (ASMR), and disability-adjusted rates (ASDR) across all age demographics through 2036 in the absence of targeted preventative measures. The multivariable-adjusted MR analysis validated a dose-dependent causal link, indicating that Class I obesity (BMI 30-34.9 kg/m 2 ) was associated with a 27% heightened risk of endometrioid carcinoma (95% CI 1.19-1.36; P < 0.001), which is below the existing screening thresholds. A gradual increase in risk for endometrioid cancer was identified across obesity Classes I-III, independent of confounding variables, while no association was found for non-endometrioid subtypes. The results' robustness was affirmed through IVW and pleiotropy-resistant MR methodologies. CONCLUSIONS: An elevated body mass index (BMI) is a modifiable causal factor for uterine cancer, especially endometrial cancer. This type of cancer disproportionately affects older populations and regions with high socio-demographic indices (SDI). Findings from Mendelian randomization (MR) and the Global Burden of Disease (GBD) highlight the urgent need for targeted obesity interventions to reduce disease burden in vulnerable populations.