Objective To integrate the cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) and the prospective Kailuan cohort study to systematically investigate the association of weight-adjusted waist circumference index (WWI) with cardiovascular disease (CVD) and all-cause mortality. Furthermore, Mendelian randomization (MR) analysis was employed to explore the causal relationships between the two components of WWI (body weight and waist circumference) and CVD as well as mortality, thereby providing genetic-level support for the rationality of WWI as a composite indicator.

Methods WWI was calculated as waist circumference(cm)/ \sqrt\textbody weight (kg) . In the NHANES cross-sectional study, multivariable logistic regression models were employed to examine the association between WWI and CVD. In the cohort study based on the Kailuan population, participants were categorized into quartiles based on WWI. Cox proportional hazards models were used to assess the associations of WWI with CVD (including its subtypes) and all-cause mortality. Stratified analyses were conducted according to age, sex, education level, income level, hypertension, diabetes, smoking, and drinking habits. Furthermore, univariable and multivariable Mendelian randomization (MR) analyses, primarily using the inverse-variance weighted (IVW) method, were performed to investigate the causal relationships between body weight as well as waist circumference and CVD.

Results The NHANES cross-sectional analysis revealed a positive association between WWI and the prevalence risk of CVD (P for trend ＜ 0.001). The cohort study demonstrated that with increasing levels of WWI, the risks of both CVD and all-cause mortality were higher. Using the first quartile as the reference, after correcting for all covariates, the hazard ratio (HR) for CVD in the highest quartile was 1.35 (95%CI: 1.28 to 1.44). Subgroup analyses indicated that the association between WWI and CVD risk was more pronounced among younger individuals, those with higher education, and those with diabetes. Univariable MR analyses showed causal associations of body weight with atrial fibrillation, cerebral infarction, stroke, myocardial infarction, and heart failure, as well as causal associations of waist circumference with atrial fibrillation, cerebral hemorrhage, cerebral infarction, stroke, and heart failure. However, in multivariable MR analyses, after adjusting for the influence of waist circumference, the causal associations of body weight with cerebral infarction and myocardial infarction disappeared; conversely, after adjusting for the influence of body weight, the causal associations of waist circumference with cerebral hemorrhage and cerebral infarction disappeared.

Conclusions In summary, WWI demonstrated a positive association with both CVD and all-cause mortality. MR analyses indicated that body weight and waist circumference have interdependent causal relationships with CVD and mortality. This provides genetic-level evidence supporting the validity of WWI as a composite anthropometric index.