Abstract Body (Do not enter title and authors here): Background: Premature atherosclerotic cardiovascular disease (pASCVD) is a significant public health issue globally. Thus, we aimed to evaluate the global prevalence of CVD risk factors, risk-related genetic polymorphisms, and to identify potential predictors.

Methods: We conducted a comprehensive search of electronic databases up to June 2025 to identify studies comparing patients with pASCVD to age-matched healthy controls. The primary endpoint focused on the global and regional prevalence of risk factors, while secondary included identifying predictors and optimal cutoff values.

Results: A total of 260 studies comprising 8,221,010 participants (325,391 patients and 7,895,619 controls; mean age of 48.08±3.4 yrs) were included. Factors such as male gender, white race, smoking, alcohol consumption, physical inactivity were significantly more prevalent in patients compared to controls. Risk-enhancing genetic polymorphisms associated with endothelial dysfunction (eNOS G894T, T-786C, and 4a/4b), homocysteine levels (MTHFR C677T), vascular oxidative stress (CYBA 930A/G, ACE DD, and AGTR1 A1166C), thrombosis risk (Factor V G1691A and Factor II G20210A), and lipid metabolism (ApoE ε4) also showed a higher prevalence among patients (Fig. 1). Fig. 2 presents the pooled prevalence of risk factors along with their regional distribution. Predictors of pASCVD included male gender, black race, current smoking, physical inactivity, and heavy alcohol use; conversely, younger age (<45 years) was associated with a lower pASCVD risk (OR: 1.54, 1.39, 3.48, 2.11, 1.32, 0.72, respectively). The strongest clinical predictors of premature ASCVD were diabetes, dyslipidemia, hypertension, family history, and obesity (OR: 3.79, 3.09, 3.07, 2.65, and 2.32, respectively; p<0.005 for all). The best cutoff predictors were: LDL-C ≥160 mg/dL (OR: 3.49), TC ≥200 mg/dL (OR: 2.41), TG ≥150 mg/dL (OR: 1.83), HDL-C ≤50 mg/dL (OR: 1.52); Lp(a) ≥50 mg/dL (OR: 2.80); homocysteine >15 μmol/L (OR: 2.21); and CRP ≥10 mg/L (OR: 1.71) (Fig. 3).

Conclusions: Key predictors of pASCVD include male, gender, recognized CVD risk factors, elevated CRP, homocysteine, and selected atherosclerosis-related genetic variants. Early detection and targeted prevention strategies are crucial to reducing the global burden of pASCVD. The final meta-analysis will also address the impact of FH and the predictive role of genetic factors based on the extensive studies available.