Evaluation of Serum Homocysteine and Lipoprotein(a) as Emerging Risk Markers in Premature Coronary Artery Disease: Systematic Review

The present systematic review aimed to evaluate and synthesize current evidence on the role of serum homocysteine and lipoprotein(a) as emerging biomarkers in premature coronary artery disease (CAD).An extensive literature search was conducted across PubMed, Scopus, Web of Science, and Google Scholar databases for studies published between January 2000 and June 2025.Following PRISMA guidelines, 26 studies were selected after screening 1,028 articles based on predefined inclusion and exclusion criteria.The included studies demonstrated that elevated serum homocysteine and Lp(a) levels were consistently associated with an increased risk of premature CAD, particularly in individuals under 45 years of age.Both markers showed a significant correlation with the extent and severity of atherosclerotic lesions, independent of traditional risk factors such as hypertension, diabetes, and dyslipidemia.Several studies indicated that combined elevation of homocysteine and Lp(a) conferred a synergistic risk, potentially due to enhanced oxidative stress, endothelial dysfunction, and impaired fibrinolysis.Furthermore, genetic polymorphisms, especially in the MTHFR gene, and nutritional deficiencies of folate and vitamin B12 were identified as major determinants of elevated homocysteine levels in affected individuals.Despite substantial evidence supporting their pathophysiological role, variations in assay standardization, cutoff values, and population heterogeneity limit their integration into routine cardiovascular risk assessment.The findings suggest that simultaneous estimation of homocysteine and Lp(a) could enhance early identification of individuals at high risk for premature CAD, especially in regions with high genetic susceptibility and nutritional deficiencies.However, large-scale prospective studies with standardized methodologies are warranted to establish definitive cutoff thresholds and evaluate the clinical utility of targeted therapeutic interventions aimed at modulating these biomarkers.