Background/Objectives: Lipoprotein (a) [Lp(a)] plays a significant role in atherosclerosis and cardiovascular disease (CVD). Genetic regulation of Lp(a) involves variations in the apo(a) LPA gene, as specific polymorphisms like rs10455872 and rs3798220, both linked to higher Lp(a) levels and CVD. CVD remains the leading global cause of death, with high Lp(a) levels increasingly recognized as a significant factor in younger patients with no other CVD risk factors. We aimed to evaluate the association of LPA genetic variations with Lp(a) levels and its effect on cardiovascular risk as there are existing inconsistent findings. Methods: This case–control study included 251 subjects with a median age of 52 years (interquartile range, IQR = 17) and elevated Lp(a) levels. Cases were subjects who experienced early cardiovascular incidents (women < 65, men < 55 years old), and the control group included subjects without such history. Genotyping of LPA gene polymorphisms (rs10455872 and rs3798220) was performed, and demographic data with Lp(a) levels were collected. To evaluate the association between the LPA genotypes and the risk of cardiovascular incidents (CVI), several logistic regression models were performed. The cut-off points for Lp(a) levels were determined using diagnostic test accuracy measures. Results: The rs3798220-C allele was associated with higher Lp(a) levels (288 ± 166 nmol/L in cases vs. 189 ± 102 nmol/L in controls, p < 0.001) and myocardial infarction (53% in cases vs. 36% in controls, p = 0.036). Among cases, 28.9% carried the rs3798220-C allele, compared to 18.7% in controls. The rs10455872-G allele was slightly more prevalent in controls (34.15% vs. 29.69%) but without further significant associations. In this study, the cut-off Lp(a) value of 151 nmol/L, for patients with a positive family history of early CVD, is associated with a higher chance of developing CVI. Conclusions: This study demonstrates an association between the LPA rs3798220-C allele and higher Lp(a) levels, as well as an increased risk of early onset myocardial infarction. However, the obtained association should further be evaluated at a much larger scale.

Lipoprotein (a) is a highly atherogenic, lipid particle whose concentration is genetically determined, and represents an independent risk factor for cardiovascular disease. On the other hand, metabolic syndrome represents a cluster of interconnected cardiovascular risk factors (obesity, insulin resistance, arterial hypertension, dyslipidemia) that are a direct consequence of an unhealthy lifestyle. Some evidence suggests a connection between each component of metabolic syndrome and high levels of lipoprotein (a). Still, the exact mechanisms are not fully understood and may involve complex interactions between various metabolic pathways. High levels of lp(a) are associated with insulin resistance, a key feature of type 2 diabetes mellitus and obesity. Although there is no significant association between lp(a) and other lipid levels (LDL-C, HDL-C, triglycerides), studies have shown a strong synergistic effect of genetically elevated LDL-C and Lp (a) on the development of cardiovascular events. Also, there is supporting evidence that hypertensive patients with high levels of lp(a) have higher cardiovascular risk, there is no direct association between hypertension and lp (a). Treatment of metabolic syndrome is often long-term and challenging but very important to reduce the overall cardiovascular risk, especially in individuals with higher levels of Lp (a), in whom the risk of developing cardiovascular disease is much higher.