Unmasking Genetic Predispositions: Factor V Leiden and the Evolving Landscape of Coronary Artery Disease in Pakistan

Abstract

Cardiovascular disease (CVD) continues to impose a substantial burden on global health systems, with coronary artery disease (CAD) remaining the leading cause of morbidity and mortality worldwide. In Pakistan, this burden is particularly concerning, as CAD not only presents with high prevalence but also manifests at younger ages and often with increased clinical complexity. While conventional risk factors such as hypertension, diabetes mellitus, sedentary lifestyle, and tobacco use contribute significantly to disease progression, they do not fully account for the early onset and severity observed in many patients. This underscores the need to explore underlying genetic predispositions that may contribute to disease susceptibility [1,2]. In this context, the study by Pathan et al. [3] provides valuable insight into the genetic determinants of CAD. The authors focus on the Factor V Leiden (FVL) mutation, a well-characterized genetic variant associated with resistance to activated protein C and a resultant prothrombotic state. Although its role in venous thromboembolism is well established, the association between FVL and arterial thrombosis, including CAD, has remained inconsistent across different populations [4]. The findings of this case–control study are noteworthy. The authors demonstrate a statistically significant association between the FVL mutation and CAD, with the heterozygous GA genotype observed more frequently in CAD patients (15%) compared with controls (4%), corresponding to an approximately fourfold increased risk. Furthermore, the study reports a significant relationship between the presence of the mutant allele and angiographic severity, with higher frequencies of GA and AA genotypes among patients with multi-vessel disease. These findings suggest that the FVL polymorphism may not only contribute to disease susceptibility but may also be associated with more extensive coronary involvement. Importantly, the study also reaffirms the role of traditional cardiovascular risk factors, including hypertension, dyslipidemia, hyperglycemia, and elevated fibrinogen levels, all of which were significantly more prevalent among CAD patients. The coexistence of these metabolic abnormalities with prothrombotic genetic variants highlights a potential synergistic effect, contributing to enhanced thrombotic tendency and accelerated atherosclerotic progression. Notably, the independent association of the FVL polymorphism with CAD risk, even after adjustment for confounders, suggests that genetic predisposition may represent an additional layer of risk beyond conventional factors [5]. From a clinical perspective, these findings prompt important considerations. The concept of integrating genetic screening into cardiovascular risk assessment, particularly among younger individuals or those with a strong family history of CAD, aligns with the emerging paradigm of precision medicine. However, it is essential to interpret these results with caution. Current international guidelines do not support routine screening for FVL in CAD patients, and the evidence base remains insufficient to warrant immediate changes in clinical practice. Several limitations inherent to the study design must also be acknowledged. The relatively modest sample size and single-population focus may limit generalizability, while the case–control design precludes definitive causal inference. Additionally, CAD is a multifactorial and polygenic disorder, and the evaluation of a single genetic polymorphism may not fully capture the complexity of its genetic architecture. Nevertheless, this study makes a meaningful contribution to the growing body of literature exploring genetic determinants of CAD in South Asian populations. It reinforces the importance of population-specific research and highlights the potential role of thrombophilia-related genetic variants in cardiovascular disease pathogenesis. The work by Pathan et al. advances our understanding of the interplay between genetic and traditional risk factors in CAD. While further large-scale, multi-center, and longitudinal studies are required to validate these findings, this study provides an important step toward more individualized approaches to cardiovascular risk assessment and prevention. References Agosti P, Mancini I, Sadeghian S, Pagliari MT, Abbasi SH, Pourhosseini H, et al. Factor V Leiden but not the factor II 20210G> A mutation is a risk factor for premature coronary artery disease: a case-control study in Iran. Res Pract Thromb Haemost. 2023;7(1):100048-56. 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