Risk of Myocardial Infarction Related to Factor V Leiden Mutation: A Meta-Analysis Moataz Dowaidar and Ahmad Settin Background: Myocardial infarction (MI) can be due to inherited thrombophilia caused by resistance to activated protein C resulting from factor V Leiden (FVL) mutation. Objectives: The objectives of this study were to estimate the frequency of FVL mutation among MI cases in various populations and calculate the overall risk related to it. Subjects and Methods: Subjects comprised 7790 cases with MI and 19,276 healthy controls collected from 41 relevant studies in the search databases. The resulting frequency of FVL mutation among cases and the odds ratio were compared and integrated in a meta-analysis format. Results: Although there was marked variation of the frequency of FVL mutation among different populations including MI and healthy controls, most studies reported a positive risk related to it. Compilation of analyzed studies resulted in an overall frequency of FVL mutation of 6.791% among MI cases, which was significantly higher than that among controls (1.304%, p ¼ 0.0) with an overall odds ratio of 1.608 (95% confidence interval, 1.98–4.44). Conclusion: There is a definite risk related to the carriage of FVL mutation among MI cases. This should have a potential impact on the genetic counseling of family members of affected cases for proper prophylaxis. Introduction F actor V is a protein of the coagulation system that is not enzymatically active but functions as a cofactor. Its defi- ciency leads to predisposition for hemorrhage, whereas some mutations (most notably factor V Leiden [FVL]) predispose to thrombosis (Rosing and Tans, 1997). The human factor V gene is located on chromosome 1q21– 25 encoding a 7-kb mRNA, which encodes a prefactor V in- cluding a 28-amino acid residue signal peptide and a mature protein composed of 2196 amino acid residues (Cripe et al., 1992). The gene contains 25 exons that range in size from 72 to 2820 bp (Nicolaes and Dahlba ¨ ck, 2002). Activated protein C (APC) resistance phenotype is associ- ated in a majority of patients with heterozygosity or homo- zygosity due to a single point mutation in the factor V gene: a G to A transition at nucleotide position 1691 in which arginine 506 in the APC cleavage site is replaced by glutamine. This mutation type previously known as FVL or FV:Q506 is now updated as F5 NM_000130.3: c. 1601G>A: p.Arg534Gln in reference to the standard nomenclature proposed by the Human Genome Variation Society. The resulting amino acid substitution due to this mutation slows down the proteolytic inactivation of factor Va, thereby increasing the generation of thrombin (Samaha et al., 1995; Seligsohn and Lubetsky, 2001). So, FVL remains an important heritable cause of hypercoag- ulability since its discovery more than 10 years ago. Clinical suspicion should be high in cases of unexplained ve- nous thrombosis. APC resistance and FVL mutation (F5 NM_000130.3: c. 1601G>A: p.Arg534Gln) can be diagnosed with high sensitivity and specificity by using clotting time- based functional assays and genetic assays, respectively, allowing for evidence-guided clinical decision making re- garding the benefit of long-term anticoagulation for therapy and prophylaxis (Rosendorff and Dorfman, 2007; Varga, 2007). Acute myocardial infarction (MI) is defined as death or necrosis of myocardial cells due to lack of blood supply. Risk factors include hyperlipidemia, diabetes mellitus, hyperten- sion, smoking, male sex, and family history of atherosclerotic arterial disease (Grines et al., 1999). Interactively, hereditary thrombophilias such as FVL may confer a higher risk because of the involvement of coronary arteries (Glueck et al., 2007). FVL shows an uneven geographical distribution, ranging from virtual absence in natives of Africa, America, Asia, and Australia, to estimated prevalence of 15% in some areas of Sweden and Cyprus (Holm et al., 1996; Rees, 1996). FVL is relatively frequent in normal individuals, in populations of European origin where heterozygosis occurs in 3%–7% and homozygosis in about 0.1%–0.3% of the general U.S. and European populations (Press et al., 2002). For Asia, a 2.5% Genetics Unit, Egypt and Research Center, College of Medicine, Qassim University, Mansoura University Children Hospital, Buraydah, Saudi Arabia. GENETIC TESTING AND MOLECULAR BIOMARKERS Volume 14, Number 4, 2010 ª Mary Ann Liebert, Inc. Pp. 493–498 DOI: 10.1089/gtmb.2010.0017 493