The frequency of FVL mutation in healthy European Caucasian populations ranges from 2.5% to 13.3% (pooled prevalence 4.7%), with Greece [29
] and Sweden [30
] showing the highest prevalence and Italy [31
] and Netherlands [14
] the lowest. The epidemiology of FVL has been presented in several reviews. [10
] In a cohort of 4,047 U.S men and women the prevalence of FVL was found to be the highest in European Americans (5.27%) compared to other racial/ethnic groups; 2.21% in Hispanic Americans, 1.23% in African Americans, 0.45% in Asian Americans, and 1.25% in Native Americans (p < 0.001). [35
] The frequency of FVL in persons of African descent is estimated to range from 0% to 1.3%. [9
FVL has been well established as a risk factor for venous thromboembolism. The overall prevalence of FVL in patients with venous thromboembolism is 18.3%; being lower in African Americans (1.2–2.9%) [33
] and higher for Swedes.[30
] Among participants of the Physicians’ Health Study [35
] the frequency of FVL was significantly higher in men with thromboembolism (11.6%) compared to those that did not experience a thromboembolic event (6%). This higher frequency was associated with a 2.7 fold risk [95% CI 1.3, 5.6] of venous thromboembolism (p=0.0008). Homozygosity for the FVL mutation further increases this risk [14
] as do factors such as smoking, OCP use, surgery, immobility etc. [2
FVL mutation has been hypothesized as an important risk factor for arterial thromboembolic events (predominantly myocardial infarction and stroke), which are the leading causes of illness and death in the United States. However the overall prevalence of 5.4% among patients is very similar to that in healthy population controls. [10
] FVL mutation was not found to be associated with myocardial infarction (6.1%; p >0.2) or cerebrovascular disease (4.3% percent; p >0.2). [35
] Furthermore, most population-based, case-control studies and pooled analyses confirm that FVL mutation is not a risk factor for myocardial infarction or cerebrovascular disease. [19
] The association of FVL mutation with thrombosis in the arterial circulation is at best modest (OR=1.21, 95% CI [0.99–1.49]) and remains equivocal. [10
Our patient population was comprised of individuals requiring chronic anticoagulation and did not have significant predisposing conditions for DVT (e.g. surgery, etc.). As expected the prevalence of FVL was lower in African American (1.3%) compared to European American patients (8.6%, ). Surprisingly, no patient was found to be homozygous for the mutation and we did not encounter the presence of FVL mutation in patients with conditions such as atrial fibrillation or low ejection fraction. The latter finding may be due to small sample size in this subgroup (n=68), 45.6% of which was constituted by African Americans patients (n = 31), or perhaps chance.
In our study the frequency of FVL mutation among African American patients with venous thromboembolism was 2.0%, similar to that reported by Dowling and Hooper. [36
] We observed a similar frequency for African American patients with arterial thromboembolism (1.8%). This lack of difference in the frequency of FVL by site of thromboembolism could be due to the rarity of the mutation or due to its relative lack of contribution to the thromboembolic disease in this racial group ().
The GA genotype frequency among European Americans in our study was similar to that reported by Ridker and Rosendaal. [2
] Results of univariate analysis, although statistically non-significant, indicate an approximate two-fold difference in frequency of the GA genotype among European-American subjects being treated for venous (18.2%) versus arterial (8.9%) thromboembolism (). However after statistical adjustments for other variables, the odds ratio exceeds 6.
To understand reasons for this change in effect size in European American patients further analysis was conducted. The significant difference in the age (mean ± SD) between patients with arterial thromboembolism (67.7 ± 12.3) and venous thromboembolism (55.6 ± 17.3) partly explains the change in effect size. This difference in age was even more pronounced among European American patients with the GA genotype and arterial thromboembolism (75.2 ± 8.4) and patients with the GA genotype and venous thromboembolism (57.3 ± 17.0). These substantial age differences result in a dramatic increase in the odds ratio for the GA mutation in European Americans when age is included in the logistic regression model.
Our results indicate that European American patients with the GA genotype were approximately six times more likely to suffer from a venous, rather than arterial thromboembolism after controlling comorbidities and demographic variables (). As reported by Dilley et al [37
], the GA genotype was not found to be associated with an increased risk of arterial versus venous thromboembolism in African American patients. This could be due to the low power of the study to detect allelic effects in African Americans. Given the low frequency of the ‘A’ allele among the African Americans in this study (0.67%), there would need to be a sample size of 1154 African Americans to detect an Odds Ratio of 2 with 80% power at α = 0.05.
The influence of FVL mutation in European American but not in African American patients raises the concern of confounding due to population stratification. When comparing the frequency of the FVL mutation, among various racial and ethnic groups one has to consider the contribution of racial admixture. The difference in the reported frequencies of FVL mutation could be due to racial differences or to the various degree of racial admixture within a given racial/ethnic group. Although several ethnic groups are represented in the Alabama European American population, there is a large constituency of those with Scotch/Irish and English ancestry. [44
] The degree of racial admixture among African Americans is known to vary considerably among those living in different geographic regions of the US. [46
] Thus, if one is attempting to determine whether a mutation varies between any groups that are being compared it is important that the two groups are recruited from the same geographic region. [49
] Although the small sample size and the evaluation of only one gene did not allow us to conduct admixture studies the patients recruited all resided in a relatively defined area which is the third least migratory region of the US. [50