Haplotypes encoding the factor VIII 1241Glu variation and the risk of myocardial infarction

There are also indications that elevated FVIII levels contribute to the risk of arterial thrombosis [5–11]. In 2003, Machiah et al. [12] reported a missense single nucleotide polymorphism (SNP) in the X-chromosomal FVIII gene, c94901 g, which causes an amino acid change in the B-domain of FVIII, Asp1241Glu (D1241E). This amino acid change was associated with a decrease in FVIII:C. Machiah et al. found that this polymorphism accounts for approximately 5% of total variation in FVIII:C in the population of the Genetic Analysis of Idiopathic Thrombophilia (GAIT) study [12]. More recently, Scanavini et al. [13] reported that 1241E was associated with an 11% reduction in FVIII:C in 145 healthy women and 150 women with venous thrombosis. It is unclear by which mechanism the 1241E variant influences the levels of FVIII. Scanavini et al. [13] hypothesized that the variation was involved in activated protein C (APC) resistance, but could not demonstrate this. On the website of SeattleSNPs [14], SNP and haplotype data are presented for a wide variety of genes, including the gene encoding FVIII. These data are based on the re-sequencing of these genes in 23 subjects of European–American descent. In this population, the SNP encoding 1241E is present in at least three different haplotypes, HT1, HT3 and HT5, of which possibly only one is responsible for the reported effects on FVIII levels. Recently, we investigated the effects of these three haplotypes on levels of FVIII and on the risk of venous thrombosis [15]. We confirmed a reduction in levels of FVIII, but this effect was restricted to only one of the three haplotypes, HT1, in men. In this group, men with HT1, a reduction in venous thrombosis risk was observed; however, the reduction in risk could only partially be explained through the reduction in FVIII levels [15]. This suggested that functional variations in the FVIII molecule may also contribute to the development of venous thrombosis. To investigate whether these three FVIII gene haplotypes also affect the risk of arterial thrombosis, we studied the effects of these haplotypes in two population-based case-control studies on myocardial infarction: Study of Myocardial Infarctions Leiden (SMILE) and Risk of Arterial Thrombosis in Relation to Oral Contraceptives study (RATIO). Both studies have been described previously in more detail [16,17]. In brief, SMILE consists of 560 patients, all men below the age of 70, diagnosed with a first myocardial infarction. The control group consists of 646 men who do not have a history of myocardial infarction. Control subjects were frequency matched to patients on 10-year age groups. Plasma and DNA samples were available for all participants. RATIO consists of three substudies for different vascular events: ischemic stroke, peripheral vascular disease and myocardial infarction. Only patients with myocardial infarction were included in the present study. Patients were 248 women between the ages of 18 and 49 who were hospitalized for a first