Association of the factor XII 46C>T polymorphism with risk of coronary heart disease (CHD) in the WOSCOPS study

Abstract

Aim: To evaluate the contribution of the 46C>T polymorphism of the Factor XII (FXII) gene to risk for coronary heart disease (CHD) in the West of Scotland Coronary Prevention Study (WOSCOPS) of men with high cholesterol. Background: WOSCOPS is a primary prevention trial that demonstrated the effectiveness of pravastatin in reducing morbidity and mortality from CHD. FXII is a protein of the contact system that plays a key role in both coagulation and fibrinolysis. Elevated activated FXII (FXIIa) levels have been previously associated with CHD. Plasma FXIIa levels are strongly determined by a 46C>T polymorphism in the FXII gene. Results: 441 CHD cases and 990 controls were genotyped. The frequency of TT homozygotes was 8.3% in controls and 11.8% in cases (P=0.04). When compared with the CC+CT group (after adjustment for age, blood pressure, BMI, fibrinogen and lipid levels) the TT genotype was an independent risk factor for CHD (OR 1.48 95% CI 1.01–2.17), an effect that was only significant in the pravastatin group (OR 1.95 95% CI 1.09–3.47) and not in the placebo group (OR 1.20, 95%CI 0.72–2.02). Compared with risk in the placebo group as a whole (reference group), and after adjustment for other risk factors, men with the CC or CT genotype, but not the TT genotype showed a significant benefit from pravastatin treatment (OR, respectively, 0.61 (0.46–0.81) and 0.56 (0.40–0.79) compared with 1.10 (0.64–1.96). In a subgroup of these men, subjects with the TT genotype had, as expected, baseline levels of FXIIa that were 50% lower than those with the CC genotype, with CT subjects having intermediate levels (P<0.001 by Kruskal–Wallis test). Conclusions: The TT genotype of the FXII 46C>T polymorphism is associated with a high risk of CHD in men with high cholesterol. We hypothesise that reduced fibrinolysis in these men, as a consequence of lower plasma FXIIa, may be the mechanism leading to higher risk, and that pravastatin treatment may enhance this effect.

Introduction

The serine protease Factor XII (FXII or Hageman Factor) is the first coagulation factor in the intrinsic pathway of coagulation cascade [1], [2]. It is activated during the contact phase [2], a system consisting of the plasma proteins FXII, prekallikrein, Factor XI and high-molecular-weight kininogen [3]. The system is initiated by the conversion of FXII to its activated form FXIIa [2], which then activates factor XI [4] and prekallikrein [5], thereby, creating the potential for the dissemination of reactions along several pathways concerned with coagulation and fibrinolysis and tissue defence and repair. These pathways include the production of bradykinin from HMWK [6], and the classical pathway of complement [7] and activation of factor IX [8] and factor VII [9] in the coagulation system. FXIIa activates the fibrinolytic pathway, indirectly through activation of urokinase [10], [11], [12] and possibly also directly by the conversion of plasminogen to plasmin [13].

Several studies have suggested that FXII [14] or FXIIa levels [15], [16], [17], [18], [19] are involved in modulating the risk of coronary heart disease (CHD). High FXIIa levels have been reported in survivors of an acute myocardial infarction (MI) compared with healthy control subjects in several [14], [15], [16], but not in all studies [17]. In addition, FXIIa is associated positively with plasma lipids, tissue-type plasminogen activator (t-PA) antigen and plasma insulin [15]. The second Northwick Heart Park Study (NPHS) also showed that in healthy middle-aged men FXIIa was positively and independently associated with the major conventional risk factors for CHD, including age, current smoking, BMI and triglyceride levels [17]. NPHS has also reported that FXIIa levels in the highest tertile of distribution (>2.0 ng/l) are associated with approximately 2-fold higher risk of CHD over 5 years of prospective surveillance of a cohort of healthy men, and that this effect is independent of other risk factors [19].

A common polymorphism within the FXII gene has recently been identified [20]. This is due to a sequence variation 46C>T, with the T allele creating a novel methionine initiating codon that reduces the translation efficiency of FXII [20]. As would be predicted from this, several studies have shown that the T allele, and particularly the TT genotype, is associated with significantly lower levels of FXIIa [16], [19], [20], and, thus, our original hypothesis was that men with the TT genotype would have low risk of CHD. Here we have investigated the relationship between the 46C>T polymorphism and the risk for CHD in the West of Scotland Coronary Prevention Study (WOSCOPS), which demonstrated a significant reduction in CHD events in men treated with pravastatin for 5 years compared with a placebo-treated group [21]. It has been reported that statin use is associated with a significant reduction in FXIIa levels [22], and we, therefore, examined whether the 46C>T polymorphism and specifically the TT genotype was associated with effects on CHD risk separately in the treatment and placebo subjects.