Background: Factor VIII activity (FVIII:C) levels present an high heritability. However, a few genetic polymorphisms have been demonstrated to contribute to FVIII:C broad variability. Observations in mouse models suggest that low-density lipoprotein receptor (LDLR) may play a role in regulating FVIII plasma levels. In the current study we assessed the association between a common polymorphism of the LDLR gene (rs688, C to T transition in the exon 12) and FVIII:C levels in a subset of patients from the angiography-based Verona Heart Study (VHS), with or without coronary artery disease (CAD). Methods: A total number of 983 subjects (692 CAD and 291 CAD-free) not assuming anticoagulants at enrolment in the VHS were included in the present study. For all these subjects data about both FVIII:C levels and LDLR rs688 genotype were available. Results: The carriers of T allele presented higher FVIII:C levels than CC homozygotes (168 ± 54 vs. 160 ± 51 IU/dL, P = 0.031 by t-test). In a linear regression model adjusted for sex, age, blood group, inflammation status and renal function, the carriership of T allele remained an independent determinant of FVIII:C levels (standardized beta-coefficient 0.079, P = 0.013). On the other hand, no significant association was found between the rs688 polymorphism and plasma lipid concentrations. Consistently with FVIII:C levels, the carriership of T allele was more represented in CAD patients than in CAD-free subjects (69.9% vs. 62.5%, P = 0.023) and remained significantly associated with CAD after adjustment for all the traditional atherosclerosis risk factors, including lipid profile (OR 1.53 with 95%CI 1.04–2.25, P = 0.031). Conclusions: Our data suggest that the LDLR rs688 genotype, modulating splicing efficiency, predicts FVIII:C levels. Carriers of T allele may have an increased risk of CAD independently from cholesterol levels.
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