The -675 4G/5G polymorphism at the Plasminogen Activator Inhibitor 1 (PAI-1) gene modulates plasma Plasminogen Activator Inhibitor 1 concentrations in response to dietary fat consumption

The objective of the study was to determine whether Plasminogen Activator Inhibitor Type 1 (PAI-1) -675 4G/5G polymorphism is associated with the response of functional plasma PAI-1 concentrations to changes in the amount and quality of dietary fat in healthy subjects. PAI-1 is the major inhibitor of fibrinolysis, and a lower level of fibrinolytic activity could be implicated in an increased risk of IHD. Fifty-nine healthy Spanish volunteers (ten 4G/4G homozygotes, twenty-eight heterozygotes 4G/5G and twenty-one 5G/5G homozygotes) consumed three diets for periods of 4 weeks each: a SFA-rich diet (38 % fat, 20 % SFA), followed by a carbohydrate-rich diet (30 % fat, 55 % carbohydrate) and a MUFA-rich diet (38 % fat, 22 % MUFA) according to a randomized crossover design. At the end of each dietary period plasma lipid and functional plasma PAI-1 concentrations were determined. Subjects carrying the 4G allele (4G/4G and 4G/5G) showed a significant decrease in PAI-1 concentrations after the MUFA diet, compared with the SFA-rich and carbohydrate-rich diets (genotype £ diet interaction: P¼ 0·028). 5G/5G homozygotes had the lowest plasma PAI-1 concentrations compared with 4G/4G and 4G/5G subjects (genotype: P¼ 0·002), without any changes as a result of the amount and the quality of the dietary fat. In summary, no differences in plasma PAI-1 concentration response were found after changes in dietary fat intake in 5G/5G homozygotes, although these subjects displayed the lowest concentrations of PAI-1. On the other hand, carriers of the 4G allele are more likely to hyper-respond to the presence of MUFA in the diet because of a greater decrease in PAI-1 concentrations. PAI-1 -675 4G/5G polymorphism: Nutrigenetics: Dietary fat: Functional PAI-1: MUFA-rich diet Plasminogen Activator Inhibitor Type 1 (PAI-1) is a protein that reduces plasma fibrinolytic capacity. Its production is encoded by a gene with several polymorphisms. The presence of the 4G allele at a common insertion–deletion polymorphism in the promoter of the PAI-1 gene has been associated with elevated plasma PAI-1 concentration and activity 1 . Carriers of the 4G allele (4G/4G and 4G/5G) may be at increased risk of IHD 2,3 , but this could depend on interactions with other environmental factors, which may explain why results obtained from Western populations have been ambiguous. On the other hand, previous studies have shown that the presence of the 5G allele in the -675 4G/5G polymorphism decreases gene expression, which predisposes to lower plasma PAI-1 concentrations 5 . A recent meta-analysis suggests the importance of this polymorphism because of a per-allele relative risk of about 1·06 of coronary disease in individuals with the -675 4G variant of the PAI-1 gene 6 .