Interactive effect of PAI-1 4G/5G genotype and salt intake on PAI-1 antigen

Activation of the renin-angiotensin-aldosterone system (RAAS) is associated with increased circulating PAI-1 antigen and increased risk of thrombotic cardiovascular events. A 4G/5G polymorphism located 675 bp upstream from the transcription start site of the PAI-I gene affects PAI-1 antigen concentrations. To test the hypothesis that PAI-I 4G/5G genotype influences the effect of activation of the RAAS on PAI-1 expression, we measured morning PAI-1 antigen concentrations in 76 subjects with essential hypertension during low (10 mmol/d) and high (200 mmol/d) salt intake. Low salt intake was associated with activation of the RAAS as measured by plasma renin activity (2.3 +/-0.2 versus 0.5 +/-0.0 ng angiotensin I-. mL(-1) h(-1), P <0.001) and aldosterone (529 +/- 40 versus 145 +/- 12 pmol/L). PAI-1 kantigen concentrations were 17.9 +/-2.7, 19.2 +/-2.5, and 27.8 +/-4.0 ng/mL during high salt intake and 19.2 +/-2.7, 21.6 +/-2.9, and 38.9 +/-7.2 ng/mL during low salt intake in the 5G/5G (n=14), 4G/5G (n=40), and 4G/4G (n=22) groups, respectively. There was a significant effect of both salt intake (F=6.0, P=0.017) and PAI-I 4G/5G genotype (F=7.6, P=0.001) on PAI-1 antigen. More importantly, there was a significant interactive effect (F= 7.8, P=0.001) of salt intake and PAI-I 4G/5G genotype on PAI-I antigen. PAI-1 4G/5G genotype influenced the relationship between serum triglycerides and PAI-1 antigen such that the relationship was significant only in 4G homozygotes during either high (R-2=0.31, P=0.014) or low (R-2=0.37, P=0.006) salt intake. This study identifies an important gene-by-environment interaction that may influence cardiovascular morbidity and the response to pharmacological therapies that interrupt the RAAS.