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

Brown NJ, Murphey LJ, Srikuma N, Koschachuhanan N, Williams GH, Vaughan DE
Arterioscler Thromb Vasc Biol. 2001 21 (6): 1071-7

PMID: 11397722 · DOI:10.1161/01.atv.21.6.1071

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-1 gene affects PAI-1 antigen concentrations. To test the hypothesis that PAI-1 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 antigen 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-1 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-1 4G/5G genotype on PAI-1 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.

MeSH Terms (14)

Blood Pressure Female Fibrinolysis Genotype Humans Hypertension Male Middle Aged Plasminogen Activator Inhibitor 1 Polymorphism, Genetic Renin-Angiotensin System Sodium Thrombosis Triglycerides

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