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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1071.)
© 2001 American Heart Association, Inc.

Thrombosis

Interactive Effect of PAI-1 4G/5G Genotype and Salt Intake on PAI-1 Antigen

Nancy J. Brown; Laine J. Murphey; Nadarajah Srikuma; Natapong Koschachuhanan; Gordon H. Williams; Douglas E. Vaughan

From the Divisions of Clinical Pharmacology (N.J.B., L.J.M.) and Cardiovascular Medicine (D.E.V.), Vanderbilt University Medical Center, and the Veterans Administration Medical Center (D.E.V.), Nashville, Tenn; and the Endocrine Hypertension Division, Harvard Medical School and Brigham and Women’s Hospital, Boston, Mass (N.S., N.K., G.H.W.).

Abstract—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 (R²=0.31, P=0.014) or low (R²=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.

Key Words: thrombosis • genetics • fibrinolysis • coagulation

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