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-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.
Brown
N J
NJ
Divisions of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232-6602, USA.
Murphey
L J
LJ
Srikuma
N
N
Koschachuhanan
N
N
Williams
G H
GH
Vaughan
D E
DE
D001794:Blood Pressure; D005260:Female; D005342:Fibrinolysis; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000235:genetics* / Q000276:immunology; D011110:Polymorphism, Genetic; D012084:Renin-Angiotensin System; D012964:Sodium / Q000378:metabolism*; D013927:Thrombosis / Q000235:genetics; D014280:Triglycerides / Q000097:blood
D017395:Plasminogen Activator Inhibitor 1; D014280:Triglycerides; D012964:Sodium