Epistatic effects of ACE I/D and AGT gene variants on left ventricular mass in hypertensive patients: the HyperGEN study

Identifying predictors of left ventricular hypertrophy has been an active study topic because of its association with cardiovascular morbidity and mortality. We examined the epistatic effect (gene–gene interaction) of two genes (angiotensin-converting enzyme ( ACE ) insertion/deletion (I/D); angiotensinogen ( AGT ) -6G-A, M235T, -20A-C) in the renin–angiotensin system on left ventricular mass (LVM) among hypertensive participants in the Hypertension Genetic Epidemiology Network study. Included were 2156 participants aged 20–87 years (60% women, 63% African American). We employed mixed linear regression models to assess main effects of four genetic variants on echocardigraphically determined LVM (indexed for height), and ACE -by- AGT epistatic effects. There was evidence that AGT -6G-A was associated with LVM among white participants: adjusted mean LVM (gm –2.7 ) increased with ‘G’ allele copy number (‘AA’:41.2, ‘AG’:42.3, ‘GG’:44.0; P =0.03). There was also evidence of an ACE I/D-by- AGT -20A-C epistatic effect among white participants (interaction P =0.03): among ACE ‘DD’ participants, AGT -20A-C ‘C’ allele carriers had lower mean LVM than ‘AA’ homozygotes (‘DD/CC’:39.2, ‘DD/AC’:39.9, ‘DD/AA’:43.9), with no similar significant effect among ACE ‘I’ allele carriers (‘ID/CC’:47.2, ‘ID/AC’:43.4, ‘ID/AA’:42.6; ‘II/CC’: NA, ‘II/AC’:41.3, ‘II/AA’:43.1). These findings indicate that renin–angiotensin system variants in at least two genes may interact to modulate LVM.