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.