Role of PC-1 and ACE genes on insulin resistance and cardiac mass in never-treated hypertensive patients. Suggestive evidence for a digenic additive modulation

BACKGROUND AND AIM: Insulin resistance and increased left ventricular mass (LVM) characterize patients with essential hypertension. Some genetic polymorphisms play a role in the modulation of both insulin resistance and LVM. The aim of this work was to investigate whether the PC-1 and ACE genes exert a polygenic control of insulin resistance and LVM in hypertensive patients. METHODS AND RESULTS: In 158 never-treated hypertensive patients, we evaluated insulin resistance by HOMA index [insulin (microU/mL) x glucose (mmol/L)]/22.5 and LVM by echocardiograms. Genetic polymorphisms were obtained by polymerase chain reaction. PC-1 X121Q genotype carriers (K121Q+Q121Q, n=46) had higher HOMA (3.14+/-1.28 vs. 2.49+/-1.25; p=0.002) and LVM (137+/-34 vs. 127+/-24 g/m2; p=0.02) than K121K patients (n=112). Similarly, ACE DD carriers (n=56) showed higher HOMA (3.94+/-1.13 vs. 1.98+/-0.72; p<0.00001) and LVM (142+/-26 vs. 123+/-25 g/m2; p=0.00004) than XI (ID+II, n=102) patients. When considering both PC-1 and ACE polymorphisms, HOMA (p<0.00001) and LVM (p=0.00003) progressively increased from K121K/XI to X121Q/XI, K121K/DD and X121Q/DD patients. The association of both gene polymorphisms with LVM was no longer significant after adjusting for HOMA values. As compared to K121K/XI patients (i.e. no at risk alleles), X121Q/DD patients had a significantly increased risk (OR: 4.4, 95% C.I. 1.4-14.0, p=0.011) to have left ventricular hypertrophy. CONCLUSIONS: In hypertensive patients PC-1 K121Q and ACE I/D polymorphisms have an additive deleterious effect on insulin resistance and, consequently, on LVM, thus increasing the global cardiovascular risk. Identification of carriers of the at-risk genotypes may help set up prevention strategies to be specifically targeted at these patients.