Angiotensin-Converting Enzyme I/D and α-Adducin Gly460Trp Polymorphisms

The angiotensin-converting enzyme (ACE )I/D and the α-adducin (ADD1 )Gly460Trp polymorphisms are associated with cardiovascular risk factors. In a prospective population study and in cell models, we investigated the combined effects of these 2 polymorphisms. We randomly recruited 1287 white subjects (women: 50.0%; mean age: 55.9 years). We obtained outcomes from registries and repeat examinations (median 3). Over 9.0 years (median), 178 fatal or nonfatal cardiovascular events occurred. InADD1 Trp allele carriers, the multivariate-adjusted hazard ratios associated withACE DD versusI were 1.72 (P =0.007) for total mortality, 2.35 (P =0.02) for cardiovascular mortality, 2.02 (P =0.005) for all cardiovascular events, and 2.59 (P =0.03) for heart failure. In contrast, these hazard ratios did not reach significance inADD1 GlyGly homozygotes (0.08≤P ≤0.90). The positive predictive value and attributable risk associated withACE DD homozygosity combined with mutatedADD1 were 36.2% and 10.3%, respectively. To clarify our epidemiological observations, we investigated the effects of mutated humanADD1 on the membrane-bound ACE activity in fibroblasts from 51 volunteers and in transfected human embryonic kidney cells (31 experiments). In fibroblasts (5.10 versus 3.63 nanomoles of generated hippuric acid per milligram of protein per minute;P =0.0021) and human embryonic kidney cells (1.086 versus 0.081 nmol/mg per minute;P =0.017), the membrane-bound ACE activity increased in the presence but not absence of theADD1 Trp allele. In conclusion, the combination ofACE DD homozygosity and mutatedADD1 worsened cardiovascular prognosis to a similar extent as classic risk factors, possibly because of increased membrane-bound ACE activity in subjects carrying theADD1 Trp allele.