Angiotensin-converting enzyme I/D and alpha-adducin Gly460Trp polymorphisms:from angiotensin-converting enzyme activity to cardiovascular outcome

The angiotensin-converting enzyme (ACE) I/D and the alpha-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. In ADD1 Trp allele carriers, the multivariate-adjusted hazard ratios
associated with ACE DD versus I 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 in ADD1 GlyGly homozygotes (0.08P0.90). The positive predictive value and attributable risk
associated with ACE DD homozygosity combined with mutated ADD1 were 36.2% and 10.3%, respectively. To clarify
our epidemiological observations, we investigated the effects of mutated human ADD1 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 the ADD1 Trp allele. In conclusion, the combination of ACE DD homozygosity and mutated
ADD1 worsened cardiovascular prognosis to a similar extent as classic risk factors, possibly because of increased
membrane-bound ACE activity in subjects carrying the ADD1 Trp allele.