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Media type:
E-Article
Title:
Angiotensin-Converting Enzyme I/D and α-Adducin Gly460Trp Polymorphisms : From Angiotensin-Converting Enzyme Activity to Cardiovascular Outcome
:
From Angiotensin-Converting Enzyme Activity to Cardiovascular Outcome
Description:
<jats:p>
The angiotensin-converting enzyme (
<jats:italic>ACE</jats:italic>
)
<jats:italic>I/D</jats:italic>
and the α-adducin (
<jats:italic>ADD1</jats:italic>
)
<jats:italic>Gly460Trp</jats:italic>
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
<jats:italic>ADD1 Trp</jats:italic>
allele carriers, the multivariate-adjusted hazard ratios associated with
<jats:italic>ACE DD</jats:italic>
versus
<jats:italic>I</jats:italic>
were 1.72 (
<jats:italic>P</jats:italic>
=0.007) for total mortality, 2.35 (
<jats:italic>P</jats:italic>
=0.02) for cardiovascular mortality, 2.02 (
<jats:italic>P</jats:italic>
=0.005) for all cardiovascular events, and 2.59 (
<jats:italic>P</jats:italic>
=0.03) for heart failure. In contrast, these hazard ratios did not reach significance in
<jats:italic>ADD1 GlyGly</jats:italic>
homozygotes (0.08≤
<jats:italic>P</jats:italic>
≤0.90). The positive predictive value and attributable risk associated with
<jats:italic>ACE DD</jats:italic>
homozygosity combined with mutated
<jats:italic>ADD1</jats:italic>
were 36.2% and 10.3%, respectively. To clarify our epidemiological observations, we investigated the effects of mutated human
<jats:italic>ADD1</jats:italic>
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;
<jats:italic>P</jats:italic>
=0.0021) and human embryonic kidney cells (1.086 versus 0.081 nmol/mg per minute;
<jats:italic>P</jats:italic>
=0.017), the membrane-bound ACE activity increased in the presence but not absence of the
<jats:italic>ADD1 Trp</jats:italic>
allele. In conclusion, the combination of
<jats:italic>ACE DD</jats:italic>
homozygosity and mutated
<jats:italic>ADD1</jats:italic>
worsened cardiovascular prognosis to a similar extent as classic risk factors, possibly because of increased membrane-bound ACE activity in subjects carrying the
<jats:italic>ADD1 Trp</jats:italic>
allele.
</jats:p>