© 2000 American Heart Association, Inc.
Clinical Research |
A Variant of p22phox, Involved in Generation of Reactive Oxygen Species in the Vessel Wall, Is Associated With Progression of Coronary Atherosclerosis
From the Sections of Cardiology and Atherosclerosis, Department of Medicine (C.C., C.M.B., D.-S.L., A.J.M.), Baylor College of Medicine, Houston, Tex; Cornell University Medical College (A.G.), New York, NY.
Correspondence to A.J. Marian, MD, Assistant Professor of Medicine, Section of Cardiology, One Baylor Plaza, 543E, Houston, TX 77030. E-mail amarian{at}bcm.tmc.edu
Abstract—A series of pro-oxidant
and antioxidant enzymes, such as the NADPH oxidase system, maintain the
redox state in the vessel wall. A major component of NADPH oxidase is
p22phox, which is implicated in
atherosclerosis. We prospectively studied the
association of the histidine (H)72
tyrosine (Y) mutation
in p22phox with the severity and
progression/regression of coronary artery disease (CAD), plasma
lipid levels, clinical events, and response to treatment with
fluvastatin in a well-characterized population.
Genotypes were determined by polymerase chain reaction and
restriction digestion with RsaI enzyme in 368 subjects
in the Lipoprotein and Coronary Atherosclerosis
Study (LCAS). Fasting plasma lipids and quantitative coronary
angiograms were obtained at baseline and 2.5 years after randomization
to fluvastatin or placebo. Subjects with CC
genotype (n=157) were identified by the presence of 396-bp and
113-bp products on gel electrophoresis. Those with TT (n=39) were
identified by the presence of 316-bp, 113-bp, and 80-bp products,
and those with CT (n=172) by the presence of 396-bp, 316-bp, 113-bp,
and 80-bp products. Baseline and final plasma levels of lipids and
the baseline severity of CAD were not significantly different among the
genotypes. In the placebo group, subjects with the mutation had
a 3- to 5-fold greater loss in mean minimum lumen diameter (MLD) (TT:
-0.15±0.15; CT: -0.17±0.26; and CC: -0.03±0.22 mm;
P=0.006) and lesion-specific MLD (TT: -0.15±0.06; CT:
-0.18±0.03; and CC: -0.06±0.03 mm; P=0.038)
than those without. Progression was also more (TT: 8/17 [47%]; CT:
35/73 [48%]; and CC: 17/62 [27%]) and regression less (TT: 0/17
[0%]; CT: 1/73 [1%]; and CC: 11/72 [18%]) common in those with
the mutation (P=0.002). The C242T mutation
in p22phox, involved in maintaining the redox
state in the vessel wall, is associated with progression of
coronary atherosclerosis in the LCAS
population.
Key Words: atherosclerosis • genetics • coronary disease • reactive oxygen species • polymorphism
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