© 2000 American Heart Association, Inc.
Vascular Biology |
Plasma Levels of Extracellular Superoxide Dismutase in an Australian Population
Genetic Contribution to Normal Variation and Correlations With Plasma Nitric Oxide and Apolipoprotein A-I Levels
From the Department of Genetics (M.C.M., S.A.C.), Southwest Foundation for Biomedical Research, San Antonio, Tex; the Laboratory of Clinical Pharmaceutics (T.A.), Gifu Pharmaceutical University, Gifu, Japan; and the Department of Cardiovascular Medicine (D.E.L.W., X.L.W.), University of New South Wales, Prince Henry/Prince of Wales Hospital, Sydney, Australia.
Correspondence to M.C. Mahaney, PhD, Department of Genetics, Southwest Foundation for Biomedical Research, PO Box 760549, San Antonio, TX 78245-0549. E-mail mmahaney{at}darwin.sfbr.org
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Abstract |
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Abstract—Extracellular superoxide dismutase (EC-SOD) is a major superoxide scavenger and may be important to normal vascular function and cardiovascular health. We analyzed family data from 610 healthy Australians to detect and quantify the effects of genes on normal variation in plasma levels of EC-SOD and to test for pleiotropy with plasma nitric oxide (NO) and apolipoprotein A-I (apoA-I). Using maximum-likelihood–based variance decomposition methods, we determined that sex, age, and plasma levels of HDL cholesterol, apoA-I, and creatinine accounted for 38.6% of the variance in plasma EC-SOD levels and that additive genes accounted for 35% (P<0.00002). Multivariate analyses of plasma levels of EC-SOD, NOx (a measure of basal NO production), and apoA-I detected significant genetic correlations, indicating pleiotropy between EC-SOD and apoA-I (genetic correlation [
G]=-0.45) and between NOx and apoA-I
(G=0.58) but not between EC-SOD and NOx.
Genes shared by EC-SOD and apoA-I account for 20% of the genetic
variance and, respectively, 7% and 9% of the phenotypic variance in
both traits. Shared genes also account for >33% of the genetic
variance and 5% and 15% of the respective phenotypic variance in
NOx and apoA-I. In healthy individuals, over a third of the
variance in EC-SOD plasma levels is due to the additive effects of
genes. Some genes influence EC-SOD and apoA-I levels. The same is true
of NOx and apoA-I but not of EC-SOD and NOx.
These patterns of pleiotropy can guide subsequent attempts to identify
the genes and physiological mechanisms
underlying them.
Key Words: superoxide dismutase • nitric oxide • apolipoproteins • heritability • pleiotropy
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Introduction |
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Reactive oxygen species (ROS), such as superoxide anions, the hydroxyl radical, hydrogen peroxide, and peroxynitrites, are produced by many cell types, including endothelial cells, smooth muscle cells, neutrophils, monocytes, and platelets,1 and are implicated in many pathologies, including those affecting the cardiovascular system. Superoxide radicals react with various molecules, resulting in either direct damage or potentially harmful products. Of particular interest to cardiovascular biology is their avid reaction with nitric oxide (NO), which is constantly produced by endothelium and facilitates the maintenance of basal vascular tone, to form peroxynitrite, a potent oxidant.1 2 3 4 Abundant peroxynitrite, as identified by nitrotyrosine, is detected in atherosclerotic lesions, and overproduction of peroxynitrite has been implicated in atherogenesis.3 5 6 7
One protective response of tissues against untoward effects of ROS is production of antioxidative molecules, such as superoxide dismutase (SOD). Whereas each of the 3 isoenzymes of SOD (secreted extracellular SOD [EC-SOD], cytosolic CuZn-SOD, and mitochondrial Mn-SOD)8 9 10 has specific cellular locations and functions, all reduce superoxide radicals to hydrogen peroxide and molecular oxygen. Over 90% of EC-SOD is found in the interstitial spaces of tissues and extracellular fluids and is responsible for the majority of SOD activity of plasma, lymph, and synovial fluid.8 11 12 EC-SOD has a high affinity for heparin sulfate proteoglycans13 14 15 present in the connective tissue matrix and on cell surfaces, particularly surfaces of endothelial cells. Endothelium surface–bound EC-SOD is the primary source of circulating plasma EC-SOD, and levels are in equilibrium between these 2 phases.11 12 16 It is a key component in the antioxidation capability of the vascular wall and likely contributes to atherogenesis.
Results of a recent study in an Australian population with coronary artery disease are consistent with a relation between EC-SOD bioavailability and cardiovascular disease risk.17 When individuals with a mutation known to produce extremely high EC-SOD levels were excluded, plasma EC-SOD levels were inversely associated with smoking behavior so that those of current smokers were lowest, those of exsmokers were intermediate, and those of nonsmokers were highest. Furthermore, patients with a history of myocardial infarction had lower plasma EC-SOD levels.
Known genetic effects on plasma EC-SOD levels are limited to those
attributed to a single base-pair substitution, Arg213
Gly at the
heparin-binding domain, in the structural gene for EC-SOD located on
chromosome 4 (4pter-q21). This mutation has been identified and found
to be associated with very high plasma EC-SOD levels in several
populations, albeit with a low prevalence: eg, 6% in Japanese, 3.2%
in Australian whites, and 2.2% in Swedes.17 18 19 20 21
The mutation impairs the affinity of EC-SOD for heparin at the
endothelial cell surface,18 22 23 but
given the equilibrium between plasma and endothelial
cell surface EC-SOD, it appears to be directly responsible for markedly
increased plasma EC-SOD levels in those who possess it. Although it is
known that the Arg213Gly mutation was responsible for a bimodal
distribution of EC-SOD levels in the Australian study population cited
above,17 the genetic contribution to quantitative
variation in the more common range of this phenotype, exhibited
by 93% to 97% of that population, is still unknown.
Slightly more is known about the genetic contribution to normal
variation in endothelial constitutive NO, a key
molecule in peroxynitrite production against which EC-SOD is a
protective response. Analyses of data from a study of healthy
members of >100 Australian families showed that genes and plasma
levels of apoA-I significantly influence normal variation in plasma NO
levels.24 The potential role of EC-SOD plus these
observations on NO motivated the 2 principal objectives of the
present study. The first was to detect and measure the effects of
genes on normal quantitative variation in plasma levels of EC-SOD in
individuals not possessing the Arg213Gly mutation. The second
objective was to discern the extent to which genes influencing plasma
EC-SOD levels also influenced plasma levels of NO and apoA-I.
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Methods |
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Subjects
We collected blood samples from 610 members of 144 nuclear families, a majority of which provided the data for the earlier study in which we detected the effects of genes and apoA-I on variation in plasma NO levels.24 Subjects were healthy volunteers recruited from the ongoing Heart Health Education Program for family-based primary coronary disease prevention. Ascertainment was random with respect to cardiovascular disease risk. All volunteers were white, of European origin, and residing in Sydney; none were current smokers. They were advised to remain on their usual diets before blood collection, and all were healthy at the time of study. Written consent was obtained from every subject and/or subject’s parent. The study was approved by the Ethics Committee of the University of New South Wales.
A 4-mL venous blood sample was drawn into an EDTA tube after an overnight fast (12 to 14 hours). The blood sample was maintained at 4°C for 2 to 4 hours and centrifuged at 3500 rpm (2000g). Plasma was stored at -70°C in aliquots until analysis for EC-SOD.
Measurements of EC-SOD Levels and Biochemical
Analyses
Circulating plasma EC-SOD levels were measured as described
previously.25 Plasma levels of total
cholesterol, HDL cholesterol,
triglycerides, glucose, and creatinine were
measured by the Clinical Chemistry Department, Prince of Wales
Hospital, Sydney, Australia, by using standard enzymatic methods. LDL
cholesterol levels were calculated by use of the
Friedewald formula. We measured levels of apoA-I, apoB, and
Lp(a) by using ELISA methods developed in our
laboratory.26 Plasma NO levels (NOx,
measured as the metabolites nitrite and nitrate) were assayed as
described by Wang et al.27
Statistical Genetic Analysis
Pedigree and phenotype data management and preparation
were accomplished by using the computer package PEDSYS.28
Statistical genetic analyses were conducted with the use of
maximum-likelihood methods implemented in Sequential Oliogenic Linkage
Analysis Routines (SOLAR)29 and a modified version
of Pedigree Analysis Programs (PAP) 3.030 to
compute likelihoods of genetic models on phenotypic data distributed in
pedigrees.
Initial univariate analyses
simultaneously estimated the mean effects of potential
covariates and the proportions of the phenotypic variance in each of
the 3 traits that were attributable to the additive effects of genes
(heritability, or h2) and unmeasured
environmental factors (e2). We estimated
h2 as
G2/P2,
where G2 is the variance due
to the effects of genes, and
P2 is the phenotypic
variance. In addition to effects of sex and sex-specific age terms, we
screened the following for inclusion as covariates in genetic models
for each trait: plasma levels of the other 2 phenotypes, total
cholesterol, HDL cholesterol,
triglycerides, apoB, Lp(a), glucose, and
creatinine.
Multivariate quantitative genetic analyses were
conducted to determine the extent to which variation in plasma levels
of EC-SOD, NOx, and apoA-I were attributable to
the additive effects of shared genes and shared nongenetic factors. We
used an analytical approach developed by Blangero and
Konigsberg31 and described in detail by Mahaney et
al32 to model the multivariate
phenotype of an individual as a linear function of the
measurements on individuals’ traits, the population means of these
traits, and the covariates and their regression coefficients, plus the
additive genetic values and random environmental deviations. From this
model, we also estimated the additive genetic and environmental
(nongenetic) correlations, G and
E, between trait pairs. Respectively, these 2
correlations estimate the effects of shared genes (ie, pleiotropy) and
shared, unmeasured, nongenetic factors on the phenotypic variance in a
trait. We used maximum-likelihood estimates of the 2 to obtain
estimates of total phenotypic correlation, P,
between trait pairs as described elsewhere.32
Significance of all parameters, including variance components, covariate effects, and correlations, was assessed by natural log likelihood ratio tests,33 in which -2xnatural log likelihood of a restricted model (in which the parameter value to be tested is fixed at zero) is compared with that same statistic for a more general model in which that parameter value is estimated. An additional likelihood ratio test in which the absolute value of the genetic correlation was fixed at 1.0 was used to test the hypothesis of complete pleiotropy, ie, the case for which all additive genetic variance in 2 traits is due to the same shared genes. Although critical values for including covariates in genetic models after initial screens corresponded to P=0.10, we did not consider maximum estimates of, for example, heritabilities, correlations, and covariate effects to be significant in the final analyses at P>0.05.
Analyses of nuclear family data may lead to inflated h2 estimates because of the confounding of additive genetic and common familial environmental effects. Spousal correlations (rsp) were estimated for each trait, and rsp values significantly >0.0 were considered evidence of such confounding.
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Results |
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Of the 610 participants in the present study, 300 were females (mean ages were as follows: parent and offspring generations combined, 24.1±4.9 years; parent generation, 39.0±4.8 years; and offspring generation, 10.3±3.3 years), and 310 were males (mean ages were as follows: parent and offspring generations combined, 25.5±17.0 years; parent generation, 42.5±7.8 years; and offspring generation, 10.7±3.8 years). These individuals belonged to 144 nuclear families ranging in size from 3 to 6 members, with a modal size of 4 (2 parents and 2 children). Measures of plasma EC-SOD levels were obtained for 515 individuals; NOx levels, for 550; and apoA-I levels, for 562. Data for 15 individuals (2.97% of the sample) with EC-SOD levels >700 ng/L, all of whom were determined to possess the Arg213
Gly mutation,20 were identified as "outliers"
and eliminated from further analysis. Summary statistics for
age and the 3 phenotypes for the remaining individuals in the
sample, none of whom was found to have the Arg213Gly mutation, are
presented in Table 1
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Maximum-likelihood parameter estimates and their standard
errors from the unrestricted univariate quantitative
genetic model for each of the 3 traits are presented in Table 2. In addition to age and sex terms,
those covariates with potential utility for better characterization of
the variance component model for each trait (ie, P<0.10 in
the initial covariate screen) were also included. For EC-SOD, these
covariates included plasma levels of HDL cholesterol,
creatinine, and apoA-I and accounted for 38.6% of the
phenotypic variance of this trait. Two variables, apoA-I and apoB,
contributed only 6% of the phenotypic variance in
NOx. Over 25% of the phenotypic variance in
apoA-I was due to the effects of HDL cholesterol,
triglycerides, apoB, NOx, and EC-SOD.
Genes contributed significantly to the remaining residual phenotypic
variance in plasma levels of EC-SOD (h2=0.58,
P<0.000001), NOx
(h2=0.18, P=0.000016), and apoA-I
(h2=0.62, P<0.000001). Respectively,
these estimates indicate that additive genetic effects account for
35.6%, 16.7%, and 15.7% of the total phenotypic variance in EC-SOD,
NOx, and apoA-I. Because no
rsp value was significantly >0.0 (SOD
rsp=-0.03, NOx
rsp=-0.02, and apoA-I
rsp=0.06; P>0.10), inflation of the
heritability estimates due to common familial environmental effects is
unlikely in these data.
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Using parameter estimates from Table 2
as the new
initial values, we maximized the likelihood of a single trivariate
quantitative genetic model that included plasma EC-SOD,
NOx, and apoA-I on the same family data to
estimate genetic and nongenetic correlations between these traits (note
that because they were included as the primary phenotypes in
this trivariate model, plasma levels for these 3 traits were not
included also as covariates). Maximum-likelihood estimates of the
correlations due to shared effects of additive genes and shared effects
of nongenetic factors and the phenotypic correlations derived from them
are presented in Table 3. Plasma
levels of EC-SOD exhibit a significant negative genetic correlation
with apoA-I levels only (G=-0.45). In
contrast, plasma apoA-I levels show a significant, but positive,
genetic correlation with plasma levels of NOx
(G=0.58). Likelihood ratio tests rejected the
hypothesis of complete pleiotropy for both significant correlations
(P<0.05). None of the correlations due to unmeasured
nongenetic factors was significant (P>0.09).
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The squared additive genetic correlation is interpreted as the
proportion of the additive genetic variance in each of the 2 traits
attributable to shared genetic effects (Table 4). Shared genetic effects account for
20% of the additive genetic variance in plasma levels of EC-SOD and
apoA-I. NOx and apoA-I share nearly 34% of their
additive genetic effects. Similar treatment of the nonsignificant
correlations between EC-SOD and NOx reveals that
shared genetic effects would account for <3% of the additive genetic
variance in these 2 traits.
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The proportion of the total phenotypic variance in each trait of a trait pair that is due to the effects of shared genes equals the product of the squared additive genetic correlation, h2, and the proportion of the total phenotypic variance not attributable to covariate effects. For EC-SOD and NOx, these proportions are negligible; but for EC-SOD and apoA-I, respectively, the proportions of the total phenotypic variance due to shared gene effects are 7.2% and 9.3%; and, for NOx and apoA-I, the respective proportions are 5.7% and 15.5%.
Analogous calculations applied to correlations due to shared, unmeasured, nongenetic factors provides tentative evidence for such an effect between plasma levels of EC-SOD and apoA-I only. Shared unmeasured nongenetic factors account for <1% of the total phenotypic variance in either of these 2 traits.
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Discussion |
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Because plasma EC-SOD levels have been shown to be correlated with history of cardiovascular disease and its risk factors,17 genes influencing quantitative variation in plasma EC-SOD levels are likely to contribute also to interindividual variance in cardiovascular disease susceptibility. To our knowledge, this is the first reported quantification of the effect of genes on normal quantitative variation in plasma levels of EC-SOD in this or any other population. We have learned that >35% of the total phenotypic variance in circulating plasma levels of EC-SOD is attributable to the effects of genes other than 1 previously described mutation.17 Although obtained from analysis of data from nuclear families, our finding of a nonsignificant spousal correlation suggests that the magnitude of this estimated genetic effect is unlikely to be inflated by common familial environmental factors. This is true also for the NOx and apoA-I heritability estimates and for the correlations obtained in subsequent multivariate analyses.
To our knowledge, little is known of the possible interactions of growth, development, and maturation on differences in plasma EC-SOD levels in children, adolescents, and adults.34 If they existed, such interactions might tend to obscure, rather than inflate, evidence of additive genetic effects on variation in a sample like ours, in which the data from both adults in the parental generation and their preadult offspring were analyzed. Consequently, we are confident that the estimates of heritability and genetic correlation presented in the present study are, at worst, conservative ones.
Contrary to our expectations, given the reported concordance between EC-SOD expression and inducible NO synthase expression in human and rabbit atherosclerotic lesions,35 we have also learned that in these Australian families EC-SOD levels are related to NOx levels through their separate pleiotropic interactions with plasma levels of apoA-I. Significant positive pleiotropy between apoA-I and NOx indicates that a common gene or suite of genes contributes to correlated upregulation and downregulation of production for both phenotypes. We believe that this pleiotropy is biologically important: over a third of the additive genetic variance in both traits and nearly 16% and 6% of the total phenotypic variance in apoA-I and NOx, respectively, are attributable to the additive effects of the same gene or genes. Because the pleiotropy is incomplete, other genes, not shared by these 2 traits, account for >60% of the additive genetic variance in these 2 traits.
EC-SOD and apoA-I also share genes in common, but this pleiotropic
relation is a negative one. When mechanisms that influence plasma
levels of EC-SOD are upregulated, those influencing plasma levels of
apoA-I are downregulated, or vice versa. This pleiotropy is somewhat
weaker than that between plasma levels of NOx and
apoA-I, accounting for one fifth of the additive genetic variance in
plasma EC-SOD and apoA-I levels and 7% and 9% of their respective
total phenotypic variance. Genes other than those producing this
negative pleiotropy are responsible for the remaining additive genetic
variance in plasma levels of EC-SOD and apoA-I.
A lack of pleiotropy between EC-SOD and NOx when both exhibit pleiotropy with apoA-I indicates that the 2 observed pleiotropic relations (EC-SOD with apoA-I and NOx with apoA-I) are attributable to 2 independent sets of genes. However, our findings are from analyses of data obtained from healthy families with no frank cardiovascular disease and the correlated expression of EC-SOD and inducible NOS, leading us to expect the pleiotropy between EC-SOD and NOx that was observed in studies of atherosclerotic lesions.33 It is possible that interaction with internal or external environmental factors, normal or pathological, that are not present in the families in the present study could effect the gene expression necessary to establish this "missing" pleiotropy.
It is highly unlikely that the genetic correlations detected in the present study are reflective of linkage rather than pleiotropy. That would require strong linkage disequilibrium resulting from multiple mutations at different loci within a very narrow region (eg, <<1 cM) of a chromosome.
The ultimate objective of any cardiovascular disease genetics research includes the unambiguous identification and complete characterization of the individual genes responsible for quantitative variation in a risk factor for, or susceptibility to, cardiovascular disease. The present study does not identify the specific loci responsible for our observations, but quantifying the extent to which variation in EC-SOD is heritable is a necessary prerequisite to initiating a formal search for those loci (ie, one cannot localize and identify genes for traits having no measurable genetic component). Whereas statistical power to localize and identify the actual loci involved is proportional to the effect size (ie, heritability) of those loci,29 this power can also be improved greatly by exploiting the pleiotropy observed between these phenotypes in a multivariate whole genome linkage screen.36 37 38
At this time, obvious candidate genes include structural loci for the 3
traits and/or loci whose products are thought to be central to
regulating their production: eg, apoAI at 11q23,
ecNOS at 7q35 to 36, iNOS at 17cen-q12, and
ecSOD at 4pter-q21. One or more of these loci may contribute
to the detected pleiotropy. The previously noted effect of the
dominant-acting Arg213Gly mutation in the ecSOD locus on
plasma levels of EC-SOD17 and linkage of
ecNOS4 genotypes to variation in
NOx levels in many of these same families lend
credence to this possibility.24 However, it is just
as likely that other loci, including those that currently may be
unknown and/or whose effects on one or more of these traits has yet to
be appreciated, also are involved.
The actual regulatory mechanisms responsible for these pleiotropic relations remain speculative. A possible role for apoA-I may derive from recent reports that it is readily oxidizable in vitro.39 40 Although in vivo apoA-I oxidation remains to be demonstrated, a recent study suggests that compared with native apoA-I, oxidized apoA-I may promote more efficient reverse cholesterol transport.41 Therefore, a possible functional link between apoA-I and NO and between apoA-I and EC-SOD is a scenario casting apoA-I as an antioxidant or ROS recipient whereby overproduction of NO might necessitate increased apoA-I production to counter the untoward oxidation effect.
In summary, genes influence a significant proportion of the quantitative phenotypic variation in plasma levels of EC-SOD in healthy Australians. Some, but not all, of these genes also contribute significantly to variation in plasma levels of apoA-I but not NOx. Although a small, but significant, proportion of normal variation in plasma levels of NOx is attributable to the effects of genes that also influence variation in plasma apoA-I levels, these genes, or their effects, are not shared with plasma EC-SOD. Given the hypothesized importance of mechanisms that counter ROS to the maintenance of healthy endothelial function and prevention or amelioration of cardiovascular disease,42 our results warrant further studies. The objectives of these studies should include localizing and identifying the genes responsible for this pleiotropy in healthy individuals, determining whether it is maintained in the presence of cardiovascular disease and/or exposure to pathological levels of other known risk factors, and investigating its possible physiological bases.
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Acknowledgments |
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This study was supported primarily by a grant from the National Health and Medical Research Council of Australia to X.L.W. and D.E.L.W. Partial support to M.C.M. and S.A.C. was provided by grants (P01 HL-45522 and R01 HL-54141) from the National Institutes of Health and to T.A. from the Ministry of Education, Science, Sports and Culture, Japan.
Received July 9, 1999; accepted October 1, 1999.
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References |
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|---|
1. Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and the ugly. Am J Physiol.. 1996;271:C1424–C1437.
2. Kroncke K-D, Fehsel K, Kolb-Bachofen V. Nitric oxide: cytotoxicity versus cytoprotection–how, why, when and where? Nitric Oxide. 1997;1:107–120.[Medline] [Order article via Infotrieve]
3.
White CR, Brock TA, Chang L-Y, Crapo J, Briscoe P, Ku
D, Bradley WA, Gianturco SH, Gore J, Freeman BA, Tarpey MM. Superoxide
and peroxynitrite in atherosclerosis. Proc Natl
Acad Sci U S A. 1994;91:1044–1048.
4. Squadrito GL, Pryor WA. The formation of peroxynitrite in vivo from nitric oxide and superoxide. Chem Biol Interact. 1995;96:203–206.[Medline] [Order article via Infotrieve]
5. Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA. Apparent hydroxyl radical formation by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci U S A. 1990;86:1620–1624.
6. Beckman JS, Ye YZ, Anderson PG, Chen J, Accavitti MA, Tarpey MM, White RC. Extensive nitration of protein tyrosines in human atherosclerosis detected by immunohistochemistry. Biol Chem Hoppe Seyler. 1994;375:81–88.[Medline] [Order article via Infotrieve]
7. Buttery LDK, Springall DR, Chester AH, Evans TJ, Standfield N, Parums DV, Yacoub MH, Polak JM. Inducible nitric oxide synthase is present within human atherosclerotic lesions and promotes the formation and activity of peroxynitrite. Lab Invest. 1996;75:77–85.[Medline] [Order article via Infotrieve]
8.
Stralin P, Karlsson K, Johansson BO, Marklund SL. The
interstitium of the human arterial wall contains very large
amounts of extracellular superoxide dismutase. Arterioscler
Thromb Vasc Biol. 1995;15:2032–2036.
9.
Marklund SL. Human copper-containing superoxide
dismutase of high molecular weight. Proc Natl Acad Sci
U S A. 1982;79:7634–7638.
10.
Weisiger RA, Fridovich I. Mitochondrial superoxide
dismutase: site of synthesis and intramitochondrial localization.
J Biol Chem. 1973;248:4793–4896.
11. Karlsson K, Sandstrom J, Edlund A, Edlund T, Marklund SL. Pharmacokinetics of extracellular-superoxide dismutase in the vascular system. Free Radic Biol Med. 1993;14:185–190.[Medline] [Order article via Infotrieve]
12. Karlsson K, Marklund SL. Extracellular superoxide dismutase in the vascular system of mammals. Biochem J. 1988;255:223–228.[Medline] [Order article via Infotrieve]
13.
Abrahamsson T, Brandt U, Marklund SL, Sjoqvist PO.
Vascular bound recombinant extracellular superoxide dismutase type C
protects against the detrimental effects of superoxide radicals on
endothelium-dependent arterial relaxation.
Circ Res. 1992;70:264–271.
14. Karlsson K, Marklund SL. Extracellular superoxide dismutase association with cell surface-bound sulfated glucosaminoglycans. Basic Life Sci. 1988;49:647–650.[Medline] [Order article via Infotrieve]
15. Sandstrom J, Karlsson K, Edlund T, Marklund SL. Heparin-affinity patterns and composition of extracellular-superoxide dismutase in human plasma and tissues. Biochem J. 1993;294:853–847.
16. Karlsson K, Marklund SL. Heparin-induced release of extracellular-superoxide dismutase to human blood plasma. Biochem J. 1987;242:55–59.[Medline] [Order article via Infotrieve]
17.
Wang XL, Adachi T, Sim AS, Wilcken DEL. Plasma
extracellular superoxide dismutase levels in an Australian population
with coronary artery disease. Arterioscler Thromb Vasc
Biol. 1998;18:1915–1921.
18.
Sandstrom J, Nilsson P, Karlsson K, Marklund SL.
10-fold increase in human plasma extracellular superoxide dismutase
content caused by a mutation in heparin-binding domain. J
Biol Chem. 1994;269:19163–19166.
19. Folz RJ, Crapo JD. Extracellular superoxide dismutase (SOD3): tissue-specific expression, genomic characterization, and computer-assisted sequence analysis of the human EC SOD gene. Genomics. 1994;22:162–171.[Medline] [Order article via Infotrieve]
20.
Folz RJ, Peno-Green L, Crapo JD. Identification of a
homozygous missense mutation (Arg to Gly) in the critical binding
region of the human EC-SOD gene (SOD3) and its association with
dramatically increased serum enzyme levels. Hum Mol Genet. 1994;3:2251–2254.
21. Yamada H, Yamada Y, Adachi T, Goto H, Ogasawara N, Futenma A, Kitano M, Hirano K, Kato K. Molecular analysis of extracellular-superoxide dismutase gene associated with high levels in serum. Jpn J Hum Genet. 1995;40:177–184.[Medline] [Order article via Infotrieve]
22. Adachi T, Yamada H, Yamada Y, Morihara N, Yamazaki N, Murakami T, Futenma A, Kato K, Hirano K. Substitution of glycine for arginine-213 in extracellular-superoxide dismutase impairs affinity for heparin and endothelial cell surface. Biochem J. 1996;313:235–239.
23. Karlsson K, Sandstrom J, Edlund A, Marklund SL. Turnover of extracellular-superoxide dismutase in tissues. Lab Invest. 1994;70:705–710.[Medline] [Order article via Infotrieve]
24.
Wang XL, Mahaney MC, Sim AS, Wang J, Wang J, Blangero
J, Almasy L, Badenhop RB, Wilcken DEL. Genetic contribution of the
endothelial constitutive nitric oxide synthase gene to
plasma nitric oxide levels. Arterioscler Thromb Vasc Biol. 1997;17:3147–3153.
25. Adachi T, Ohta H, Yamada H, Futenma A, Kato K, Hirano K. Quantitative analysis of extracellular-superoxide dismutase in serum and urine by ELISA with monoclonal antibody. Clin Chim Acta. 1992;212:89–102.[Medline] [Order article via Infotrieve]
26.
Wang XL, Tam C, McCredie RM, Wilcken DEL. Determinants
of severity of coronary artery disease in Australian men and
women. Circulation. 1994;89:1974–1981.
27. Wang J, Brown MA, Tam SH, Chan MC, Whitworth JA Effects of diet on measurement of nitric oxide metabolites. Clin Exp Pharmacol Physiol. 1997;24:418–420.[Medline] [Order article via Infotrieve]
28. Dyke B. PEDSYS: A Pedigree Data Management System. San Antonio, Tex: Population Genetics Laboratory, Southwest Foundation for Biomedical Research; 1998.
29. Almasy L, Blangero J. Multipoint quantitative linkage analysis in general pedigrees. Am J Hum Genet. 1998;62:1198–1211.[Medline] [Order article via Infotrieve]
30. Hasstedt SJ. Pedigree Analysis Package, version 3.0. Salt Lake City, Utah: Department of Genetics, University of Utah; 1989.
31. Blangero J, Konigsberg LW. Multivariate segregation analysis using the mixed model. Genet Epidemiol. 1991;8:299–316.[Medline] [Order article via Infotrieve]
32.
Mahaney MC, Blangero J, Comuzzie AG, VandeBerg JL,
Stern MP, MacCluer JW. Plasma HDL cholesterol,
triglycerides, and adiposity: a quantitative genetic test
of the conjoint trait hypothesis in the San Antonio Family Heart Study.
Circulation. 1995;92:3240–3248.
33. Edwards AWF. Likelihood. Cambridge,.UK: Cambridge University Press; 1972.
34. Elhadd TA, Khan F, Kirk G, McLaren M, Newton R, Greene SA, Belch JJF. Influence of puberty on endothelial dysfunction and oxidative stress in young patients with type 1 diabetes. Diabetes Care. 1998;21:1990–1996.[Abstract]
35.
Luoma JS, Stralin P, Marklund SL, Hiltunen TP, Sarkioja
T, Yla-Hertualla S. Expression of extracellular SOD and iNOS in
macrophages and smooth muscle cells in human and rabbit
atherosclerotic lesions: colocalization with epitopes characteristic of
oxidized LDL and peroxynitrite-modified proteins. Arterioscler
Thromb Vasc Biol. 1998;18:157–167.
36. Comuzzie AG, Mahaney MC, Almasy L, Dyer TD, Blangero J. Exploiting pleiotropy to map genes for oligogenic phenotypes using extended pedigree data. Genet Epidemiol. 1997;14:975–980.[Medline] [Order article via Infotrieve]
37. Czerwinski SA, Mahaney MC, Williams JT, Almasy L, Blangero J. Genetic analysis of personality traits and alcoholism using a mixed discrete continuous trait variance component model. Genet Epidemiol. 1999;17(Suppl 1):S121–S126.
38. Ott J, Rabinowitz D. A principal-components approach based on heritability for combining phenotype information. Hum Hered. 1999;49:106–111.[Medline] [Order article via Infotrieve]
39.
Garner B, Wedlock R, Witting PK, Rye K-A, Stock R.
Oxidation of high density lipoproteins, I: formation of methionine
sulfoxide in apolipoproteins AI and AII is an early event that
accompanies lipid peroxidation and can be enhanced by
-tocopherol. J Biol Chem. 1998;273:6080–6087.
40.
Garner B, Waldeck R, Witting PK, Rye K-A, Stock R.
Oxidation of high density lipoproteins, I: evidence for direct
reduction of lipid hydroperoxides by methionine residues of
apolipoprotein AI and AII. J Biol Chem. 1998;273:6088–6095.
41.
Wang W-Q, Merriam DL, Moses AS, Francis GA. Enhanced
cholesterol efflux by tyrosyl radical-oxidized high density
lipoprotein is mediated by apolipoprotein AI-AII heterodimers.
J Biol Chem. 1998;273:17391–17398.
42. Rudic RD, Sessa WC. Nitric oxide in endothelial dysfunction and vascular remodeling: clinical correlates and experimental links. Am J Hum Genet. 1999;64:673–677.[Medline] [Order article via Infotrieve]
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