© 1995 American Heart Association, Inc.
Articles |
A Polymorphism of the Paraoxonase Gene Associated With Variation in Plasma Lipoproteins in a Genetic Isolate
From the Departments of Medicine and Clinical Biochemistry (R.A.H., P.W.C.) and Biochemistry (P.W.C.), St Michael's Hospital, University of Toronto, Ontario, and the School of Nursing (J.H.B.), University of Victoria, British Columbia, Canada.
Correspondence to Robert A. Hegele, MD, DNA Research Laboratory, St Michael's Hospital, 30 Bond St, Toronto, Ontario, Canada M5B 1W8.
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Abstract |
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Abstract The Hutterite Brethren are a genetic isolate characterized by high indices of relatedness and a communal agrarian lifestyle. We hypothesized that variation of the paraoxonase (PON) gene that underlies the interindividual variation in plasma PON activity would be associated with variation in fasting plasma lipoprotein variables in this group. In 793 Hutterites, we measured plasma lipids, lipoproteins, and apolipoproteins and analyzed DNA for genotypes of the protein polymorphism at amino acid residue 192 of PON. We observed that genotypes of PON were significantly associated with variation in plasma concentrations of total, HDL, non-HDL, and LDL cholesterol, total triglycerides, and apolipoprotein (apo) B. Homozygotes for the low-activity variant of PON had significantly lower levels of plasma apoB-related biochemical variables than heterozygotes and homozygotes for the high-activity variant of PON. Homozygotes for the low-activity variant of PON also had significantly lower ratios of total cholesterol/HDL cholesterol, LDL cholesterol/HDL cholesterol, and apoB/apoA-I than heterozygotes and homozygotes for the high-activity variant of PON. We found no evidence for a gene-gender interaction for any plasma lipoprotein variable. The PON polymorphism accounted for about 1% of the variation in total cholesterol and related lipoprotein traits in the Hutterites. These observations suggest that PON is a significant genetic determinant of plasma lipoprotein levels.
Key Words: association study • DNA • lipids • oxidation • polygenic traits
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Introduction |
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Complex quantitative traits such as plasma lipoproteins are considered to be influenced by both genetic and nongenetic factors.1 Analyses of the genetic determinants of interindividual variation in plasma lipoproteins must take into account both the number of gene products that contribute to pathogenesis and the interactions of the gene products within biochemical and physiological pathways.1 We have identified2 significant associations between candidate genes in lipoprotein metabolism and variation in plasma lipoproteins in the Hutterite Brethren, a North American religious genetic isolate. The Hutterites are useful for studying genetic determinants of quantitative traits such as plasma lipoproteins because their gene pool is small, their indices of relatedness are high, and they share environmental factors.3
Paraoxonase (PON, EC 3.1.1.2) is an arylesterase that hydrolyzes
paraoxon, an active toxic metabolite of parathion, thus providing
protection against organophosphate poisoning.4 Its
physiological substrate is unknown.5 6 Serum PON activity
in humans is genetically determined and has been reported to have up to
40-fold interindividual variation.5 Genetic variation in
PON has been found to be the major determinant of interindividual
variation of PON activity.6 7 The actual molecular basis
for the PON polymorphism is a Gln
Arg substitution; however, there is
a discrepancy in the numbering of the amino acid
residues.6 7 Depending on the amino acid taken to be the
N-terminal residue, the GlnArg substitution occurs at
either residue 191, as reported by Adkins et al,7 or
residue 192, as reported by Humbert et al.6 When using the
numbering of Humbert et al, the PON allozyme that has glutamine at
residue 192 (192Q) has low activity, while the second PON allozyme,
which has arginine at residue 192 (192R), has high
activity.6
Several pieces of evidence suggest that PON may have a significant role in lipoprotein metabolism. First, PON is an important structural component of the apolipoprotein (apo) A-I–containing lipoprotein subpopulation of HDL particles,8 although the physiological relevance of this biochemical association has not been determined. Second, PON purified from human HDL decreases the oxidative modification of LDL in vitro.9 Third, plasma PON activity is significantly related to variation in plasma concentrations of triglycerides, LDL cholesterol (LDL-C), apoA-II, and apoB.10 For these reasons, we were interested in identifying associations between the genotype of PON underlying the variation in serum PON activity and fasting plasma lipoprotein variables in the Hutterites.
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Methods |
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Study Subjects
The Hutterite Brethren are an Anabaptist sect with approximately 30 000 members who live in Western Canada and the adjacent American states. They have an agrarian lifestyle and live on communal farms called colonies.2 3 Contemporary Hutterites are descended from fewer than 100 unrelated founders.3 11 The Hutterites have had a high intrinsic growth rate and their population remains closed to migration.11 A high degree of consanguinity relative to the founders has accumulated over about 12 generations, with the average inbreeding coefficient of the current generation being .05.3
Hutterite society has a static inter- and intragenerational lifestyle.11 Colonies are surrogates for extended families; women marry between colonies, but men remain within a colony.11 The incidence of coronary heart disease (CHD) in the Hutterites is unknown, but the prevalence of risk factors appears to be comparable to that found in other populations.12 Smoking is forbidden, but alcohol is not.12 Meals are taken communally, and the diet is high in animal fat.12 Mechanized farming techniques have reduced the amount of aerobic work-related exercise.12
Subjects from 21 colonies of two Alberta Hutterite sects took part in the Canadian Heart Health Survey screening for CHD risk factors.2 13 14 Physical examination included determination of body mass index (BMI; weight/height2) and four separate blood pressure determinations. Plasma samples from 846 Hutterites were obtained with informed consent. Exclusion criteria included an inadequate blood sample available for all biochemical and/or genetic determinations. The study was approved by ethical review panels of the Universities of Alberta and Toronto.
Biochemical Analyses
All biochemical determinations were made in the J. Alick Little
Lipid Research Laboratory at St Michael's Hospital. The plasma
concentrations of total cholesterol, triglycerides, and HDL and
non–HDL cholesterol (non–HDL-C) were determined as
described.13 LDL-C was calculated,13 and
apoA-I and apoB were measured by nephelometry.15
Genetic Analyses
Leukocyte DNA was prepared as described16 and was
used for genotype analysis with the Taq polymerase chain
reaction. Sufficient DNA and phenotypic information were obtained for
most analyses from 793 Hutterites. Genotypes for PON codon 192 were
determined as described.6 As a control genetic variable,
genotypes for the DNA polymorphisms underlying the apoE isoforms were
determined by using polymerase chain reaction amplification of exon 4
and restriction isotyping with Hha I as
described.17
Statistical Analysis
SAS (version 6) was used for all statistical
comparisons.18 Because the distribution of each variable
was significantly nonnormal in this data set, each variable was
transformed and subjected to analysis of normality for parametric
statistical analyses. Logarithmically transformed total cholesterol,
LDL-C, non–HDL-C, and HDL-C had distributions that were not
significantly different from normal (data not shown). After
triglyceride values were transformed19 their distribution
was not significantly different from normal. Logarithmic transformation
also made the distributions of apoA-I and apoB more normal. The
transformed variables were used for statistical analyses but the
nontransformed values are presented in the tables.
ANOVA was performed by using the general linear models procedure to determine the sources of variation for biochemical traits, with F tests computed from the type III sums of squares.18 This form of the sums of squares applies to unbalanced study designs and reports the effect of an independent variable after adjustment for all other variables included in the model. Dependent variables were transformed plasma total cholesterol, LDL-C, non–HDL-C, HDL-C, triglycerides, apoA-I, and apoB. Independent variables were age, log BMI, gender, and colony of origin, with the latter variable included to correct for variation that was related to other shared genetic and environmental factors. Also included as independent variables were genotypes of PON and apoE. ApoE genotype as determined by restriction isotyping was included in all multivariate analyses since it is a genetic variable that has been consistently associated with variation in plasma lipoproteins.20 Since we wished to identify significant gene-gender interactions, we included interaction terms with gender for each genotype system.
When a significant contribution to variation of a biochemical trait was
detected for genotype, the general linear models procedure for
least-squares means was used to determine the level of significance of
differences in pairwise comparisons between genotype classes.
Least-squares means, also known as population marginal means, are the
values for class means after adjustment for all covariates included in
the model.18 When a significant association was identified
within the whole group, baseline traits among individuals classified by
genotype were subsequently compared by using a nonparametric test for
significant differences between groups (Kruskal-Wallis test,
2 approximation, NPAR1WAY
routine18 ). Deviation of genotype frequencies from those
predicted by the Hardy-Weinberg law was also tested by
2 analysis.
Regression analysis was performed, and partial regression coefficients were used to estimate the percent of phenotypic variation that was due to genotypic variation. This analysis is complex for datasets containing subjects in the age range of 18 through 74 years. The approach used for analysis of data from the Lipid Research Clinics Project19 was used. We included three terms (age, age2, and age3) to adjust for the age-dependent changes in lipoproteins and the natural log of BMI to adjust for the effects of obesity.2 13 19
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Results |
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Allele and Genotype Frequencies
The frequencies of PON alleles 192Q and 192R were .71 and .29, respectively. The frequencies of the 192Q/192Q, 192Q/192R, and 192R/192R genotypes were .51, .41, and .08, respectively. Allele frequencies were similar to those reported in other Caucasian populations,6 7 and there was no significant deviation of PON genotype frequencies from those predicted by the Hardy-Weinberg law in this sample of Hutterites (
2=0.74, NS). The allele frequencies of apoE isoforms E4, E3, and E2 were .056, .940, and .004, respectively. While allele frequencies were different from those observed in other Caucasian populations,20 there was no significant deviation of apoE genotype frequencies from those predicted by the Hardy-Weinberg law in this sample of Hutterites.2
Determinants of Variation in Biochemical Variables
Significant associations were found between the logarithm of total
plasma cholesterol and age, logarithm of BMI, colony of origin, PON
genotype, and apoE genotype. These independent genotype variables were
each also significantly associated with the natural logarithms of
plasma LDL-C, non–HDL-C, HDL-C, and apoB (Table 1
).
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Significant associations were found between transformed plasma triglycerides and age, logarithm of BMI, colony of origin, and PON genotype. Apo E genotype was not significantly associated with transformed plasma triglycerides.
Significant associations were found between the logarithm of plasma apoA-I and age, logarithm of BMI, colony of origin, and apoE isotype. PON genotype was not significantly associated with the logarithm of plasma apoA-I.
No significant associations were found between any biochemical trait and gender. No significant associations were found between any biochemical trait and the genotype-gender interaction terms for either PON or apoE.
After completing the above analyses, we hypothesized a posteriori that
ratios of the apoB-containing to the apoA-I–containing lipoproteins
would differ between the PON genotypes. Logarithmic transformation made
the distributions of the ratios more normal. The results of the ANOVA
are shown (Table 2). Both PON and apoE genotypes were
significant sources of variation for the ratios of total
cholesterol/HDL-C, LDL-C/HDL-C, and apoB/apoA-I.
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Since PON genotype was significantly associated with variation in plasma apoB-related traits, such as total cholesterol, LDL-C, non–HDL-C, and apoB, in addition to HDL-C, we tested for differences between PON genotypic classes for biochemical variables. A similar analysis has been performed for these subjects classified by apoE genotype.2
Pairwise Comparison of PON Genotypic Classes Using Least-Square
Means
To test whether the between-group differences in biochemical
variables identified by the nonparametric analysis were
significant, pairwise comparisons of the genotype class least-square
means were made (Table 3). These confirmed that PON 192Q
homozygotes had significantly lower total cholesterol, LDL-C,
non–HDL-C, triglycerides, and apoB than heterozygotes. In addition,
PON 192Q homozygotes had significantly higher HDL-C than did
heterozygotes. PON 192Q homozygotes had significantly lower total
cholesterol, non–HDL-C, triglycerides, and apoB than PON 192R
homozygotes. PON 192Q homozygotes had significantly lower ratios of
total cholesterol/HDL-C, LDL-C/HDL-C, and apoB/apoA-I than
heterozygotes. There were also significant differences in the ratios of
total cholesterol/HDL-C and apoB/apoA-I between both classes of
homozygotes. Finally, PON 192R homozygotes had significantly higher
triglycerides than heterozygotes.
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Biochemical Variables in Subjects Classed by PON Genotype
Among Hutterites classified by PON genotype, there were no
significant between-group differences in age or BMI (Table 4). However, there were significant between-group
differences in plasma triglycerides, LDL-C, non–HDL-C, HDL-C, and
apoB. In addition, there were significant between-group differences for
the ratios of total cholesterol/HDL-C, LDL-C/HDL-C, and apoB/apoA-I.
There was also a nonsignificant trend for a between-group difference in
total cholesterol. The results of the nonparametric analysis were
consistent with the phenotype-genotype associations found using ANOVA
(Tables 1
and 2).
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Upon examining the group means, plasma total cholesterol, LDL-C, non–HDL-C, and apoB concentrations and the means of all three ratios were lower in homozygotes for the PON 192Q variant than the other genotypes. Mean plasma HDL-C was higher in homozygotes for the PON 192Q variant than the other genotypes. There was also a difference in mean plasma triglycerides among subjects classified by PON genotypes, with 192Q homozygotes having the lowest, heterozygotes being intermediate, and 192R homozygotes having the highest mean.
Regression Analysis
Regression analysis18 was performed to estimate
the percent of phenotypic variation that was determined by genetic
variation (Table 5). The model including age, log BMI,
colony of origin, and genotypes of PON was able to account for 43% of
the variation in plasma total cholesterol. About 1% of the total
variation in plasma total cholesterol, LDL-C, non–HDL-C, HDL-C, apoB,
and triglycerides was accounted for by genetic variation of PON.
Although these percentages were small, they were all highly significant
and comparable to the percent variation in these variables that was
accounted for by variation in apoE.
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Discussion |
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The principal finding of this study in 793 Hutterites is the identification of an association between PON genetic variation and plasma lipoprotein profile. This association was consistent and was confirmed by three separate statistical analyses. Homozygotes for the low-activity allele of PON had a less atherogenic lipoprotein profile. Specifically, homozygotes for the PON 192Q variant had significantly lower levels of plasma apoB-related biochemical traits, namely total cholesterol, LDL-C, non–HDL-C, triglycerides, and apoB, than subjects heterozygous for PON 192Q and 192R. Homozygotes for the PON 192Q variant also had significantly higher levels of plasma HDL-C than heterozygotes. In addition, the ratios of total cholesterol/HDL-C, LDL-C/HDL-C, and apoB/apoA-I were all significantly lower in homozygotes for the PON 192Q variant than in heterozygotes. The mean levels of most biochemical traits in homozygotes for the PON 192R variant were not statistically different from heterozygotes. Furthermore, the variation in plasma lipoprotein traits that was associated with genetic variation in PON was of the same order of magnitude of variation in these biochemical traits that was associated with genetic variation in apoE, an established genetic determinant of plasma lipoproteins.20 These findings suggest that PON is an important genetic determinant of plasma lipoproteins.
While there has been no other report of an association between PON genotypes and variation in plasma lipoproteins, associations have been reported between plasma PON activity and plasma lipoproteins. In a study of 163 healthy Chinese subjects,10 the PON genotype was inferred from plasma PON activity. Consistent with our findings, Chinese subjects who were inferred to be homozygous for the allele conferring low plasma PON activity had lower plasma apoB and triglycerides and higher plasma HDL.10 However, in other instances, the results do not agree. For example, among the Chinese, plasma total cholesterol and LDL-C were higher in subjects inferred to have the allele conferring low plasma PON activity, whereas we found that these variables were lower in Hutterite PON 192Q/192Q homozygotes. Also, in the Chinese, some of the associations were gender-specific, whereas no interaction between PON genotype and gender was detected among the Hutterites. This discrepancy may be due to the fact that the Chinese subjects were classified by inferring PON genotype from the level of plasma PON activity. Biochemical assays cannot distinguish heterozygotes with high PON activities from homozygotes for the 192R allele. Genotyping provides an unequivocal method of typing subjects and permits more accurate discrimination between genetic classes.
Blatter et al8 report that plasma concentrations of PON are positively correlated with plasma HDL-C and apoA-I and negatively correlated with total cholesterol and apoB. Mackness et al21 found that serum PON activity was decreased in both diabetes mellitus and familial hypercholesterolemia subjects compared with control subjects. Pavkovic et al22 report that 75% of patients with hyperlipidemia had low serum PON activities. These observations are all consistent with a relation between plasma PON and plasma lipoproteins, but they do not clarify the nature of this association.
Until now, no study of the association between PON genetic variation and plasma lipoproteins has been performed. The results of our study may thus not be entirely consistent with others because of fundamental genetic differences between the study samples, within which subjects were ascertained differently. The expression of biochemical phenotypes is also due to secondary genetic or environmental factors, which may have been different in each study sample. Studies that used plasma PON concentration or serum PON activity could have been affected by secondary nongenetic factors such as diabetes or familial hyperlipidemias that could have altered plasma PON activity.9 21 22 We classified subjects solely on the basis of the genotype of the low- and high-activity PON isoforms and found significant genotype-phenotype associations.
In the Hutterites, most significant genotype-phenotype associations were due to differences between PON 192Q homozygotes and PON 192Q/192R heterozygotes. This finding is compatible with a recessive effect of the allele on the lipoprotein phenotypes. However, it may also reflect a lack of power in detecting differences between PON 192R/192R homozygotes and the two other genotypic classes. Also, separating the data by gender failed to reveal additional important phenotype-genotype associations.
There are at least two possible interpretations of the strong, significant association between PON genetic variation and phenotypic variation. First, the PON variants affect PON function in vivo and this in turn affects lipoprotein metabolism and plasma lipoprotein concentrations. Alternatively, in this Hutterite sample, PON allele 192Q may be in linkage disequilibrium with another functional mutation in PON or at another gene on chromosome 7 and may thus serve as a marker for the actual causative mutation. A similar association might be difficult to detect in the general population, where among unrelated subjects many different functional mutations and markers may exist at this locus.
Blatter et al8 used immunoaffinity chromatography to find that PON was present in a distinct subspecies of HDL that was triglyceride-rich and contained only apoA-I and apoJ (clusterin). Mackness et al23 showed that serum activity of PON and plasma concentrations of HDL-C, apoA-I, and apoA-II were all reduced in subjects with fish-eye disease. Its presence in a distinct HDL subspecies, rather than a nonspecific association with different HDL particles, suggests that PON could have a specific, lipid-related function. However, the associations between PON genotype, plasma activity, and concentration with plasma lipoprotein concentration may not only be due to the physical association of PON with a specific HDL subspecies. PON may have a more fundamental role in lipoprotein metabolism. For example, HDL prevents the change in electrophoretic mobility of LDL that results from oxidation.24 Furthermore, addition of either HDL or purified PON reduces oxidation of LDL.8 Parthasarathy et al25 found that HDL prevents LDL that was subjected to oxidizing conditions from being taken up by cultured macrophages. We might speculate that homozygotes for PON 192Q had lower levels of apoB-related biochemical traits because of increased oxidation and peripheral uptake of LDL particles, resulting in lower plasma total cholesterol, LDL-C, non–HDL-C, and apoB. Alternatively, that the mean ratios of apoB-related variables to apoA-I–related variables were significantly lower in the PON 192Q homozygotes than in heterozygotes suggests that low PON activity affects both classes of lipoproteins. For example, low PON activity may be associated with a decrease in transfer of lipids from HDL to LDL.
The association of PON with HDL may be important for other reasons. HDL might protect against CHD by prevention of lipid peroxidation in LDL and subsequent foam cell formation. HDL is present in some tissue fluids at concentrations severalfold above those of LDL.26 In pericardial fluid PON activity is correlated with HDL levels, and subjects with CHD have low PON activity in their pericardial fluid.27 PON activity is reduced after myocardial infarction.28 Such observations suggest that PON and/or HDL may have a more general role in protecting against oxidative damage in biological systems.
The association of PON genotype with the ratios of total cholesterol/HDL-C, LDL-C/HDL-C, and apoB/apoA-I suggests an alternative hypothesis that PON could affect the efficiency of lipid transfer. It is of relevance that PON has been found in a subfraction of HDL in association with apoJ.8 29 Since the effect of the PON polymorphism would appear to be recessive, any hypothesized mechanism would require that either a single PON 192R allele is sufficient for the effect or that PON activity levels must be significantly reduced for the limiting effect of PON to be observed.
The precise function of PON is still not known, although it can
neutralize exogenous toxic organophosphates. Speculation has centered
on an extensive role in lipoprotein metabolism, with phospholipase,
acyltransferase, and cholesterol ester hydrolase activities being
invoked.30 31 An important physiological role is further
suggested by the conservation of the PON gene across
species.6 The glutaminearginine substitution affects
the charge of the enzyme and could affect substrate turnover near the
active site.6 The presence of 192R in the high-activity
human allozyme compares with the 192K residue in the rabbit enzyme,
which also rapidly turns over paraoxon.6
In summary, genetic variation in PON was associated with variation in plasma lipoprotein traits in this Hutterite sample. Recessive effects on the phenotype, such as the generally less atherogenic plasma lipoprotein profile seen in PON 192Q homozygotes, are likely to be more readily identified in such subpopulations. Newer approaches to rapidly screen for regions of genomic DNA that are identical by descent32 and to perform combined segregation and linkage analysis in highly related populations33 could further help to identify genes that are important in polygenic diseases and to identify high-risk individuals who are candidates for interventions.
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Acknowledgments |
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This work was supported by grants from the Medical Research Council of Canada, the National Health Research and Development Program of Canada, and the Heart and Stroke Foundations of Ontario and Canada. Dr Hegele is a McDonald Scholar of the Heart and Stroke Foundation of Canada. We would like to thank Greg Ip, Erin Irving, Edwin Lee, Teresa Lippingwell, Patricia Ram, Stefan Sadiakian, Liling Tu, and Cheri Tully for their valuable technical assistance with this project. Dr Adele Csima, Department of Biostatistics, University of Toronto, provided expert advice regarding statistics.
Received May 24, 1994; accepted October 10, 1994.
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L. S. Rozek, T. S. Hatsukami, R. J. Richter, J. Ranchalis, K. Nakayama, L. A. McKinstry, D. A. Gortner, E. Boyko, G. D. Schellenberg, C. E. Furlong, et al. The correlation of paraoxonase (PON1) activity with lipid and lipoprotein levels differs with vascular disease status J. Lipid Res., September 1, 2005; 46(9): 1888 - 1895. [Abstract] [Full Text] [PDF]
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V. G. Cabana, C. A. Reardon, N. Feng, S. Neath, J. Lukens, and G. S. Getz Serum paraoxonase: effect of the apolipoprotein composition of HDL and the acute phase response J. Lipid Res., April 1, 2003; 44(4): 780 - 792. [Abstract] [Full Text] [PDF]
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R. C. Sorenson, C. L. Bisgaier, M. Aviram, C. Hsu, S. Billecke, and B. N. La Du Human Serum Paraoxonase/Arylesterase's Retained Hydrophobic N-Terminal Leader Sequence Associates With HDLs by Binding Phospholipids : Apolipoprotein A-I Stabilizes Activity Arterioscler Thromb Vasc Biol, September 1, 1999; 19(9): 2214 - 2225. [Abstract] [Full Text] [PDF]
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D. Ombres, G. Pannitteri, A. Montali, A. Candeloro, F. Seccareccia, F. Campagna, R. Cantini, P. P. Campa, G. Ricci, and M. Arca The Gln-Arg192 Polymorphism of Human Paraoxonase Gene Is Not Associated With Coronary Artery Disease in Italian Patients Arterioscler Thromb Vasc Biol, October 1, 1998; 18(10): 1611 - 1616. [Abstract] [Full Text] [PDF]
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M. Aviram, S. Billecke, R. Sorenson, C. Bisgaier, R. Newton, M. Rosenblat, J. Erogul, C. Hsu, C. Dunlop, and B. La Du Paraoxonase Active Site Required for Protection Against LDL Oxidation Involves Its Free Sulfhydryl Group and Is Different From That Required for Its Arylesterase/Paraoxonase Activities : Selective Action of Human Paraoxonase Allozymes Q and R Arterioscler Thromb Vasc Biol, October 1, 1998; 18(10): 1617 - 1624. [Abstract] [Full Text] [PDF]
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R. A. Hegele, P. W. Connelly, A. J. G. Hanley, F. Sun, S. B. Harris, and B. Zinman Common Genomic Variation in the APOC3 Promoter Associated With Variation in Plasma Lipoproteins Arterioscler Thromb Vasc Biol, November 1, 1997; 17(11): 2753 - 2758. [Abstract] [Full Text]
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R. A. Hegele, W. C. Breckenridge, J. H. Brunt, and P. W. Connelly Genetic Variation in Factor VII Associated with Variation in Plasma Lipoprotein(a) Concentration Arterioscler Thromb Vasc Biol, September 1, 1997; 17(9): 1701 - 1706. [Abstract] [Full Text]
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M. Odawara, Y. Tachi, and K. Yamashita Paraoxonase Polymorphism (Gln192-Arg) Is Associated with Coronary Heart Disease in Japanese Noninsulin-Dependent Diabetes Mellitus J. Clin. Endocrinol. Metab., July 1, 1997; 82(7): 2257 - 2260. [Abstract] [Full Text] [PDF]
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R. A. Hegele, P. W. Connelly, A. J.G. Hanley, F. Sun, S. B. Harris, and B. Zinman Common Genomic Variants Associated With Variation in Plasma Lipoproteins in Young Aboriginal Canadians Arterioscler Thromb Vasc Biol, June 1, 1997; 17(6): 1060 - 1066. [Abstract] [Full Text]
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D. K. Sanghera, N. Saha, C. E. Aston, and M. I. Kamboh Genetic Polymorphism of Paraoxonase and the Risk of Coronary Heart Disease Arterioscler Thromb Vasc Biol, June 1, 1997; 17(6): 1067 - 1073. [Abstract] [Full Text]
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R. A. Hegele, S. B. Harris, A. J. G. Hanley, F. Sun, P. W. Connelly, and B. Zinman Angiotensinogen Gene Variation Associated With Variation in Blood Pressure in Aboriginal Canadians Hypertension, May 1, 1997; 29(5): 1073 - 1077. [Abstract] [Full Text]
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D. N. Nevin, A. Zambon, C. E. Furlong, R. J. Richter, R. Humbert, J. E. Hokanson, and J. D. Brunzell Paraoxonase Genotypes, Lipoprotein Lipase Activity, and HDL Arterioscler Thromb Vasc Biol, October 1, 1996; 16(10): 1243 - 1249. [Abstract] [Full Text]
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R. A. Hegele, J. H. Brunt, and P. W. Connelly Genetic and Biochemical Factors Associated With Variation in Blood Pressure in a Genetic Isolate Hypertension, February 1, 1996; 27(2): 308 - 312. [Abstract] [Full Text]
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C. A. Abbott, M. I. Mackness, S. Kumar, A. J. Boulton, and P. N. Durrington Serum Paraoxonase Activity, Concentration, and Phenotype Distribution in Diabetes Mellitus and Its Relationship to Serum Lipids and Lipoproteins Arterioscler Thromb Vasc Biol, November 1, 1995; 15(11): 1812 - 1818. [Abstract] [Full Text]
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R. A. Hegele, J. H. Brunt, and P. W. Connelly Multiple Genetic Determinants of Variation of Plasma Lipoproteins in Alberta Hutterites Arterioscler Thromb Vasc Biol, July 1, 1995; 15(7): 861 - 871. [Abstract] [Full Text]
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