Biomedical subjects

C F Sing

Publications and source records attributed to C F Sing.

At least 55 records · Page 3Linked to original sources

PubMed1996

Erythrocyte sodium transport and the probability of having hypertension.

BACKGROUND: A number of alterations of ion transport and concentrations have been reported in erythrocytes from patients with hypertension and their young normotensive offspring. Of these, only sodium-lithium countertransport appears to be capable of predicting the effects of genetic variation on interindividual differences in blood pressure. OBJECTIVE: As a first step toward identifying other erythrocyte traits capable of predicting the effects of genetic variation on interindividual differences in blood pressure, we evaluated whether furosemide-sensitive sodium or potassium cotransport, ouabain-sensitive sodium pump, passive permeability to sodium or potassium, or intracellular concentrations of sodium or potassium are predictors of the probability of having hypertension in a general Caucasian population; we also attempted to confirm our previous inference that sodium-lithium countertransport is a predictor of the probability of having hypertension in this population. METHODS: The sample for analyses consisted of 199 unrelated men, aged 56-91 years, and 216 unrelated, nonpregnant women, aged 53-87 years, from the population of Rochester, Minnesota. Logistic regression was used to assess the relationship between predictor traits and blood pressure diagnostic status (normotension or hypertension). We assessed whether each erythrocyte trait was a predictor of the probability of having hypertension when the trait was considered by itself and when it was considered after the effects of other identified predictors of the probability of hypertension were included in the logistic regression models. RESULTS: When each erythrocyte trait was considered by itself, the predictors of the probability of having hypertension were sodium-lithium countertransport in men and sodium-lithium countertransport, sodium and potassium cotransport, and intracellular sodium concentration in women. When each erythrocyte trait was considered after other predictors had been included in the logistic regression models, none of the erythrocyte traits made an additional contribution to prediction of the probability of having hypertension unless its interactions with other predictors were also included in the models. CONCLUSIONS: Multiple measures of erythrocyte ion transport are associated with hypertension in the general Caucasian population; however, most of these associations are context-dependent inasmuch as they are gender-specific and dependent on levels of other predictor traits.

Aged↗

PubMed1995

Impact of apolipoprotein E genotype variation on means, variances, and correlations of plasma lipid, lipoprotein, and apolipoprotein traits in octogenarians.

The impact of apolipoprotein (apo) E genotype variation on means, variances and correlations between plasma lipid traits was studied in male and female octogenarians. Females had significantly higher mean levels of all 10 of the measured plasma lipid traits than males. The subset of concomitants (i.e., age, height, weight, body mass index, glucose and uric acid) that made a statistically significant contribution to interindividual variability was different in males and females for every trait considered. Gender-specific associations between variation in apo E genotype and variation in particular measures of lipid metabolism, adjusted for concomitant variation, were observed: in females there were no statistically significant associations while in males the means of the three common apo E genotypes were significantly different for adjusted measures of total cholesterol, low density lipoprotein cholesterol and low density lipoprotein-apo B. The common apo E genotypes were heterogeneous with respect to intragenotypic variance for adjusted log-transformed triglyceride levels in females only. Finally, the three common apo E genotypes were heterogeneous with respect to the correlation between traits, adjusted for concomitant variation, and gender influenced the manner in which the genotypes differed for specific correlations. This study documents that variation in the apo E gene has a significant impact on means, variances and correlations of plasma lipid traits in octogenarians, but the effects are context-, that is gender- and age-, dependent.

Aged↗

PubMed1995

Apolipoprotein E polymorphism predicts death from coronary heart disease in a longitudinal study of elderly Finnish men.

BACKGROUND: There is ample evidence from cross-sectional studies of an association between allelic variation of the gene coding for apolipoprotein E (apoE) and interindividual variation in plasma lipids, and the presence of coronary heart disease (CHD). There have been no prospective studies, however, to evaluate the usefulness of allelic variation of the apoE gene for predicting CHD. METHODS AND RESULTS: Two samples of elderly Finnish men were followed for 5 years, one in the east (n = 297) and the other in the southwest of Finland (n = 369). At baseline, when the apoE genotypes were assessed, the men were 65 to 84 years old. At the end of the follow-up, the vital status of each man was determined, and cause of death was coded. At baseline, relative frequencies of the three alleles-epsilon 2, epsilon 3, and epsilon 4--were 0.037, 0.827, and 0.136 in the eastern and 0.062, 0.763, and 0.175 in the southwestern samples, respectively (chi 2 = 8.89, df = 2, P < .012 for difference between the samples). During the 5-year follow-up, a total of 28 deaths from CHD were recorded in the eastern and 42 in the southwestern sample. Relative CHD mortality was not heterogeneous between the samples. Among those who died from CHD, there was a doubling of the relative epsilon 4 allele frequency in both samples (chi 2 = 4.70, df = 1, P < .03 for the eastern sample; chi 2 = 7.11, df = 1, P < .01 for the southwestern sample). CONCLUSIONS: Allelic variation in the apoE gene is a statistically significant predictor of CHD death in these samples of elderly Finnish men.

Aged↗

PubMed1995

Variation at the M235T locus of the angiotensinogen gene and essential hypertension: a population-based case-control study from Rochester, Minnesota.

A variant of the angiotensinogen gene, M235T, has been associated with essential hypertension in selected subjects from Paris, France and Salt Lake City, Utah. In the present report, we studied a population-based sample consisting of 104 subjects diagnosed with hypertension before age 60 and 195 matched normotensive individuals from Rochester, Minnesota. We determined whether there was a relationship between the M235T polymorphism of the angiotensinogen gene and the occurrence of essential hypertension using two methods. First, a contingency chi-square analysis was carried out to test for an association between the M235T polymorphism and hypertension status. Second, multivariable conditional logistic regression was used to determine whether variation at the M235T polymorphism was a significant predictor of the probability of having essential hypertension. We detected no statistically significant association between the M235T polymorphism and the occurrence of essential hypertension. In particular, the association was not significant in either gender or in a subset of severely hypertensive subjects requiring two or more anti-hypertensive medications. Furthermore, variation in the number of M235T alleles did not make a significant contribution to predicting the probability of having essential hypertension, either alone or in conjunction with other predictor variables. These results suggest that the contribution of variation in the angiotensinogen gene to the occurrence of essential hypertension is less than initially suspected, or may not be constant across populations.

Aged↗

PubMed1995

Impact of a common mutation of the LDL receptor gene, in French-Canadian patients with familial hypercholesterolemia, on means, variances and correlations among traits of lipid metabolism.

Structural and functional studies of the gene coding for the low density lipoprotein receptor in patients with familial hypercholesterolemia have uncovered over 180 mutant alleles of the gene. Although the classical familial hypercholesterolemia phenotype is well known, the range of phenotypic variability in lipid traits associated with particular mutations in familial hypercholesterolemia has not been extensively documented. We investigated the phenotypic distributions of plasma markers of lipid metabolism from a large sample of unrelated individuals who are heterozygous for a single mutation, a > 10 kb deletion in the low density lipoprotein receptor gene, and compared these distributions with those from a sample of healthy controls. Patients were pair-matched for sex and age with healthy individuals selected from a previously studied French-Canadian population from the same region. We examined the level and variation of seven lipid traits, the correlations between the traits, and the amount of overlap of the sample distributions for each trait. The low density lipoprotein receptor defect was found to affect the levels and variability of traits, and correlations between traits. There was some overlap of the distributions of lipid traits including that for low density lipoprotein cholesterol, which is a cardinal feature of familial hypercholesterolemia. The low density lipoprotein receptor gene has a sex-specific pleiotropic effect and should be considered as a variability gene as well as a level gene. The extensive dynamic changes observed in the relationships between lipid traits testify to the biological complexity of genome type-environment interactions.

Adult↗

PubMed1995

Cladistic analysis of the apolipoprotein AI-CIII-AIV gene cluster using a healthy French Canadian sample. I. Haploid analysis.

A cladistic analysis was carried out to identify haplotypes hypothesized to differ for functional DNA sequence variations within the apolipoprotein (apo) AI-CIII-AIV gene cluster that affect plasma lipid, lipoprotein and apolipoprotein levels. A sample of unrelated healthy French Canadians was studied. First, a cladogram of the observed apo AI-CIII-AIV haplotypes was estimated. Then this cladogram was used to define a statistical analysis of the association between haplotype variation and variation in plasma lipid, lipoprotein and apolipoprotein levels. Three haplotypes were identified which were associated with small (5-12% of the total sum of squares) pleiotropic effects on plasma lipid, lipoprotein and apolipoprotein traits and these effects were context, i.e. gender, dependent.

Adult↗

PubMed1994

Traversing the biological complexity in the hierarchy between genome and CAD endpoints in the population at large.

An emerging challenge facing those who are concerned about the efficacy of public health programs is to understand how information from the DNA revolution might be used to improve our ability to predict the initiation, progression and severity of a common disease having a complex multifactorial etiology. In the course of research to evaluate the role of information about DNA, combinations of genome types and environmental exposures that predispose to disease will be identified. Such information is expected to be useful in efforts to identify individuals and families at higher risk of disease and to predict their responses to a proposed therapy. This paper begins with a discussion of the features of a realistic biological model for the study of a common multifactorial disease. We present evidence for the complexity in the relationship between genome type variation and variation in risk of coronary artery disease (CAD) and review the preliminary results of our studies to determine whether information about genome type variation can improve our ability to predict the distribution of CAD among individuals in the population at large. Such studies make it apparent that new analytical strategies are necessary to deal with the plethora of genome type information available for the evaluation of risk of a common disease like CAD. This shift in the research paradigm will build upon new strategies to understand the organization of natural systems that are coming from outside the mainstream of genetic research.

Coronary Disease↗

PubMed1994

Apolipoprotein E polymorphism and heterozygous familial hypercholesterolemia. Sex-specific effects.

The impact of apolipoprotein (apo) E polymorphism on interindividual variation in plasma lipid, lipoprotein, and apolipoprotein levels was studied in a sample of familial hypercholesterolemic (FH) patients (147 women, 116 men) with the same mutation, a > 10-kilobase deletion of the low-density lipoprotein (LDL) receptor gene. Each trait was adjusted for concomitants (age, age squared, height, weight, weight squared) for each sex separately before the apoE genotypic effects were estimated. The relative contribution of concomitants to sample variability was found to be very different in women and in men. Allelic variation in the apoE gene was shown to explain a statistically significant portion of the variability in adjusted lipid traits. Moreover, the contribution of apoE polymorphism was different between sexes. In women, there was significant variability (P < .01) among apoE genotypes for total cholesterol, LDL cholesterol, and total and LDL apoB. In men, significant variability (P < .01) was observed among apoE genotypes in very-low-density lipoprotein (VLDL) cholesterol and triglyceride levels. Women with the epsilon 3/2 genotype had significantly lower means for total cholesterol, LDL cholesterol, and LDL apoB than women with the epsilon 3/3 genotype (P < .05). In men, the mean VLDL cholesterol was significantly higher for the epsilon 2/2 genotype and was significantly lower for the epsilon 4/2 genotype than the mean for the epsilon 3/3 genotype (P < .05). Overall, the greatest influence was associated with the epsilon 2 allele, and the LDL cholesterol-lowering effect of this allele was present only in FH women. No statistically significant apoE effect was shown on lipoprotein(a) levels in either sex.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1994

The gender-specific apolipoprotein E genotype influence on the distribution of plasma lipids and apolipoproteins in the population of Rochester, MN. III. Correlations and covariances.

The gender-specific influence that the apolipoprotein E (ApoE) polymorphism has on the correlations and covariances between pairs of nine plasma lipid and apolipoprotein traits (total cholesterol; in triglycerides; high-density-lipoprotein cholesterol; apolipoproteins AI, AII, B, CII, lnCIII, and lnE) was studied in 507 unrelated individuals representative of the adult population of Rochester, MN. Analyses are presented separately for females and males. The Apo E polymorphism had a significant influence on a large number (10 of 36) of correlations and covariances in females and on a small number (3 of 36) in males. The contribution of allelic variation in the Apo E gene to the definition of multivariate measures of the 36-dimensional correlation structure was evaluated. The influence of Apo E genotype on correlation structure was gender dependent. These findings were used to demonstrate how heterogeneity of risk-factor correlations and covariances among genotype-gender subgroups of the population at large may influence the evaluation of risk of coronary artery disease.

Analysis of Variance↗

PubMed1993

A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping. IV. Nested analyses with cladogram uncertainty and recombination.

We previously developed an analytical strategy based on cladistic theory to identify subsets of haplotypes that are associated with significant phenotypic deviations. Our initial approach was limited to segments of DNA in which little recombination occurs. In such cases, a cladogram can be constructed from the restriction site data to estimate the evolutionary steps that interrelate the observed haplotypes to one another. The cladogram is then used to define a nested statistical design for identifying mutational steps associated with significant phenotypic deviations. The central assumption behind this strategy is that a mutation responsible for a particular phenotypic effect is embedded within the evolutionary history that is represented by the cladogram. The power of this approach depends on the accuracy of the cladogram in portraying the evolutionary history of the DNA region. This accuracy can be diminished both by recombination and by uncertainty in the estimated cladogram topology. In a previous paper, we presented an algorithm for estimating the set of likely claodgrams and recombination events. In this paper we present an algorithm for defining a nested statistical design under cladogram uncertainty and recombination. Given the nested design, phenotypic associations can be examined using either a nested analysis of variance (for haploids or homozygous strains) or permutation testing (for outcrossed, diploid gene regions). In this paper we also extend this analytical strategy to include categorical phenotypes in addition to quantitative phenotypes. Some worked examples are presented using Drosophila data sets. These examples illustrate that having some recombination may actually enhance the biological inferences that may derived from a cladistic analysis. In particular, recombination can be used to assign a physical localization to a given subregion for mutations responsible for significant phenotypic effects.

Algorithms↗

PubMed1993

Sodium-lithium countertransport genotype and the probability of hypertension in adults.

The objective of the present study was to determine whether information about a biometrically inferred single gene with large effects on erythrocyte sodium-lithium countertransport is useful in predicting the probability of having hypertension. We used multivariate logistic regression to model the relationship between the probability of having hypertension and predictor traits in a sample of 382 unrelated adult women and 347 unrelated adult men from Rochester, Minn. First, we identified a set of demographic, biochemical, and physiological predictors. Second, we analyzed whether the relationship between the probability of having hypertension and the identified predictor traits was heterogeneous between the biometrically inferred single locus genotypes with large effects on sodium-lithium countertransport level. Third, if there was no heterogeneity, we assessed whether sodium-lithium countertransport genotypes made an additional contribution to predicting the probability of having hypertension after other predictors were considered. In women, the predictors of the probability of having hypertension were age, plasma apolipoprotein CIII, body mass index, and an interaction term involving age and body mass index. The relationship between the probability of having hypertension and the identified predictors was not heterogeneous between sodium-lithium countertransport genotypes, and genotype did not contribute to the prediction of the probability of having hypertension after the identified predictors were considered. In men, predictors of the probability of having hypertension were age, plasma levels of high-density lipoprotein cholesterol, apolipoproteins AI and CII, sodium-lithium countertransport level, and sodium-lithium countertransport genotype. The relationship between the probability of having hypertension and sodium-lithium countertransport level and age were heterogeneous between biometrically inferred sodium-lithium countertransport genotypes.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMed1992

Application of cladistics to the analysis of genotype-phenotype relationships.

We seek to understand the relative contribution of allelic variations of a particular gene to the determination of an individual's risk of atherosclerosis or hypertension. Work in progress is focusing on the identification and characterization of mutations in candidate genes that are known to be involved in determining the phenotypic expression of intermediate biochemical and physiological traits that are in the pathway of causation between genetic variation and variation in risk of disease. The statistical strategy described in this paper is designed to aid geneticists and molecular biologists in their search to find the DNA sequences responsible for the genetic component of variation in these traits. With this information we will have a more complete understanding of the nature of the organization of the genetic variation responsible for quantitative variation in risk of disease. It will then be possible to fully evaluate the utility of measured genetic information in predicting the risk of common diseases having a complex multifactorial etiology, such as atherosclerosis and hypertension.

Alleles↗

PubMed1992

A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping and DNA sequence data. III. Cladogram estimation.

We previously developed a cladistic approach to identify subsets of haplotypes defined by restriction endonuclease mapping or DNA sequencing that are associated with significant phenotypic deviations. Our approach was limited to segments of DNA in which little recombination occurs. In such cases, a cladogram can be constructed from the restriction site or sequence data that represents the evolutionary steps that interrelate the observed haplotypes. The cladogram is used to define a nested statistical design to identify mutational steps associated with significant phenotypic deviations. The central assumption behind this strategy is that any undetected mutation causing a phenotypic effect is embedded within the same evolutionary history that is represented by the cladogram. The power of this approach depends upon the confidence one has in the particular cladogram used to draw inferences. In this paper, we present a strategy for estimating the set of cladograms that are consistent with a particular sample of either restriction site or nucleotide sequence data and that includes the possibility of recombination. We first evaluate the limits of parsimony in constructing cladograms. Once these limits have been determined, we construct the set of parsimonious and nonparsimonious cladograms that is consistent with these limits. Our estimation procedure also identifies haplotypes that are candidates for being products of recombination. If recombination is extensive, our algorithm subdivides the DNA region into two or more subsections, each having little or no internal recombination. We apply this estimation procedure to three data sets to illustrate varying degrees of cladogram ambiguity and recombination.

Alcohol Dehydrogenase↗

PubMed1992

Twenty-four-hour blood pressure profiles in normotensive sons of hypertensive parents.

We investigated whether blood pressures are higher in normotensive offspring of hypertensive parents than in normotensive offspring of normotensive parents outside the physician's office and, if so, whether these higher blood pressures are dependent on the level of dietary sodium intake. We compared 24-hour ambulatory blood pressure profiles between 11 normotensive sons of two hypertensive parents and 11 normotensive sons of two normotensive parents; profiles were recorded after 1 week of a low sodium diet (10 meq/day) and after 1 week of a high sodium diet (200 meq/day). The sons of hypertensive parents were on average 6 years older than the sons of normotensive parents (47 +/- 5 [SD] versus 41 +/- 4 years, p < 0.05). The shift from low to high sodium diet did not significantly change the magnitude of differences in office or ambulatory blood pressures between the groups (i.e., no group-by-diet interaction); thus, we assessed group effects by contrasting blood pressure means for each group pooled across diets. Age-adjusted office blood pressure was higher in sons of hypertensive parents than in sons of normotensive parents (116 +/- 7/80 +/- 6 versus 111 +/- 7/75 +/- 6 mm Hg; p = 0.020 for systolic and p = 0.003 for diastolic blood pressure).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1992

Sodium-lithium countertransport and probability of hypertension in Caucasians 47 to 89 years old.

The objectives of the present study were to determine whether sodium-lithium countertransport contributes to predicting the probability of having hypertension and to determine whether it does so after other predictor traits have been considered. We used logistic regression to model the relation between sodium-lithium countertransport and the probability of having hypertension, estimated by the prevalence of hypertension among 172 men and 252 women, aged 47-89 years, from the Caucasian population of Rochester, Minn. When sodium-lithium countertransport was the only predictor trait considered, it made a statistically significant contribution to prediction both in men (model chi(2)1df = 20.50, p < 0.001) and in women (model chi(2)1df = 16.69, p < 0.001). For each standard deviation increase in sodium-lithium counter-transport, the expected odds of having hypertension increased 2.25 times in men (95% confidence interval [CI], 1.44-3.51) and 1.77 times in women (95% CI, 1.32-2.37). When sodium-lithium countertransport was not considered, the other traits identified as predictors were age, body mass index, and plasma apolipoprotein CII and CII squared; plasma apolipoprotein AI was an additional predictor in women but not in men. When sodium-lithium countertransport was added to models that included the other predictors, it improved prediction both in men (increase in model chi(2)1df = 12.29, p < 0.001) and in women (increase in model chi(2)1df = 4.86, p < 0.027). Based on these complete models, when the other predictors remained at their mean values, each standard deviation increase in sodium-lithium countertransport increased the expected odds of having hypertension 2.06 times in men (95% CI, 1.31-3.22) and 1.48 times in women (95% CI, 1.04-2.21). These results establish that sodium-lithium countertransport provides information that is helpful in predicting the probability of having hypertension and is not reflected in other identified predictor traits.

Aged↗

PubMed1992

Biological complexity and strategies for finding DNA variations responsible for inter-individual variation in risk of a common chronic disease, coronary artery disease.

Most common chronic diseases of humans aggregate, but do not segregate, in families. The segregation-linkage research paradigm has not provided great insights into their genetic etiology. In this paper, using coronary artery disease as an example, we discuss hierarchical organization, coherence, emergent properties and dynamism as features that characterize the complexity of genotype-phenotype relationships. We summarize a research strategy for evaluating the contribution of genetic and environmental factors to the prediction of inter-individual variation in risk of disease. We then review a statistical strategy that employs cladistic theory to identify individuals carrying mutant DNA sequences responsible for an observed association between marker variation in a gene and inter-individual variation in biological traits that determine risk of a common multifactorial disease. Finding these DNA sequences is a necessary step in our search for an understanding of the nature of the mapping of genetic variation into variation in risk of a disease like coronary artery disease.

Coronary Disease↗

PubMed1992

The gender-specific apolipoprotein E genotype influence on the distribution of plasma lipids and apolipoproteins in the population of Rochester, Minnesota. II. Regression relationships with concomitants.

The influence of the apolipoprotein E (Apo E) polymorphism and gender on the regression relationships between each of nine plasma lipid and apolipoprotein traits (total cholesterol; ln triglycerides; high-density-lipoprotein cholesterol; apolipoproteins AI, AII, B, and CII; ln CIII; and ln E) and four concomitants (age, weight, waist-to-hip ratio, and smoking) was studied in 507 unrelated individuals representative of the adult population of Rochester, MN. Analyses are presented separately for females and males. Each lipid and apolipoprotein trait exhibited at least one Apo E genotype-specific regression relationship with the concomitants investigated in this study. In most cases the heterogeneity of regression was associated with differences between the epsilon 32 and epsilon 33 genotype. This study documents that the influence of Apo E genotype on average levels of plasma lipids and apolipoproteins varies among subdivisions of the population defined by age, body size, and smoking status.

Adult↗

PubMed1991

Genetic structure and the search for genotype-phenotype relationships: an example from disequilibrium in the Apo B gene region.

We analyzed allelic associations (disequilibria) for four restriction fragment length polymorphisms (RFLPs) in the region of the 43-kb Apo B gene in a sample of 233 unrelated individuals from Montreal, Canada, sampled for health. This total sample (T) included 160 individuals of known French Canadian (FC) ancestry. We present a rigorous application of current methodology to these samples, including estimation of type II error probabilities and correlations between markers for estimates of disequilibria. We then consider the utility of these estimates of allelic disequilibria for the interpretation of genotype-phenotype relations. Significant deviations from Hardy-Weinberg equilibrium were not predicted by proximity to other markers in disequilibrium. We found significant quadri-allelic disequilibrium for two marker pairs despite absence of significant deviations from Hardy-Weinberg equilibrium for either marker or tri-allelic disequilibrium, respectively. Altogether these results underscore the complexity of the genotypic structure of the data. A combination of nonevolutionary factors, including sampling for health, small sample size and data exclusion due to methodological constraints of not successfully typing all members of the sample for every RFLP, is a likely explanation for this complexity. These types of factors are common to many RFLP studies. Patterns of composite di-allelic disequilibrium indicated that some RFLP allele pairs may have a longer shared evolutionary history than others and that disequilibrium is not predicted by distance between RFLPs. Type II error probabilities were generally much higher than those for type I errors. Correlations between marker pairs for disequilibria were generally not high. We show from a review of 14 published studies of association between the XbaI RFLP and variation in a total of 15 lipid traits that deviations from Hardy-Weinberg equilibrium can cause substantial differences in the estimation of variability associated with phenotypic differences among marker genotypes relative to Hardy-Weinberg conditions.

Adult↗