Biomedical subjects

C F Sing

Publications and source records attributed to C F Sing.

At least 19 recordsLinked to original sources

PubMed1997

Association between common alleles of the low-density lipoprotein receptor gene region and interindividual variation in plasma lipid and apolipoprotein levels in a population-based sample from Rochester, Minnesota.

This paper presents an analysis of the relationship between variation in the low-density lipoprotein receptor (LDLR) gene region and interindividual variation in plasma lipid and apolipoprotein levels in a sample representative of the adult population of Rochester, Minn. (217 females and 187 males aged 26 to 63). This relationship was analyzed by estimating the average excesses of alleles of the LDLR gene defined using RFLP markers both singly and simultaneously. We also used a cladistic approach to illustrate the consequences of incorporating evolutionary information into the analysis of genotype-phenotype relationships. Although results from both approaches supported the inference that common variation in the LDLR gene region associates with small effects on plasma lipid and apolipoprotein levels, only the cladistic approach provides direction for further work aimed at identifying the functional DNA sequence variations responsible for the observed associations.

Adult↗

PubMed1997

A biometrical study of the relationship between sodium-lithium countertransport and triglycerides.

We addressed the question: Is there evidence that allelic variation in a single unmeasured gene that has a large effect on maximal activity of erythrocyte sodium-lithium countertransport (Na-Li CNT) also has pleiotropic effects on variation in plasma triglyceride levels? Complex segregation analysis models that included plasma triglyceride levels as a covariate were considered as explanations for interindividual variation in Na-Li CNT. A sample of 711 healthy adults from 254 pedigrees enrolled in the Rochester Family Heart Study was selected for this study. The majority of the pedigrees supported the hypothesis that variations in a single unmeasured non-transmitted environmental factor have large effects on the Na-Li CNT distribution. Only gender-specific first-order covariate parameters were necessary in the complex segregation models suggesting that the form of the relationship between Na-Li CNT and plasma triglyceride level was not influenced by variation in the inferred environmental factor with large effects. Stratification of the sample by this inferred environmental factor resulted in three classes of individuals with significant differences in the distributions of coronary heart disease risk factor traits, as well as interindividual variation in both Na-Li CNT and plasma triglyceride levels. These results, along with other observations from the Rochester Family Heart Study sample, emphasize the complex and multifactorial nature of the causes of interindividual variation in Na-Li CNT. Our study further suggests that new research strategies are needed for studying the relationships between genetic and environmental variation and variation in quantitative traits such as Na-Li CNT that have been identified as risk factors for hypertension.

Adult↗

PubMed1997

The response of renal plasma flow to angiotensin II infusion in a population-based sample and its association with the parental history of essential hypertension.

BACKGROUND: Results from previous studies suggested that a blunted response of renal plasma flow (RPF) to angiotensin II infusion during a high-sodium diet (a phenotype associated with nonmodulation) is an intermediate phenotype for essential hypertension. OBJECTIVE: To determine whether RPF traits used to investigate nonmodulation have the characteristics of intermediate traits when examined in a population-based sample of adults aged 20-49.9 years. DESIGN AND METHODS: We examined the frequency distribution of baseline RPF and of its response to All infusion using maximum-likelihood commingling analysis in order to investigate the null hypothesis that the distributions of these traits are unimodal. We also examined the null hypothesis that there is no association between these candidate intermediate traits and the parental history of essential hypertension. RESULTS: There was some evidence for the commingling of multiple distributions underlying these traits both for women and for men but the commingled distributions overlapped substantially and the inferences about the commingling of distributions were sensitive to the method of RPF measurement, exclusion of outliers, and the method of adjustment for concomitants. There was no statistically significant association between any of the RPF traits and a parental history of essential hypertension. CONCLUSIONS: There is not sufficiently strong evidence to advocate the use of this set of intermediate traits to identify high-risk individuals or to relate genetic variation to the variation in risk of essential hypertension within this age range in the population at large.

Adult↗

PubMed1997

The role of the apolipoprotein E polymorphism in the prediction of coronary artery disease age of onset.

We investigated the role of the apolipoprotein (Apo) E polymorphism in the prediction of CAD age of onset in a sample of unrelated living male (n = 65) and female (n = 54) Caucasian subjects diagnosed with CAD. Cumulative distributions of age at the first diagnosis of CAD were estimated for each Apo E genotype and tested for homogeneity using the log-rank test. The Apo epsilon 33 genotype was used as a reference group for all hypothesis tests. Analyses were performed separately in males and females. We found evidence suggesting that the presence of the Apo epsilon 32 genotype in males is associated with a significantly earlier CAD age of onset. These results suggest that the Apo E polymorphism may be a gender-specific predictor of CAD age of onset.

Adult↗

PubMed1996

Genetic architecture of common multifactorial diseases.

The purpose of this paper is to foster a dialogue among those interested in the genetic analysis of common chronic diseases. The need for an alternative to the Cartesian-Mendelian research strategy is discussed. A biological model that considers an individual's health to be an emergent property of a complex adaptive system is presented. A review of the contribution of the gene coding for apolipoprotein E to the genetic architecture of measures of lipid metabolism documents that an individual's coronary artery health has all the features expected of a complex adaptive system. Suggestions for enhancing our ability to use genetic information to predict onset, progression and severity of disease are offered.

Apolipoproteins E↗

PubMed1996

Genotypes with the apolipoprotein epsilon4 allele are predictors of coronary heart disease mortality in a longitudinal study of elderly Finnish men.

Earlier we reported that allelic variation in the gene coding for apolipoprotein (apoE is a significant predictor of variation in the risk of coronary heart disease (CHD) death in a longitudinal study of elderly Finnish men. Here we address the question: which of the apoE genotypes confers the risk information in these men, and whether such information persists after other CHD risk factors are considered? We followed two cohorts of elderly Finnish men aged 65 to 84 years, one in Eastern (n = 281) and the other in the Southwestern (n = 344) Finland for 5 years during which 26 (9.3%) of the men from the Eastern cohort and 40 (11.6%) of the men in the Southwestern cohort died from CHD. Baseline high density lipoprotein (HDL) cholesterol and (HDL cholesterol)2 in the Eastern cohort and age, and total and HDL cholesterol and smoking status in the Southwestern cohort were significant predictors of CHD death (P < 0.05). The apoE genotypes were significant predictors in the Southwestern cohort at P = 0.02 and in the Eastern cohort at P = 0.18. In multivariable models, information about apoE genotypes improved the prediction at P = 0.1O level of statistical significance in both cohorts. When genotypes were considered separately, the episilon2/4 combined with the epsilon4/4 in the Eastern cohort (odds ratio = 7.69, 95% CI = 1.67-35.52) and the epsilon 3/4 in the Southwestern cohort (odds ratio = 2.44, 95% CI = 1.165.10) had sigificantly greater odds of CHD death compared to the common F3/3 genotype. We conclude that apoE genotypes confer risk information about CHD death in two cohorts of elderly Finnish men in a longitudinal study, and this information persists after adjustment for other CHD risk factors. Because different genotypes were predictors in these two cohorts, we further conclude that the utility of a particular genotype as a predictor of CHD death in other populations may depend on the distribution of risk factor profiles at baseline, geographically defined environmental exposures, the CHD mortality history, and the evolutionary history of background genotypes in the population considered.

Age Factors↗

PubMed1996

Probability of having hypertension: effects of sex, history of hypertension in parents, and other risk factors.

The objective of the present study was to determine whether paternal and maternal history of hypertension contributes to the probability of an individual having hypertension before and after other measured traits, including sex, are considered. A cross-sectional sample of 217 men and 196 women was selected from the general Caucasion population of Rochester, Minnesota without respect to the hypertension status of subjects and their parents. Logistic regression analyses indicated that when no other information was considered, paternal history of hypertension contributed to the probability of having hypertension in men (chi 2 = 4.14, df = 1, p = 0.042) and in women (chi 2 = 4.12, df = 1, p = 0.042). The odds ratio associated with paternal history of hypertension was 2.80 in men (95% confidence interval [CI] = 1.0-8.0); the odds ratio was 4.11 in women (95% CI = 0.9-19.3). Maternal history of hypertension provided a marginally significant contribution to the prediction of probability of having hypertension in men (chi 2 = 3.86, df = 1, p = 0.049 in men), and less so in women (chi 2 = 3.31, df = 1, p = 0.068). The odds ratios associated with maternal history of hypertension were 2.85 in men (95% CI = 0.9-8.8) and 3.60 in women (95% CI = 0.8-16.9). A stepwise selection algorithm was used to select other predictors of hypertension in men and women. Other predictors of hypertension identified in men were age and sodium-lithium countertransport level. After these other predictors were considered, paternal but not maternal history of hypertension contributed to the probability of having hypertension in men. In a model that contained these other predictors, the partial odds ratio associated with paternal history of hypertension was 3.38 (95% CI = 1.1 = 10.1). Other predictors identified in women were age, apolipoprotein (apo) B, and apo B squared. After these other predictors were considered, neither paternal nor maternal history of hypertension made a statistically significant contribution to the probability of having hypertension in women. These results suggest that evaluation of the hypertension risk of an individual depends on the sex of the individual, the sexes of the individual's hypertensive parents, and the values of other measured risk factor traits.

Algorithms↗

PubMed1996

Genotype-environment interaction: apolipoprotein E (ApoE) gene effects and age as an index of time and spatial context in the human.

We analyzed the age-dependence of the estimates of the parameters of the genetic architecture of plasma ApoE levels associated with ApoE gene variation. Our study sample included 1988 individuals in multigeneration pedigrees from the Rochester, MN, population. We used a 30-yr sliding window across the age range (5-90 yr) to estimate the age dependency of parameters. Additive ApoE allelic variance of transformed plasma ApoE values for both genders, heritabilities for males and phenotypic and residual variance for females peaked in the 20-40-yr age windows and decreased significantly with age (P < 0.05). Phenotypic and residual variance for males and dominance variance for both genders did not vary significantly with age. All parameter estimates were significantly different from zero across all age windows for both genders. Most studies of ApoE have focused on its functions in the pathophysiology of coronary artery disease (CAD) in middle-aged and older individuals. Our findings suggest the greatest role of this gene is in determining phenotype differences among younger and middle-aged individuals. These observed genotypic effects on the plasma ApoE levels may contribute to age-dependent differences in physiological health, growth, and risk of disease.

Adolescent↗

PubMed1996

Association of genetic variation with interindividual variation in ambulatory blood pressure.

OBJECTIVE: To determine whether genetic and non-genetic components of interindividual variation in systolic and diastolic blood pressure are constant throughout the day or are time or activity dependent. METHODS: We obtained 24 h ambulatory blood pressure recordings in 263 members of 68 unrelated nuclear families (i.e. parents and their offspring) representative of the Caucasian population of Rochester, MN, USA. Using the time each patient got into bed as a reference point, we identified 198 records in which this reference point was preceded by eight consecutive active hours (out of bed) and followed by four consecutive inactive hours (in bed) in which four or more blood pressure readings taken each hour were judged to be technically satisfactory. For each hourly mean for systolic and diastolic blood pressure, we estimated total interindividual variance, variance associated with concomitant variables (generation; sex within generation strata; and age, height, weight, body mass index, and abdomen-to-hip ratio within generation and sex strata), and variance associated with additive genetic effects (i.e. the chief cause of resemblance between relatives). To assess trends in each component of interindividual blood pressure variance over the 12 h period, we estimated the slope of the linear regression line fit to the hourly estimates. RESULTS: For systolic blood pressure, total interindividual variance did not change significantly (slope of regression line = -0.23, P = 0.717). In contrast, total interindividual variance for diastolic blood pressure was greater during active hours than inactive hours (slope of regression line = -5.53, P < 0.001). For both systolic and diastolic blood pressure, variance associated with the concomitant variables was greater during active hours than during inactive hours (for systolic blood pressure slope of regression line = -2.98, P = 0.001; for diastolic blood pressure slope of regression line = -6.14, P < 0.001). Likewise, for both systolic and diastolic blood pressure, variance associated with additive genetic effects was also greater during active hours than during inactive hours (for systolic blood pressure slope of regression line = -1.65, P = 0.090; for diastolic blood pressure slope of regression line = -1.47, P = 0.018). CONCLUSIONS: This study demonstrates that components of interindividual variation in blood pressure are not constant, but are time or activity dependent.

Adolescent↗

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↗