Heritability of platelet function in families with premature coronary artery disease.

BACKGROUND: Variations in platelet function among individuals may be related to differences in platelet-related genes. The major goal of our study was to estimate the contribution of inheritance to the variability in platelet function in unaffected individuals from white and African American families with premature coronary artery disease. METHODS: Platelet reactivity, in the absence of antiplatelet agents, was assessed by in vitro aggregation and the platelet function analyzer closure time. Heritability was estimated using a variance components model. RESULTS: Both white (n = 687) and African American (n = 321) subjects exhibited moderate to strong heritability (h(2)) for epinephrine- and adenosine diphosphate-induced aggregation (0.36-0.42 for white and >0.71 for African American subjects), but heritability for collagen-induced platelet aggregation in platelet-rich plasma was prominent only in African American subjects. Platelet lag phase after collagen stimulation was heritable in both groups (0.47-0.50). A limited genotype analysis demonstrated that the C825T polymorphism of GNB3 was associated with the platelet aggregation response to 2 muM epinephrine, but the effect differed by race. CONCLUSIONS: Considering the few and modest genetic effects reported to affect platelet function, our findings suggest the likely existence of undiscovered important genes that modify platelet reactivity, some of which affect multiple aspects of platelet biology.

Quantitative genetic analysis of blood pressure reactivity to orthostatic tilt using principal components analysis.

Blood pressure (BP) reactivity to orthostatic tilt may be predictive of cardiovascular disease. However, the genetic and environmental influences on BP reactivity to tilt have not been well examined. Identifying different influences on BP at rest and BP during tilt is complicated by the intercorrelation among multiple measurements. In this study, we use principal components analysis (PCA) to reduce multivariate BP data into components that are orthogonal. The objective of this study is to characterize and examine the genetic architecture of BP at rest and during head-up tilt (HUT). Specifically, we estimate the heritability of individual BP measures and three principal components (PC) derived from multiple BP measurements during HUT. Additionally, we estimate covariate effects on these traits. The study sample consisted of 444 individuals, distributed across four large families. HUT consisted of 70 degrees head-up table tilting while strapped to a tilt table. BP reactivity (deltaBP) was defined as BP during HUT minus BP while supine. Three PC extracted from the PCA were interpreted as 'general BP' (PC1), 'pulse pressure' (PC2) and 'BP reactivity' (PC3). Variance components methods were used to estimate the heritabilities of resting BP, HUT BP, deltaBP, as well as the three BP PC. Significant (P<0.05) heritabilities were found for all BP measurements, except for systolic deltaBP at 1 and 3 min, and diastolic deltaBP at 2 min. Significant genetic effects were also found for the three PC. Each of these orthogonal components is significantly influenced by somewhat different sets of covariates.

Evidence for mendelian inheritance in the pathogenesis of lung cancer.

Segregation analyses that allowed for variable age of onset of lung cancer and smoking history were performed on 337 families, each ascertained through a lung cancer proband. Results indicated compatibility of the data with mendelian codominant inheritance of a rare major autosomal gene that produces earlier age of onset of the cancer. Segregation at this putative locus could account for 69% and 47% of the cumulative incidence of lung cancer in individuals up to ages 50 and 60, respectively. The gene was involved in only 22% of all lung cancers in persons up to age 70, a reflection of an increasing proportion of noncarriers succumbing to the effects of long-term exposure to tobacco.

A linkage study of panic disorder.

We tested for linkage between panic disorder and a battery of 29 genetic markers in 26 families. Linkage between panic disorder and 18 of the marker loci could be excluded at a recombination fraction of 0.00, nine at a recombination fraction of 0.05, and four at a recombination fraction of 0.10. The 18 loci are distributed over ten chromosomes. One locus was suggestive of linkage. The maximum lod score for alpha-haptoglobin was 2.27 at a recombination fraction of 0.0, representing odds in favor of linkage of 186.1. alpha-Haptoglobin has been mapped to chromosome 16q22. The results demonstrate that linkage studies of psychiatric disorders can yield informative results by identifying tentative linkages that merit further investigation and by excluding regions of the genome from future linkage searches.

Heritability of salt sensitivity in black Americans.

Salt sensitivity is defined as a change in blood pressure in response to changes in salt and water homeostasis. Found in 73% of hypertensive and 36% of normotensive blacks, it is generally considered a hallmark of hypertension in blacks. The higher prevalence of salt sensitivity in blacks compared with whites suggests a genetic influence on this trait, but there is little direct evidence of heritability. We determined the extent to which salt sensitivity is correlated in black families and estimated the heritability of this phenotype. Black families were recruited through a hypertensive proband. Both hypertensive and normotensive adults were phenotyped with respect to salt sensitivity with an intravenous sodium-loading, furosemide volume-depletion protocol. Salt sensitivity was defined as the difference between sodium-loaded and volume-depleted blood pressure. We enrolled 20 families, comprising 30 parent-offspring pairs and 115 adult sibling pairs. Age-adjusted familial correlations ranged from .33 to .44, .19 to .37, and .12 to .21 for mean arterial and systolic and diastolic pressure responses to the salt sensitivity maneuver, respectively. Corresponding heritability estimates were 0.26 to 0.84, 0.26 to 0.74, and 0.004 to 0.24, respectively. These data strongly suggest a heritable component of salt sensitivity.

Preliminary evidence of linkage of salt sensitivity in black Americans at the beta 2-adrenergic receptor locus.

Salt sensitivity is a heritable trait that is a hallmark of hypertension in black Americans. Genes encoding adrenergic receptors are candidate loci for the inheritance of this hypertension-related trait because of the role of these receptors in the regulation of renal sodium excretion and vascular tone. We performed this study to determine whether these loci are responsible for some of the phenotypic variation in salt sensitivity. Hypertensive black American probands were ascertained, followed by sequential ascertainment of adult sib pairs among the first-, second- and third-degree relatives of the proband. Both hypertensive and normotensive siblings were tested for salt sensitivity by an intravenous sodium-loading, lasix volume-depletion protocol. Genotyping was performed with restriction fragment length polymorphisms in genomic DNA probed with clones containing the beta 2- and alpha 2c10-adrenergic receptor genes. A total of 109 sib pairs was evaluated. Salt sensitivity was defined as the change in blood pressure in each individual, comparing the sodium-loaded with the volume-depleted state. Systolic pressure decreased by an average of 9.0 +/- 9%, diastolic pressure by 1.5 +/- 11%, and mean arterial pressure by 5.0 +/- 9%. Neither blood pressure nor salt sensitivity was linked at the alpha 2c10-adrenergic receptor locus. No evidence suggested that systolic salt sensitivity and baseline blood pressure were linked at the beta 2-adrenergic receptor locus. Model-independent sib pair linkage analysis suggested that diastolic blood pressure response to sodium loading/volume depletion is linked at the beta 2-adrenergic receptor locus (P < .006). Evidence for linkage was significant at the .05 level after adjustment for the number of phenotypic traits examined.

Evidence for possible linkage between genetic markers and affective disorders.

Studies of the underlying components of affective disorders are particularly difficult because of the confounding effects of both genetic and environmental factors. Linkage analysis is a useful tool in delineating the etiology of affective disorders, as it is unlikely that linkage between behavioral traits and blood group polymorphisms could result from environmental effects. The present study used the robust Haseman and Elston sibpair method to analyze linkage between 24 genetic markers and affective disorder in 34 nuclear families from 25 pedigrees (195 people). The probands were ascertained as part of the ongoing NIMH Collaborative Depression Study. Indications of linkage between familial pure depressive disease and MNS and depression spectrum disease and ORM were found, as had been previously suggested. There was also suggestive evidence for linkage between the latter and GC. Results are discussed in terms of methodological differences with previous studies.

Linkage analysis of depression spectrum disease.

As part of a study of the possible subgroups of unipolar affective disease, 27 families were ascertained as depression spectrum disease (DSD) families. The purpose of this study was an investigation of the linkage relationships between DSD and 30 genetic markers using the robust sib-pair and lod-score methods. Using the sib-pair methods, evidence for linkage was found with orosomucoid (ORM) on chromosome 9q (p = 0.006), regardless of whether only individuals with unipolar depression, alcoholism, or antisocial personality were considered to be affected, or whether individuals with any psychiatric disorder were considered to be affected. Weak evidence of linkage with ORM was corroborated using lod-score methods when a narrow definition of depression spectrum disease was used, although stronger evidence of linkage was found with ORM when any psychiatric disorder was considered to be affected. The maximum lod-score for ORM was 1.68 at a male recombination fraction of 0.23 and a female recombination fraction of 0.01.

Comparison of clinical effects and pharmacokinetics of once-daily Uniphyl and twice-daily Theo-Dur in asthmatic patients.

A pharmacokinetic study using theophylline syrup in adult asthmatic patients demonstrated a mean apparent volume of distribution of 0.38 liters/kg, mean elimination rate constant of 0.10 hours-1, and variable rates of clearance of theophylline (total body clearance of 0.38 to 0.96 ml/kg per minute). Subsequently, the asthmatic patients were compared using a cross-over design after maintenance Uniphyl (once daily at 8 a.m. or at 8 p.m.) and Theo-Dur (twice daily at 8 a.m. and 8 p.m.). Total daily maintenance theophylline dosage, calculated from the pharmacokinetic data, was identical in all three cross-over phases. At the end of each phase, plasma theophylline levels were measured every two hours and spirometric determinations were made every four hours (excluding 4 a.m.) for 24 hours. The following results were observed: highest peak and mean plasma theophylline concentration and area under the concentration-time curves with evening Uniphyl (p less than 0.05); prolonged time-to-peak theophylline concentration after nocturnal compared with daytime dosing; diurnal variation in pulmonary function and plasma theophylline concentrations; no significant differences between the three maintenance treatments in asthmatic symptoms or spirometric results.

Is lung sequestration of indium-111-labeled granulocytes organ specific?

Transient sequestration of polymorphonuclear leukocytes (PMN) in the normal lungs of animals occurred immediately following intravenous injection of 111In-labeled PMN. We investigated the organ specificity of this process. Equal amounts of homologous PMN, derived from the intravascular space and labeled with [111In]oxine, were infused either intravenously (i.v.) or intraarterially (i.a.) into pairs of rats. Changes in radioactivity emitted from three regions--representing lung, liver and spleen, and lower body--were determined from images during the following hour. A nonspecific character was demonstrated by the transient sequestration of activity in the lower body following i.a. infusions. However, the rate of initial clearance of activity (first 30 min) from the lungs of i.v.-infused rats was relatively slower than from the lower body of i.a.-infused rats. This suggests the presence of a lung-specific as well, which may be important for localization of PMN-related events to the lung.

Measurement of cardiac output by automated single-breath technique, and comparison with thermodilution and Fick methods in patients with cardiac disease.

Accurate noninvasive methods are needed for determination of cardiac output. Current methods are generally complex or may be unreliable. A previously described method, based on absorption of acetylene gas during a constant exhalation that enables calculation of cardiac output by estimating pulmonary capillary circulation, is incorporated in a new, automated commercial product (SensorMedics 2200). In this study, cardiac output by single-breath acetylene blood flow measured with this device was compared with the standard thermodilution and direct Fick methods in 20 patients undergoing cardiac or pulmonary artery catheterization. Patients inhaled test gas mixture to total lung capacity and exhaled at a constant rate through an adjustable resistor. Lung volumes and noninvasive acetylene blood flow value were calculated automatically. Correlation between the automated single-breath technique and both thermodilution and Fick cardiac output determinations was very high (correlation coefficients were 0.90 and 0.92, respectively), regression slopes were close to identity (0.98 and 0.90), and bias (-0.39 and -0.79 liter/min) and precision (0.94 and 1.02) were good; when shunt correction was applied, bias was reduced to 0.06 and 0.35 liter/min, respectively. Rapid, accurate, noninvasive measurement of cardiac output was easily obtained using the automated device. This technique may have a wide applicability for noninvasive evaluation of patients with cardiac disease and for monitoring effects of therapeutic interventions.

Major gene model for the inheritance of catechol-O-methyltransferase activity in five large families.

Five large families including 1,189 individuals were each ascertained through one proband with essential hypertension. Four of the probands were white and one was black. Erythrocyte catechol-o-methyltransferase (COMT) activity was measured in 551 family members. Standard statistical methods were used to investigate sex, age, and family differences in COMT activity. Maximum-likelihood methods were used to fit mixtures of normal distributions to COMT activity. COMT activity is distinctly bimodal. Pedigree segregation analyses were performed on the untransformed COMT values, their square roots, and natural logarithms in each family. In no family and under none of the three transformations was it possible to reject the hypothesis of Mendelian transmission of a major gene with two alleles in Hardy-Weinberg equilibrium. In most cases a genetic hypothesis with complete dominance or recessiveness, or a hypothesis of equal transmission probabilities was rejected. While the different transformations had a large effect on the skewness and kurtosis of the overall distribution of the data, they had little effect on the outcome of these segregation analyses. Therefore, this study strongly supports the concept that variation in COMT activity is due in large part to the effects of a major gene.

Effects of misspecification of allele frequencies on the power of Haseman-Elston sib-pair linkage method for quantitative traits.

It is well known that the Haseman-Elston (H-E) sib-pair linkage method does not assume that the genetic model underlying the trait phenotype is known without error, although this assumption is made for marker loci. However, misspecification of allele frequencies at the marker locus decreases power when some or all parental genotypes are unknown. In this study, the power of the H-E sib-pair method was compared for different types of traits when some or all parental data were missing and allele frequencies at the marker loci were misspecified. Data were generated for a quantitative trait and marker loci in nuclear families using G.A.S.P. (V3.3). Three types of traits were simulated with two equifrequent alleles with a random environmental effect (10%, 30%, and 50%). The simulated data were analyzed using (i) one of the parent's marker data, and (ii) no parental marker data, with both correct and incorrect marker allele frequencies. This test is found to be robust in most of the situations considered except for a slight decrease in power when sample size is small and when the marker locus is not very polymorphic.

Linkage relationships between a major gene for catechol-o-methyltransferase activity and 25 polymorphic marker systems.

Segregation analysis has provided evidence suggesting the existence of a major gene for catechol-o-methyltransferase (COMT) activity in man. Five large families (4 Caucasian, 1 black), with a total of 1,189 individuals, were ascertained as part of a genetic study of blood pressure. Erythrocyte COMT activity and status at 25 polymorphic genetic marker loci were determined on more than 518 individuals in these pedigrees. Genetic linkage analysis of COMT with each of the 25 marker loci was performed in two ways: 1) using parameter estimates from segregation analysis of untransformed COMT activity, and 2) using parameter estimates from segregation analysis of the power transformation of the COMT activity that maximized the likelihood of the genetic hypothesis in each family. Tight and close linkage were excluded at 21 and 15 loci, respectively. A lod score of 1.27 at theta = 0.1 was found between the loci for COMT activity and phosphogluconate dehydrogenase (PGD). Transformation of the data had little effect on the outcome of the linkage analysis.

Segregation and linkage analyses of dopamine-beta-hydroxylase activity in a six-generation pedigree.

Serum dopamine-beta-hydroxylase (DBH) levels and 30 polymorphic markers were determined on 178 individuals of the HGAR 29 family, ascertained through six probands who had clinical and electrocardiographic evidence of myocardial infarction. Individuals in this pedigree with a history of heart attack had significantly lower levels of DBH, but this difference was partly confounded with age differences. Pedigree segregation analysis showed evidence of a codominant gene for DBH segregating in the family. Linkage analysis between the putative DBH locus and 30 polymorphic marker loci, assuming a codominant model, yielded a largest lod score of 0.53, with ABO at 20% recombination. Adding this to the lod scores obtained by Elston et al [1979] and Goldin et al [1982], we obtain combined lod scores of 2.49 and 2.50 at 0.0 and 10% recombination respectively.

A major gene model for the familial aggregation of plasma IgA concentration.

Plasma IgA concentration was determined on 94 individuals of an eastern Kentucky family (IGANI) with some members having clinical and biopsy-proven IgA nephropathy, and on 197 individuals of a large Louisiana family (HGAR29) with no clinical history of IgA nephropathy but on whom 30 polymorphic markers had previously been typed. Pedigree segregation analysis was used to fit a major gene model, and a moderately large lod score for linkage to the ABO locus (1.50 at 0% recombination) suggested the existence of a recessive allele for high plasma IgA concentration. This allele is only slightly more prevalent in pedigree IGANI than in pedigree HGAR29, indicating that it is a minor, rather than a major, etiologic factor in IgA nephropathy.

Stepwise oligogenic segregation and linkage analysis illustrated with dopamine-beta-hydroxylase activity.

A stepwise oligogenic method is developed that can be used to adjust the phenotype of a quantitative trait for the effects of a previously identified single-locus component. This method assumes that a single-locus component can be adequately identified through the use of segregation and/or linkage analysis under a 1-locus model and that the variation due to that locus can be removed from the phenotype leaving a residual that can be parameterized in terms of an additional single-locus component. Segregation and/or linkage analysis can then be used in an attempt to identify an additional single-locus component in the residual phenotype. This stepwise process can be repeated until no further single-locus effects are identified. The method is illustrated using family data on the specific activity of dopamine-beta-hydroxylase (DBH), which a number of studies have suggested may be due either to the combined effects of single-locus and multifactorial components or to the combined effects of 2 loci.

Leptin and IGF-I levels in unconditioned male volunteers after short-term exercise.

We have previously shown that serum gonadotropins, particularly LH, decline after acute exercise in male volunteers. The mechanism for this decline is unknown. Plasma leptin and IGF-I concentrations were measured in seven male volunteers after acute exercise to exhaustion using the Bruce protocol. Leptin concentrations declined following exercise reaching nadir values 30-120 min after exercise. As anticipated, plasma IGF-I concentrations showed a transient rise immediately after exercise falling thereafter to nadir levels 60-90 min after exercise before returning towards baseline levels. In view of the previously described decline in gonadotropin release after acute exercise, the decline in plasma leptin levels, perhaps related to the rise in IGF-I, may play a role in exercise-induced inhibition of gonadotropin release presumably by inhibition of GnRH secretion.

Pulmonary parenchymal tissue volume in normal subjects. The effect of age and sex.

Pulmonary parenchymal tissue volume (Vt) and pulmonary capillary blood flow were determined by the acetylene-inhalation technique of Cander and Forster in 66 normal subjects (31 male and 35 female subjects) ages 8 to 66 years. In subjects under the age of 20 years, values for Vt, when factored by alveolar volume (VA) to correct for differences in body size, were essentially identical in both male and female subjects (0.248 +/- 0.039 in male subjects and 0.242 +/- 0.079 in female subjects). In subjects between the ages of 21 and 40 years, Vt/Va was significantly lower in men than women, 0.125 +/- 0.057 vs 0.193 +/- 0.046 (P less than 0.001), respectively. In subjects over the age of 41 years, although Vt/VA increased, there was no significant difference between the sexes; ie, Vt/VA decreased with advancing age up to the age of 35 years (more so in male than female subjects) and then increased back to pubertal values. The reason for the intersex changes is a greater increase of VA in male than female subjects for the same Vt. The reasons for the increase in Vt/VA in subjects over the age of 35 years are obscure.

Response to inhaled metaproterenol and isoproterenol in asthmatic and normal subjects.

Pulmonary function tests were performed before and after inhalation of 1.3 mg of metaproterenol sulfate or 150 microgram of isoproterenol hydrochloride by 40 asthmatic and 40 normal subjects. PHysiologic measurements included spirometric testing, plethysmographic studies, and maximal expiratory flow-volume curves obtained after inhalation of air and a mixture of 80 percent helium and 20 percent oxygen. In the normal subjects, pulmonary function improved significantly after inhalation of both metaproterenol and isoproterenol. There was no significant difference in responsiveness to either bronchodilator drug. In the asthmatic subjects, pulmonary function also improved significantly after both bronchodilator agents. The sites of predominant bronchodilatation were similar in the asthmatic subjects after both metaproterenol and isoproterenol; however, bronchodilatation was better overall (P less than 0.005) and for most individual tests with metaproterenol. The greater efficacy of metaproterenol in asthmatic subjects but not in normal subjects can be explained by (1) different doses of the bronchodilator drug and (2) differing bronchodilator dose-response relationships in asthmatic and normal subjects.