Biomedical subjects

J C Cohen

Publications and source records attributed to J C Cohen.

At least 19 recordsLinked to original sources

PubMed2001

Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein.

Atherogenic low density lipoproteins are cleared from the circulation by hepatic low density lipoprotein receptors (LDLR). Two inherited forms of hypercholesterolemia result from loss of LDLR activity: autosomal dominant familial hypercholesterolemia (FH), caused by mutations in the LDLR gene, and autosomal recessive hypercholesterolemia (ARH), of unknown etiology. Here we map the ARH locus to an approximately 1-centimorgan interval on chromosome 1p35 and identify six mutations in a gene encoding a putative adaptor protein (ARH). ARH contains a phosphotyrosine binding (PTB) domain, which in other proteins binds NPXY motifs in the cytoplasmic tails of cell-surface receptors, including the LDLR. ARH appears to have a tissue-specific role in LDLR function, as it is required in liver but not in fibroblasts.

Adolescent↗

PubMed2000

Premature cardiovascular disease is common in relatives of patients with premature peripheral atherosclerosis.

BACKGROUND: Numerous clinical conditions have been proposed to explain the premature onset of symptomatic peripheral vascular disease (PVD) in young adults, but the role of genetic factors has not been defined. This study was performed to determine the prevalence of cardiovascular disease among family members of patients with premature PVD. METHODS: The prevalence of early cardiovascular events occurring in first-degree relatives of 90 subjects with premature PVD (onset < or =49 years) was determined. The prevalence of occult atherosclerosis was determined by duplex ultrasonography in a cohort of 20 asymptomatic siblings. Reference groups included first-degree relatives of 80 subjects with premature coronary artery disease (CAD) and first-degree relatives of 48 healthy subjects. RESULTS: Cardiovascular events occurred at age 55 years or younger in 28% of the parents of PVD subjects, in 23% of parents of CAD subjects, and in 7% of the parents of healthy controls (P<.001). Cardiovascular events occurred in 24% of siblings of PVD subjects, in 14% of siblings of CAD subjects, and in 7% of siblings of healthy controls (P<.001). Duplex ultrasonography detected early plaques in the lower extremity circulation of 10 (50%) of the asymptomatic siblings of PVD subjects. CONCLUSIONS: Early, symptomatic cardiovascular disease is more common in first-degree relatives of individuals with premature PVD than in relatives of healthy individuals or of probands with premature CAD. Occult vascular disease in the lower extremity is prevalent among asymptomatic siblings of probands with premature PVD. These observations indicate that susceptibility to premature PVD has a familial basis.

Adult↗

PubMed2000

Cystic fibrosis revisited.

Cystic fibrosis is a pleiotropic disease whose primary defect is thought to be abnormal chloride conductance. Despite intensive study, the role of the protein in the airway and the mechanism for its direct participation in the disease pathology remain unclear. This paper reviews CFTR's cell regulatory functions and data supporting the role of CFTR in secretory epithelial cell development. A hypothesis for CF pathophysiology based on secretory cell differentiation is proposed.

Animals↗

PubMed2000

Gene transfer into the fetal primate: evidence for the secretion of transgene product.

In utero adenoviral-mediated transfer of genes via the amniotic fluid results in sustained high-efficiency expression in rodent lung and intestine. Rhesus macaque (Macaca mulatta) fetuses were injected with adenovirus vectors encoding reporter genes at different gestational ages to evaluate feasibility and timing in primates. The fetuses developed normally following gene transfer and no maternal adverse affects were noted. Highly efficient viral uptake and transgene protein expression occurred in the target organs. The lungs exhibited no immune response and transgenic protein was observed up to 30 days postinfection. Unexpectedly, large amounts of reporter gene protein were released, apparently from the lung, into the circulation and accumulated in the renal proximal tubules and bladder. PCR detection for adenovirus DNA was consistently negative in tissues not in contact with the amniotic fluid, such as kidneys, liver, gonads, and eyes. Treatment of primate fetuses at 110 days gestation with an adenovirus expressing the cystic fibrosis transmembrane conductance regulator (cftr) gene resulted in accelerated differentiation of the lung. These studies demonstrate the efficacy of in utero gene therapy in primates and its potential application to genetic diseases.

Adenoviridae↗

PubMed2000

CFTR modulates lung secretory cell proliferation and differentiation.

We have permanently reversed the lethal phenotype in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR)-deficient (knockout) mouse after in utero gene therapy with an adenovirus containing the cftr gene. The gene transfer targeted somatic stem cells in the developing lung and intestine, and these epithelial surfaces demonstrated permanent developmental changes after treatment. The survival statistics from the progeny of heterozygote-heterozygote matings after in utero cftr gene treatment demonstrated an increased mortality in the homozygous normal pups, indicating that overexpression during development was detrimental. The lungs of these pups revealed accelerated secretory cell proliferation and differentiation. The extent of proliferation and differentiation in the secretory cells of the lung parenchyma after in utero transfer of the cftr gene was evaluated with morphometric and biochemical analyses. These studies provide further support of the regulatory role of the cftr gene in the development of the secretory epithelium.

Adenoviridae↗

PubMed1999

Plasma platelet-activating factor acetylhydrolase activity is not associated with premature coronary atherosclerosis.

Platelet-activating factor acetylhydrolase activity in plasma was compared between 72 subjects with angiographically normal coronary arteries and matched controls with clinically significant obstruction. No difference was seen, and we conclude that variation in plasma platelet-activating factor acetylhydrolase activity is not a risk factor for coronary artery disease.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed1999

Under which conditions do the skin and probe decouple during sinusoidal vibrations?

Previous experiments performed on monkey and human fingertips suggested that the skin surface and stimulus probe decouple for sinusoidal displacements applied perpendicularly to the skin surface. From these observations, it was concluded that sinusoidal vibration may not be a suitable stimulus for understanding and modeling the tactile system. We repeated these experiments on human observers using stimulus frequencies ranging from 0.5 to 240 Hz and with displacement amplitudes up to 1 mm peak-to-peak (p-p). The skin and probe movements were measured in the steady-state using stroboscopic illumination and video microscopy. Contrary to previous conclusions, we found that decoupling did not occur for amplitudes less then 0.25 mm p-p, regardless of stimulus frequency. Decoupling was only observed for stimulus amplitudes greater than 0.25 mm over the stimulus-frequency range investigated. To further investigate this effect, a modified stimulus contactor was used, which permitted the measurement of the skin's movement using reflected light. Measurements were made on both the index fingertip and the thenar eminence. Regardless of body site, no decoupling between the skin and stimulus probe was observed for frequencies ranging from 20 to 100 Hz up to displacements of 0.25 mm p-p. These levels are well within the range used in most human psychophysical experiments performed on these parts of the body. We conclude that sinusoidal vibration can be used reliably to stimulate the tactile system and is an appropriate stimulus for developing models of touch.

Fingers↗

PubMed1999

Hepatic lipase: new insights from genetic and metabolic studies.

Hepatic lipase catalyses the hydrolysis of triglycerides and phospholipids in all major classes of lipoproteins. Genetic deficiency of this enzyme is associated with a unique plasma lipoprotein profile, characterized by hypertriglyceridemia and elevated concentrations of intermediate density lipoproteins and HDL. Recent studies have identified common polymorphisms in the hepatic lipase gene that are associated with low hepatic lipase activity and increased concentrations of large HDL. Association studies using these polymorphisms are elucidating the effects of variation in hepatic lipase activity on plasma lipoprotein concentrations and susceptibility to coronary atherosclerosis.

Cholesterol, HDL↗

PubMed1999

Contribution of cholesterol 7alpha-hydroxylase to the regulation of lipoprotein metabolism.

Clinical studies have clearly established a relationship between bile acid synthesis and plasma LDL-cholesterol concentrations. Interruption of the enterohepatic circulation of bile acids leads to increased bile acid synthesis and a reduction in plasma LDL-cholesterol concentrations. New studies indicate that genetic variation in cholesterol 7alpha-hydroxylase activity accounts for a significant fraction of the inter-individual variation in plasma LDL-cholesterol concentrations in the general population, and a specific CYP7A1 allele associated with increased plasma LDL-cholesterol concentrations has been identified. Studies in which cholesterol 7alpha-hydroxylase was transiently overexpressed in hamsters and mice indicate that direct manipulation of cholesterol 7alpha-hydroxylase leads to changes in plasma LDL-cholesterol concentrations. Interestingly, targeted inactivation of the gene encoding cholesterol 7alpha-hydroxylase does not lead to increased plasma LDL-cholesterol concentrations in mice.

Animals↗

PubMed1999

Testing for linkage under robust genetic models.

Robust genetic models are used to assess linkage between a quantitative trait and genetic variation at a specific locus using allele-sharing data. Little is known about the relative performance of different possible significance tests under these models. Under the robust variance components model approach there are several alternatives: standard Wald and likelihood ratio tests, a quasilikelihood Wald test, and a Monte Carlo test. This paper reports on the relative performance (significance level and power) of the robust sibling pair test and the different alternatives under the robust variance components model. Simulations show that (1) for a fixed sample size of nuclear families, the variance components model approach is more powerful than the robust sibling pair approach; (2) when the number of nuclear families is at least approximately 100 and heritability at the trait locus is moderate to high (>0.20) all tests based on the variance components model are equally effective; (3) when the number of nuclear families is less than approximately 100 or heritability at the trait locus is low (<0. 20), on balance, the Monte Carlo test provides the best power and is the most valid. The different testing procedures are applied to determine which are able to detect the known association between low density lipoprotein cholesterol and the common genotypes at the locus encoding apolipoprotein E. Results from this application show that the robust sibling pair method may be more effective in practice than that indicated by simulations.

Alleles↗

PubMed1999

Hepatic lipase (LIPC) promoter polymorphism in men with coronary artery disease. Allele frequency and effects on hepatic lipase activity and plasma HDL-C concentrations.

Hepatic lipase is an important determinant of plasma HDL concentration and LDL subclass distribution and may therefore influence susceptibility to coronary artery disease (CAD). To assess the effect of genetic variation in hepatic lipase activity on CAD susceptibility, we determined the frequency of the -514T allele of hepatic lipase in white men with CAD and in controls who did not have CAD. In men with CAD, postheparin plasma hepatic lipase activity was 15% to 20% lower in heterozygotes and 30% lower in homozygotes for the -514T allele. Allele frequencies were similar in cases and controls, however, and were consistent with Hardy-Weinberg expectation in both groups. This finding was confirmed in a second group comprising cases with premature symptomatic CAD and controls who were free of disease. These data indicate that a primary decrease in hepatic lipase activity of as much as 30% does not influence susceptibility to CAD in white men.

Alleles↗

PubMed1999

Cloning and mutational analysis of human malonyl-coenzyme A decarboxylase.

Malonyl coenzyme A (CoA) decarboxylase (E.C.4. 1.1.9) catalyzes the conversion of malonyl CoA to acetyl CoA. The metabolic role of malonyl CoA decarboxylase has not been fully defined, but deficiency of the enzyme has been associated with mild mental retardation, seizures, hypotonia, cardiomyopathy, vomiting, hypoglycemia, metabolic acidosis, and malonic aciduria. Here we report the isolation and sequencing of the human gene encoding malonyl CoA decarboxylase, and the identification of a mutation causing malonyl CoA decarboxylase deficiency. Human malonyl CoA decarboxylase cDNA sequences were identified by homology to the goose gene, and the intron/exon boundaries were determined by direct sequencing of a PAC clone containing the entire human gene. The 1479 basepair human cDNA is 70 percent identical to the goose sequence, and the intron/exon boundaries are completely conserved between the two species. The genetic mutation underlying malonyl CoA decarboxylase deficiency was determined in a patient with clinical features of this defect, malonic aciduria, and markedly reduced malonyl CoA decarboxylase activity.

Amino Acid Sequence↗

PubMed1999

Hepatic lipase activity influences high density lipoprotein subclass distribution in normotriglyceridemic men. Genetic and pharmacological evidence.

Several studies have reported an inverse relationship between hepatic lipase activity and plasma high density lipoprotein (HDL) cholesterol concentrations. The purpose of the present study was to determine whether genetic and pharmacological variation in hepatic lipase activity alters the distribution of HDL subclasses. Two independent analytical methods (nuclear magnetic resonance and gradient gel electrophoresis) were used to compare HDL subclass distributions in 11 homozygotes for the -514C allele of hepatic lipase and in 6 homozygotes for the -514T allele. Mean hepatic lipase activity was 45 +/- 15 mmol. l(-1). hr(-1) in -514C homozygotes and 20 +/- 7 mmol. l(-1). hr(-1) in -514T homozygotes. Both analytical methods indicated that HDL(2b) was significantly higher and HDL(3a) was significantly lower in -514T homozygotes than in -514C homozygotes. No differences were noted in the other HDL fractions (HDL(2a), HDL(3b), and HDL(3c)). To determine the effects of increased hepatic lipase activity, 20 men were given the synthetic anabolic steroid, stanozolol. Stanozolol treatment increased hepatic lipase activity more than two-fold (38 +/- 18 to 85 +/- 25 mmol. l(-1). hr(-1) ), and markedly reduced the plasma concentrations of the larger HDL subclasses (HDL(2b) and HDL(2a)). The plasma concentrations of the smallest HDL subclasses (HDL(3b) and HDL(3c)) were unchanged by stanozolol treatment. Taken together, these genetic and pharmacological data indicate that variation in hepatic lipase activity has highly specific effects on the distribution of HDL subclasses in the circulation.-Grundy, S. M., G. L. Vega, J. D. Otvos, D. L. Rainwater, and J. C. Cohen. Hepatic lipase activity influences high density lipoprotein subclass distribution in normotriglyceridemic men: genetic and pharmacological evidence.

Cholesterol, HDL↗

PubMed1998

Linkage between cholesterol 7alpha-hydroxylase and high plasma low-density lipoprotein cholesterol concentrations.

Interindividual differences in plasma low-density lipoprotein cholesterol (LDL-C) levels reflect both environmental variation and genetic polymorphism, but the specific genes involved and their relative contributions to the variance in LDL-C are not known. In this study we investigated the relationship between plasma LDL-C concentrations and three genes with pivotal roles in LDL metabolism: the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and cholesterol 7alpha-hydroxylase (CYP7). Analysis of 150 nuclear families indicated statistically significant linkage between plasma LDL-C concentrations and CYP7, but not LDLR or APOB. Further sibling pair analyses using individuals with high plasma LDL-C concentrations as probands indicated that the CYP7 locus was linked to high plasma LDL-C, but not to low plasma LDL-C concentrations. This finding was replicated in an independent sample. DNA sequencing revealed two linked polymorphisms in the 5' flanking region of CYP7. The allele defined by these polymorphisms was associated with increased plasma LDL-C concentrations, both in sibling pairs and in unrelated individuals. Taken together, these findings indicate that polymorphism in CYP7 contributes to heritable variation in plasma LDL-C concentrations. Common polymorphisms in LDLR and APOB account for little of the heritable variation in plasma LDL-C concentrations in the general population.

Adult↗

PubMed1998

Molecular pathophysiology of cystic fibrosis based on the rescued knockout mouse model.

Cystic fibrosis transmembrane conductance regulator (cftr) gene mutations are thought to result in cystic fibrosis due to an absence of the protein's chloride channel. Recently, the lethal intestinal blockage in the cftr knockout mouse was reversed by a single in utero dose of a recombinant adenovirus containing the human cftr gene. The rescue of these animals did not require continuous expression of the gene and the cAMP-dependent chloride channel was not permanently restored. These data suggested that cftr was required for normal development of the intestine but not for normal function of the adult organ. Phenotypic changes in the intestines and lungs of in utero cftr-treated knockout and heterozygous mice revealed that altered development was induced. The intestines of the untreated knockout mice were shown to be deficient in both intracellular calcium and UTP receptors. Both of these deficiencies were partially corrected in the rescued knockout mice, whereas treatment of heterozygous animals disrupted the normal pattern of these markers. Examination of the lungs of knockout cftr (-/-) mice with lectins showed an increase in secreted glycoconjugates containing alpha(2,6)-sialic acid and fucose as compared with control heterozygotes. The in utero-treated knockouts showed an increase in this material as well, but it was contained in intracellular vesicles. Electron microscopy of these tissues confirmed the developmental alteration of secretory cell differentiation in the lungs. These data show that cftr is required in both the lung and intestines for normal differentiation of a secretory cell population and that in its absence these cells fail to develop properly.

Animals↗

PubMed1998

Modification of development by the CFTR gene in utero.

The in utero infection of rats at 16-17 days gestation with a recombinant adenovirus carrying the human cystic fibrosis transmembrane conductance regulator (cftr) gene resulted in altered lung development and morphology. These structural alterations prompted an evaluation of concurrent functional changes in the cftr-treated lung. CFTR protein could be detected in treated lungs for up to 30 days postinfection, although it was not detected in the intestines at this time. Increased levels of secreted glycoconjugates and lipids were found in lungs treated in utero with human cftr and large vacuoles containing glycoconjugates were detected within cells of the intestines. The scope and durability of these changes suggested that in utero cftr treatment influenced the activity of secretory cells in the developing lung. Altered secretory products in the lungs of cystic fibrosis patients are thought to be associated with increased susceptibility to Pseudomonas aeruginosa infection. We challenged 3-month-old rats (treated in utero with the human cftr gene) with a lethal, intratrachial dose of this bacteria. Rats treated with cftr exhibited enhanced resistance to Pseudomonas infection when compared to controls. These animals displayed little or no associated inflammatory response. No evidence of the adenovirus transgene was detectable at the time of P. aeruginosa inoculation, indicating that continuous ectopic expression of hcftr was not required for enhanced protection. These data demonstrate that in utero, cftr expression influenced the development and function of cells involved in the primary host defense against bacterial infection in the lung.

Adenoviridae↗

PubMed1998

Hepatic lipase activity is lower in African American men than in white American men: effects of 5' flanking polymorphism in the hepatic lipase gene (LIPC).

Plasma high density lipoprotein cholesterol (HDL-C) concentrations are higher in African American men than in white men, but the mechanism(s) responsible for this ethnic difference has not been elucidated. This study examined the relationship between hepatic lipase activity, plasma HDL-C concentrations, and a hepatic lipase polymorphism (-514T) in African American and white American men. Consistent with previous reports, plasma HDL-C concentrations were significantly higher in African American men than in white American men. Mean post-heparin plasma hepatic lipase activity was significantly lower in African American than in white American men (27 +/- 12 vs. 44 +/- 17 mmol x h(-1) x l(-1), P < 0.001). The -514T hepatic lipase allele was associated with low hepatic lipase activity in both populations, and was 3-fold more common among African Americans than white Americans. Taken together, these data suggest that genetic differences in hepatic lipase activity contribute to the differences in plasma HDL-C concentrations between African American men and white American men.

Adult↗

PubMed1998

Body mass index and hepatic lipase gene (LIPC) polymorphism jointly influence postheparin plasma hepatic lipase activity.

The -514 polymorphism in the hepatic lipase gene (LIPC) is associated with decreased hepatic lipase activity. In the present study, the interaction between body mass index (BMI), the -514 polymorphism, and hepatic lipase activity was examined in 118 white men and in 51 African American men. BMI was significantly positively correlated with hepatic lipase activity in both populations. BMI was similar in men with genetic differences in hepatic lipase activity, indicating that high hepatic lipase activity did not cause increased BMI. The data therefore suggest that high BMI leads to increased hepatic lipase activity. The actions of BMI and the -514 polymorphism on hepatic lipase activity appear to be additive and independent, rather than synergistic. This finding indicates that hepatic lipase activity is a multifactorial trait, determined in part by polymorphism within the LIPC gene as well as by factors that influence BMI.

Adolescent↗