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J C Cohen

Publications and source records attributed to J C Cohen.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1998

The -514 polymorphism in the hepatic lipase gene (LIPC) does not influence androgen-mediated stimulation of hepatic lipase activity.

The -514T allele of hepatic lipase is associated with increased high density lipoprotein-cholesterol levels in men, but not in women. This observation suggests that the -514C to T polymorphism may diminish the response of hepatic lipase to androgens. To test this hypothesis, five -514T and five -514C homozygous men were treated with the anabolic steroid stanozolol for 6 days. The mean increase in hepatic lipase activity was similar in the two groups (45+/-10 vs. 51+/-10 mmol x hr(-1) x l(-1), P = 0.5). To evaluate the association between the -514 polymorphism and hepatic lipase activity at different physiological androgen concentrations, hepatic lipase genotypes and activities were measured in 44 men and 40 premenopausal women. The effect of the -514T allele on hepatic lipase activity was significant and quantitatively similar in both sexes. These data indicate that the -514 polymorphism does not influence the response of hepatic lipase activity to androgens, and that the effects of this polymorphism on hepatic lipase activity are independent of androgen action.

Adult↗
PubMed1998

Three polymorphisms associated with low hepatic lipase activity are common in African Americans.

We have shown previously that a hepatic lipase allele (designated -514T) is common among African Americans and contributes to low hepatic lipase activity in this population. To identify other hepatic lipase alleles associated with low hepatic lipase activity in this population, the coding region and intron-exon boundaries of the hepatic lipase gene were sequenced in 20 African American men with low hepatic lipase activity. Two polymorphisms (N193S and L334F) were associated with low post-heparin plasma hepatic lipase activity and were much more common in African Americans than in whites. This finding, together with our previous data on the -514T allele, indicates that at least three different hepatic lipase polymorphisms associated with low hepatic lipase activity are common among African Americans. Analysis of hepatic lipase haplotypes revealed that 97% of African Americans have at least one hepatic lipase allele that is associated with low hepatic lipase activity.

Adult↗
PubMed1997

A hepatic lipase (LIPC) allele associated with high plasma concentrations of high density lipoprotein cholesterol.

Genetic factors strongly influence interindividual variation in plasma high density lipoprotein cholesterol (HDL-C) levels, but the specific genetic polymorphisms that confer heritable variation in HDL-C levels have not been identified. In this study we examined the relationship between polymorphism in LIPC, the gene encoding hepatic lipase, and plasma HDL-C concentrations using a sequential approach comprising linkage analysis, DNA sequencing, and association studies. Linkage studies in 1465 American white subjects from 218 nuclear families indicated that allelic variation at, or closely linked to, the hepatic lipase gene accounts for a significant fraction ( approximately 25%) of the variation in plasma HDL-C concentrations. The hepatic lipase gene was then sequenced in selected individuals, and four novel polymorphisms were identified in the 5' flanking region of the gene. These polymorphisms were in complete linkage disequilibrium and thus identified a single novel allele. Association studies indicated that heterozygosity for the rare allele was associated with modestly increased concentrations of plasma HDL-C (41 +/- 11 vs. 37 +/- 10 mg/dl, P < 0.05) and apolipoprotein AI in men (131 +/- 23 vs. 122 +/- 21 mg/dl, P < 0.05) but not in women. Homozygosity for the rare allele was associated with markedly higher plasma HDL-C (63 +/- 3 mg/dl) and apolipoprotein AI (153 +/- 9 mg/dl) concentrations in men. The results of the association study were replicated in a second, independently ascertained sample. Taken together, the results of the linkage and association studies provide strong evidence that genetic variation in hepatic lipase activity is a major determinant of plasma HDL-C levels.

Analysis of Variance↗
PubMed1997

Extension of the Haseman-Elston method to multiple alleles and multiple loci: theory and practice for candidate genes.

The Haseman & Elston (1972) sibling-pair regression method has been used to detect and estimate the variance contribution to observed values of a quantitative trait by allelic variation in specific candidate genes. The procedure was developed under a model with a single biallelic trait locus. This assumption does not hold for several known systems. In this paper we prove that for candidate gene analysis the Haseman-Elston procedure extends to the case of multiple trait loci, each possibly having more than two alleles. Simulation experiments comparing single-locus to two-locus models show that fitting the extended regression equations maintains nominal significance levels, but the power to detect linkage to trait variation is not improved by including additional loci. These results indicate that the original proposal is statistically robust to violations of the underlying genetic model. Practical issues associated with quantifying the relative variance contribution by individual loci are also discussed. Applications of the extended regression equations to lipoprotein(a) and high density lipoprotein cholesterol are given for illustration.

Alleles↗
PubMed1997

Determinants of plasma platelet-activating factor acetylhydrolase: heritability and relationship to plasma lipoproteins.

Plasma platelet-activating factor acetylhydrolase (PAF-AH) is the enzyme that inactivates PAF (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine). We determined the relative contributions of genetic and environmental factors to variation in plasma PAF-AH activity in 240 individuals from 60 nuclear families. Regression of mean-offspring PAF-AH activity on the mid-parent value indicated that 62% of the variation in plasma PAF-AH activity was heritable. Spousal values were weakly negatively correlated, indicating that familial aggregation of PAF-AH activity is due to genetic rather than to environmental factors. Among normolipidemic individuals, plasma PAF-AH activity was strongly correlated with the plasma concentration of low density lipoprotein cholesterol (LDL-C), and treatment with lovastatin resulted in proportional decreases in plasma PAF-AH activity and LDL-C concentrations. To further elucidate the relationship between PAF-AH and plasma concentrations of LDL, plasma PAF-AH activity was measured in families with well-defined, monogenic disorders of LDL metabolism. Plasma PAF-AH activity cosegregated with plasma LDL-C concentrations in familial hypercholesterolemia, but not in familial hypobetalipoproteinemia. We speculate that the rate of removal of LDL from the circulation may determine the clearance rate of PAF-AH, thereby modulating the activity of PAF-AH in blood.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1996

Assessment of vibrotactile sensitivity in patients with carpal tunnel syndrome.

The effectiveness of using vibrotactile threshold measures to aid in the diagnosis of carpal tunnel syndrome (CTS) was evaluated. Thresholds for detecting 1-, 10-, and 300-Hz vibratory stimuli were measured on the fingertips of 24 CTS patients and 20 healthy control subjects. There were no significant differences in threshold for 1- and 300-Hz between the two groups. Although there were significant differences for 10-Hz stimuli, the mean patient threshold was within 1 standard deviation of the mean threshold for the control group. These results indicate that threshold testing is not a suitable diagnostic tool for CTS. Additionally, we examined whether thresholds were elevated in the presence of pain. Seven patients reported experiences of pain and no pain sessions. No significant differences in threshold were found between the two pain conditions, indicating that the presence of pain related to CTS does not affect threshold.

Adult↗
PubMed1996

Allelic variation in the gene encoding the cholesteryl ester transfer protein is associated with variation in the plasma concentrations of cholesteryl ester transfer protein.

The cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from high density lipoproteins (HDL) to triglyceride-rich lipoproteins. Mutations that abolish CETP function are associated with very high levels of HDL cholesterol, but the effect of more common allelic variation at this locus is less clear. In this study, we have measured plasma CETP concentration and plasma HDL cholesterol concentrations in 694 individuals from 106 nuclear families. Robust sibling-pair methods indicated linkage between the CETP locus and inter-individual variation in plasma CETP concentrations. Allelic variation at the CETP locus accounted for 20% of the variation in plasma CETP concentration. No relation between allelic variation at the CETP locus and plasma HDL cholesterol levels was detected. These data indicate that polymorphism in the CETP gene confers variation in plasma CETP concentration. However, this degree of variation in CETP function is not systematically associated with variation in plasma HDL-C concentrations.

Alleles↗
PubMed1995

Safety, immunogenicity, and efficacy of a recombinantly produced Plasmodium falciparum circumsporozoite protein-hepatitis B surface antigen subunit vaccine.

Twenty malaria-naive volunteers received a recombinant Plasmodium falciparum malaria vaccine (RTS,S) containing 19 NANP repeats and the carboxy terminus (amino acids 210-398) of the circumsporozoite (CS) antigen coexpressed in yeast with hepatitis B surface antigen. Ten received vaccine adjuvanted with alum, and 10 received vaccine adjuvanted with alum plus 3-deacylated monophosphoryl lipid A (MPL). Both formulations were well tolerated and immunogenic. MPL enhanced CS antibody levels (measured by ELISA, immunofluorescence, and inhibition of sporozoite invasion assays). After sporozoite challenge, 6 of 6 in the alum group and 6 of 8 in the alum-MPL group developed patent malaria. Protected subjects had higher levels of CS antibody titers on day of challenge than did nonprotected subjects. After immunization, 1 protected subject had increased cytotoxic T lymphocyte activity against CS and recall of memory T cell responses to RTS,S and selected CS.

Adult↗
PubMed1995

Evolving therapies for peptic ulcer disease: Helicobacter pylori treatment.

In the era of Helicobacter pylori, our concepts about peptic ulcer disease have undergone a major paradigm shift. New ways of thinking about the etiology of ulcers are leading to new treatment modalities. Treating peptic ulcers with antibiotics is an idea that would have been laughed at a mere decade ago, yet it has become the standard of care for H. pylori-associated disease. Our current state of knowledge, and where we seem to be heading, is the subject of this review.

Antacids↗
PubMed1994

Comparative analysis of the apo(a) gene, apo(a) glycoprotein, and plasma concentrations of Lp(a) in three ethnic groups. Evidence for no common "null" allele at the apo(a) locus.

Distributions of plasma lipoprotein(a) (Lp[a]) concentrations exhibit marked interracial differences. Apolipoprotein(a) (apo[a]), the unique constituent of Lp(a), is highly polymorphic in length due to allelic variations in the number of kringle 4(K-4)-encoding sequences. Plasma Lp(a) concentrations are inversely related to the number of K-4 repeats in the apo(a) alleles. To determine the contribution of this length variation to the interracial variation in plasma Lp(a) levels, we compared apo(a) allele size, glycoprotein size, and plasma Lp(a) concentrations in Caucasians, Chinese, and African Americans. Caucasians and African Americans had very different distributions of plasma Lp(a) concentrations yet there was no significant difference in the overall frequency distributions of their apo(a) alleles. Over the entire size spectrum of apo(a) alleles, the plasma Lp(a) levels were higher in African Americans than in Caucasians. Conversely, Caucasians and Chinese had similar plasma Lp(a) concentrations but significantly different apo(a) allele size distributions. Therefore, interracial differences in the plasma concentrations of Lp(a) are not due to differences in the frequency distributions of apo(a) alleles. We also examined the relationship between apo(a) allele size and the presence of detectable plasma apo(a) protein in plasma. Apo(a) alleles associated with no detectable plasma protein were not of uniformly large size, as had been expected, but were distributed over the entire size spectrum. From this analysis, we conclude that there is no common "null" allele at the apo(a) locus.

Alleles↗