The XbaI polymorphism at the apolipoprotein B locus and risk of atherosclerotic disease.
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Apolipoproteins B↗
Biomedical subjects
K Berg
Publications and source records attributed to K Berg.
DNA polymorphism at the locus for angiotensinogen I-converting enzyme in Norwegian patients with myocardial infarction and controls.
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Chromosome Mapping↗
Search for three known mutations in the RYR1 gene in 48 Danish families with malignant hyperthermia.
We have examined 48 Danish families in which malignant hyperthermia reactions have occurred, with respect to three of six published mutations in the gene for the calcium release channel of sarcoplasmic reticulum (the RYR1 gene) believed to cause malignant hyperthermia susceptibility in man. The mutations are Arg614Cys, also known as the "pig mutation"; Arg163Cys; and Ile403Met. The only mutation found was Arg163Cys, which was detected in only one family. The results of this study indicate that other mutations must underlie the disorder in most Danish malignant hyperthermia-susceptible families, and that the "pig mutation" is not a frequent cause of malignant hyperthermia susceptibility in Denmark.
Arginine↗
Changes in Lp(a) lipoprotein and other plasma proteins during acute myocardial infarction.
The sequential changes of Lp(a) lipoprotein concentrations in patients (n = 59) suffering acute myocardial infarction (AMI) were examined and compared with other plasma proteins. The temporal and quantitative characteristics of the responses in concentration of acute phase reactants (CRP, haptoglobin, alpha 1-antitrypsin, alpha-acid glycoprotein), lipids (total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol) and apolipoproteins AI and B were similar to previous reports. Lp(a) lipoprotein showed transient changes with an initial decrease of 10-25% compared to the 3-month control value, followed by rebound on day 7-11 above admission level, before again declining. We were able to demonstrate a quantitative relationship between infarct size and alterations in plasma levels of acute phase reactants. However, in addition to rather unusual significant fluctuations during AMI, Lp(a) lipoprotein changes seemed unrelated to infarct size. These findings do not support the view that Lp(a) lipoprotein acts as an acute phase reactant.
Acute-Phase Proteins↗
No effect on blood pressure level or variability of polymorphisms in DNA at the locus for atrial natriuretic factor (ANF).
We have examined healthy Norwegians with respect to two restriction fragment length polymorphisms at the locus for atrial natriuretic factor, detectable with the restriction enzymes XhoI and BglI, respectively. No association with systolic or diastolic blood pressure level or variability was found. Thus, the normal genes detected by examination of these restriction fragment length polymorphisms have neither "level gene" nor "variability gene" effects on normal blood pressure.
Adult↗
No effect of a BglI polymorphism at the renin (REN) locus on blood pressure level or variability.
We have studied a normal restriction fragment length polymorphism at the renin locus, detected with the restriction enzyme BglI in healthy Norwegians. No association with blood pressure level or variability was found. Thus, the normal genes detected by examination of this restriction fragment length polymorphism at the renin locus have neither "level gene" nor "variability gene" effects on normal blood pressure.
Adult↗
Human interferon-gamma quantified via a sensitive one-site monoclonal antibody in a sandwich ELISA. A PEG modification for measurement in serum.
A new, specific and sensitive one-site ELISA for precise quantification of human interferon-gamma (HuIFN-gamma) at low levels in 50% human serum samples has been developed. The assay is based on the assumption that biologically active HuIFN-gamma is present exclusively as a dimer. Thus, in contrast to previous reports, the ELISA is based on a single monoclonal antibody (MAb) which is used in two ways: as "catching" antibody and as HRPO-labelled conjugate. The sensitivity could be improved five-fold by addition of (NH4)2SO4 to the conjugate solution; the lowest detectable amount of HuIFN-gamma is < 0.5 mu/ml. Non-specific interactions were not seen in interferon samples taken from cultures, or samples diluted in ordinary media or 1% BSA. However, > 30% of the (serum) samples gave non-specific false-positive results when the method was applied to samples containing 50-100% human serum from different donors. The false signals were related to the donors but could-at the expense of the sensitivity which was reduced to 1 mu/ml-be abolished by PEG treatment of the (donor) serum samples.
Antibodies, Monoclonal↗
Photochemical treatment with the lysosomally localized dye tetra(4-sulfonatophenyl)porphine results in lysosomal release of the dye but not of beta-N-acetyl-D-glucosaminidase activity.
Tetra(4-sulfonatophenyl)porphine (TPPS4) sensitizes cells to photoinactivation mainly through formation of singlet oxygen. In human cervix carcinoma cells of the line NHIK 3025 TPPS4 localizes to a large extent in lysosomes as previously shown by fluorescence microscopical and spectroscopical techniques. In the present study photodamage to lysosomes was investigated. This was accomplished by measuring the activity of the lysosomal marker enzyme beta-N-acetyl-D-glucosaminidase (beta-AGA) after photochemical treatment (PCT). beta-AGA activity was highly sensitive to light exposure in the presence of TPPS4. The enzymatic activity was reduced by approximately 70% by non-lethal doses of photochemical treatment, indicating that inactivation of lysosomal hydrolases is not likely to contribute significantly to the cytotoxic effects of PCT. Centrifugation studies showed that TPPS4, but not beta-AGA activity, was released from lysosomes after light exposure. 20-30% of the total beta-AGA activity was resistant to the photochemical treatment. This was due to beta-AGA activity in Golgi-derived vesicles (4-5%) and in vesicles with similar density as lysosomes but not containing TPPS4. The present results indicate that lysosomal hydrolases are inactivated by photochemical treatment before they eventually escape the lysosomal compartment.
Acetylglucosaminidase↗
Legal and ethical issues in psychiatric genetic research.
Genetic research may uncover the causes of severe mental disorders, and many projects have been undertaken to locate the genes responsible for schizophrenia, bipolar disorder, and Alzheimer disease. A number of sensitive legal and ethical issues have been raised, including 1) protection of confidential data concerning research subjects; 2) the assessment of types and degree of risk to subjects who participate in such studies; 3) the legal and ethical acceptability of substituted judgement on behalf of patients who may not be competent to provide informed consent; and 4) the separation of research and clinical roles in areas such as genetic counseling. Federal regulations and other guidelines are of limited value in dealing with such concerns, and many important human subjects issues will need to be dealt with by the investigator, subject to approval by a local Institutional Review Board. There does seem to be general agreement that informed consent must be obtained, potential risks of research need to be minimized, and confidentiality of sensitive data must be protected.
Advance Directives↗
[Karyotyping of fetuses with developmental disorders. A 5-year material 1985-89].
During the period 1985 to 1989 foetal chromosomal analysis was performed in 121 of 318 pregnant women with foetal malformations detected by ultrasound. There were six failures. The percentage of foetuses karyotyped for developmental disorders increased from 13% in 1985 to 62% in 1989. An abnormal chromosomal pattern was found in 28 (24%) of the foetus. The pregnancy was terminated in 86% of cases with abnormal karyotype. The corresponding number in the group with normal chromosomes was 51%. The authors discuss the malformations leading to karyotyping, the methods used for karyotyping, the results of these tests and the consequences for the pregnancies.
Chromosome Aberrations↗
Screening for point mutations in exon 10 of the low density lipoprotein receptor gene by analysis of single-strand conformation polymorphisms: detection of a nonsense mutation-FH469-->Stop.
DNA from 40 unrelated familial hypercholesterolemia (FH) heterozygotes were subjected to analyses of single-strand conformation polymorphisms (SSCPs) of exon 10 of the low density lipoprotein receptor (LDLR) gene. Four different SSCP patterns were observed. The underlying mutations were characterized by DNA sequencing. Three of the patterns represented the three genotypes of a recently described sense mutation in codon 450. A method based upon the polymerase chain reaction (PCR) was developed to analyze this mutation. The frequencies of the wild-type (G at nucleotide 1413) and mutant (A at nucleotide 1413) alleles were 0.56 and 0.44, respectively. The fourth pattern was found in only one FH heterozygote and was caused by heterozygosity at nucleotide 1469 (G/A). Nucleotide 1469 is the second base of codon 469Trp(TGG). The G-->A mutation changes this codon into the amber stop codon, and is referred to as FH469-->Stop. The mutant receptor consists of the amino terminal 468 amino acids. Because the truncated receptor has lost the membrane-spanning domain, it will not be anchored in the cell membrane. FH469-->Stop destroys an AvaII restriction site, and this characteristic was used to develop a PCR method to establish its frequency in Norwegian FH subjects. Two out of 204 (1%) unrelated FH heterozygotes possessed the mutation.
Adult↗
Photobiological properties of hematoporphyrin diesters: evaluation for possible application in photochemotherapy of cancer.
The dimethyl, diethyl, dipropyl, dibutyl, diamyl, dihexyl and diheptyl esters of hematoporphyrin (Hp) were synthesized and shown to be more strongly retained on a reverse phase (C18) high performance liquid chromatography column than most components of Photofrin II (PII) - the sensitizer used for photochemical treatment of cancer in the clinic. The Hp diesters were found to be less efficient than PII in sensitizing cells to photoinactivation. This was partly due to de-esterification of the Hp diesters by esterase activity in the serum. The de-esterification of the Hp diesters was highly dependent on the ester group, with Hp dimethyl ester (t1/2 for conversion to Hp monomethyl ester was 6 min) being de-esterified with a rate 500 times faster than that for Hp diheptyl ester. Incubation of NHIK 3025 cells with these dyes showed that the Hp diesters were all partly located in extranuclear spots and partly diffusely distributed in the cytoplasm. The fluorescing spots may be due to lysosomally located Hp diesters, since the lysosomal marker enzyme beta-Nacetyl-D-glucosaminidase was partly inactivated by Hp diesters and light.
Biological Transport, Active↗
Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia.
Central core disease (CCD) of muscle is an inherited myopathy which is closely associated with malignant hyperthermia (MH) in humans. CCD has recently been shown to be tightly linked to the ryanodine receptor gene (RYR1) and mutations in this gene are known to be present in MH. Mutation screening of RYR1 has led to the identification of two previously undescribed mutations in different CCD pedigrees. One of these mutations was also detected in an unrelated MH pedigree whose members are asymptomatic of CCD. The data suggest a model to explain how a single mutation may result in two apparently distinct clinical phenotypes.
Adolescent↗
An action spectrum for UV-induced attachment of V79 Chinese hamster cells to a substratum.
When cells growing in monolayers are exposed to ultraviolet radiation (UV) their binding to the substratum is increased in strength. An action spectrum for such UV-induced binding was determined, using the time needed for trypsin-EDTA to detach the cells as a measure of the binding strength. This action spectrum was significantly different from the action spectrum for cell inactivation, which was also determined. At the shortest wavelengths (297/302, 313 nm) lethal fluences were needed to induce measurable binding while at the longest wavelengths (365, 405 nm) completely nonlethal fluences induced strong and persistent binding. Thus, different chromophores are involved in the two processes: while DNA may be the main chromophore for cell inactivation, other and unidentified chromophores may be more important for induction of increased cell binding to the substratum.
Animals↗
Evaluation of running conditions for SSCP analysis: application of SSCP for detection of point mutations in the LDL receptor gene.
We have performed analyses of single-strand conformation polymorphisms (SSCP) of the promoter region and the translated parts of the 18 exons of the low-density lipoprotein receptor (LDLR) gene. DNA from 20 unrelated familial hypercholesterolemia (FH) patients was studied. Four different running conditions were used for the nondenaturing gel electrophoresis to systematically evaluate how differences in the running conditions affect the sensitivity of the assay. These conditions were 15 W, 40 W, and 50 W in the absence of glycerol, and 50 W in the presence of 10% glycerol. SSCP analyses of the 18 PCR fragments for the 20 subjects revealed a total of 46 genotypes at 15 W, 45 at 50 W, 42 at 40 W, and 41 at 50 W with 10% glycerol. A total of 53 different genotypes were observed when the results of the four conditions were considered together. Assuming that the four conditions together detected 100% of the different genotypes, the sensitivity of the four individual conditions ranged between 87% (15 W) and 77% (50 W with 10% glycerol). There were marked differences among the different running conditions to detect abnormal SSCP patterns of individual exons. Therefore, different conditions should be used for the different exons of the LDLR gene.
Base Sequence↗
No effect of TaqI polymorphism at the human renal kallikrein (KLK1) locus on normal blood pressure level or variability.
Renal kallikrein is a component of the kallikrein-kinin-system (KKS). Kallikrein has been shown to cleave the precursor kininogen to release small kinins, which cause vasodilatation, increased diuresis and natriuresis. We have studied a normal restriction fragment length polymorphism (RFLP) at the renal kallikrein locus (KLK1), detectable with the restriction enzyme TaqI. In one series of 167 unrelated individuals we found a trend towards an association between genotypes in this polymorphism and level of diastolic blood pressure (DBP), but in two other series comprising 123 and 213 unrelated individuals, respectively, we found no suggestion of an association. Since the three series did not exhibit a consistent pattern of association between DBP levels and genotypes in this RFLP, we conclude that the association that appeared in one of the series was probably a chance event. There was no difference between genotypes in any of the three series, with respect to systolic blood pressure (SBP). In two series of, respectively, 157 and 120 complete monozygotic (MZ) twin pairs, there was no difference between genotypes with respect to within-pair variation in SBP or DBP. This indicates that normal KLK1 genes, expressed as variants in this RFLP, do not participate in the determination of the limits within which life-style factors may cause blood pressure (BP) changes. We conclude that neither "level gene" effects nor "variability gene" effects at the KLK1 locus are detectable with the polymorphism analyzed, in the Norwegian population.
Adult↗
Haplotype analysis at the low density lipoprotein receptor locus in normal and familial hypercholesterolemia Norwegian subjects.
We have performed haplotype analysis at the low density lipoprotein receptor (LDLR) locus in order to investigate the molecular genetics of familial hypercholesterolemia (FH) in Norway. Haplotypes were constructed using 7 restriction fragment length polymorphisms (RFLPs) in 194 subjects from 48 unrelated Norwegian FH families. Hypercholesterolemia co-segregated with haplotypes at the LDLR locus in all 48 families. Unambiguous haplotypes could be established for 190 independent chromosomes from 51 FH heterozygotes and 44 healthy normal subjects. A total of 20 different haplotypes was found. The most frequent haplotype was haplotype 3, which accounted for 32.4% or 43.1% of the normal and defective haplotypes, respectively. Haplotype 2 was significantly more frequent among the defective alleles than among the normal alleles (33.3% and 5.8%, respectively, p < 0.0001). Thus, haplotypes 2 and 3 accounted for 76.4% of the defective haplotypes. More data are needed to determine the possible existence of founder genes in the Norwegian population. Haplotypes 1, 2, 3, 5 and 8 accounted for 88.2% of the normal haplotypes. Based upon the cumulative heterozygosity index, the SphI, NcoI and 3' ApaLI RFLPs are the most informative markers in the Norwegian population.
Base Sequence↗
XbaI polymorphism in DNA at the apolipoprotein B locus is associated with myocardial infarction (MI).
High levels of low density lipoprotein (LDL) and its apolipoprotein B (apoB) are risk factors for atherosclerosis and myocardial infarction (MI). There is rich genetic polymorphism in apoB, first detected as the Ag allotypes of LDL, but today mostly examined at the DNA level. Genes contribute to the population variation in LDL and apoB levels and alleles in polymorphisms at the apoB locus are candidate genes with respect to control of lipid levels and susceptibility to atherosclerosis and MI. The XbaI polymorphism at the apoB locus, which involves the third base of threonin codon 2488 (ACC-->ACT) without changing the amino acid sequence was examined in a case-control study comprising 238 survivors of myocardial infarction (MI) and 621 controls. In univariate analysis, frequencies of genotypes in this polymorphism were not statistically different between patients and controls of either sex. However, in multivariate logistic regression analysis, the odds ratio X-X- homozygotes (homozygotes for absence of restriction site) for having MI compared to the pooled group of heterozygotes and X+X+homozygotes (homozygotes for presence of restriction site) was 2.16 (p = 0.007), after adjustments for age, sex, and levels of apoB, high density lipoprotein (HDL) cholesterol (HDLC) and Lp(a) lipoprotein. It appeared that heterozygotes do not have increased risk, compared to the X+X+ homozygotes. Stratification according to low or high levels of apoB, HDLC and Lp(a) lipoprotein, showed that the X-X- genotype was more common in patients than controls, in all subgroups.(ABSTRACT TRUNCATED AT 250 WORDS)
Alleles↗