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Biomedical subjects

V Gudnason

Publications and source records attributed to V Gudnason.

9 recordsLinked to original sources
PubMed1992

Characterization of deletions in the LDL receptor gene in patients with familial hypercholesterolemia in the United Kingdom.

A sample of 200 patients with a clinical diagnosis of heterozygous (189) or homozygous (11) familial hypercholesterolemia (FH) attending lipid clinics in the London area have been screened for the presence of major gene defects in the low density lipoprotein (LDL) receptor gene by Southern blotting of genomic DNA with specific probes. This study is part of a project to determine the frequency of known mutations in the LDL receptor gene in this population. A new polymorphism for the enzyme Bgl II was identified by hybridization with a probe specific for the promoter plus exon 1 of the LDL receptor gene. The observed frequency of the rare allele, characterized by a Bgl II fragment of 13 kb compared with 10 kb for the common allele, was 0.08 in this group of FH patients. Several individuals who were heterozygous for the rare allele were also heterozygous for a mutation elsewhere in the LDL receptor gene that is known to cause FH. Eight different mutations, seven deletions and one duplication, were detected in a total of nine patients, accounting for 4.5% of the mutant alleles in this group. Three of the mutations are apparently identical to deletions that have been described previously in FH patients of British or European origin, while the remaining five have not been described. Two of these were in patients of Polish and Asian Indian origin, while the other three were in patients of apparently British ancestry.

Alleles↗
PubMed1992

Interaction between a polymorphism of the apo A-I promoter region and smoking determines plasma levels of HDL and apo A-I.

Epidemiological studies have demonstrated that the risk of coronary artery disease (CAD) is increased in smokers but reduced in individuals with elevated plasma levels of high density lipoprotein cholesterol (HDL-C) and apolipoprotein (apo) A-I. In a sample of 315 men and women from Iceland, the mean levels of HDL-C and apo A-I in smokers were, respectively, 12% and 6% lower in men and 7% and 6% lower in women compared with nonsmokers. In the men who were nonsmokers, a guanine (G) to adenine (A) (G/A) substitution 75 bp upstream from the start of transcription of the apo A-I gene was associated with elevated levels of HDL-C and apo A-I, with those carrying the A allele having levels of HDL-C and apo A-I roughly 10% higher than those with only the G allele. This genotype effect was abolished in the men who smoked and absent in the sample of women. Based on the reported protective effect associated with elevated levels of apo A-I and HDL-C, men carrying the A allele would have roughly a 20% lower relative risk of CAD compared with those without the A allele, but only if they remained nonsmokers. This gene polymorphism would therefore be an important factor in determining those men who would most benefit from avoidance or cessation of smoking. Determining the mechanism of such interaction between genotype and environment will be important in understanding the etiology of CAD.

Adolescent↗
PubMed1991

Identification of the 664 proline to leucine mutation in the low density lipoprotein receptor in four unrelated patients with familial hypercholesterolaemia in the UK.

Mutations in the gene for the low density lipoprotein (LDL) receptor cause Familial Hypercholesterolaemia (FH). One such mutation, a cytosine to thymine change in the codon for amino acid 664, causes proline (CCG) to be replaced by leucine (CTG) at this position, and creates a Pst I site in exon 14 of the gene. This mutation, previously identified in an FH homozygote of Asian Indian origin, results in a receptor with a reduced binding affinity for LDL and in delayed processing of the precursor form of the protein in cultured cells. A total of 224 unrelated heterozygous and 4 homozygous FH patients from London was screened for this mutation using direct amplification of genomic DNA by the polymerase chain reaction (PCR) and restriction digestion of the PCR product. Four patients were identified who were heterozgous for this mutation and the C to T base change was confirmed by sequencing. Affected relatives of these patients were also found to have the mutation. The effect of the mutation on LDL-receptor function in lymphoblastoid cell lines obtained from two of these patients was similar to that observed in heterozygous relatives of the original proband (MM). Eight polymorphisms of the LDL receptor gene were used to determine the haplotype of the defective allele carried by the patients and the individual (MM) in whom the mutation was first discovered. Two different haplotypes were found, suggesting that the mutation, which occurs at a CpG 'hotspot', has arisen independently at least twice. The presence of the same single base change in the LDL-receptor gene in several unrelated patients has not previously been reported in a population which is not geographically or culturally isolated.

Adolescent↗
PubMed1989

Polymorphism of the c-Ha-ras-1 proto-oncogene in sporadic and familial breast cancer.

Two studies on breast cancer patients are described. Our aim was to examine whether the combined frequency of rare c-Ha-ras-1 alleles in cancer patients was raised. Firstly, the c-Ha-ras-1 locus in 56 breast cancer patients and 48 controls was examined for restriction fragment length polymorphism (RFLP) by Southern blot analysis of leukocyte DNA. Four predominant allelic fragments were found in both groups together with a variety of rare alleles. The 2 groups did not differ significantly in overall distribution of c-Ha-ras-1 alleles. Rare alleles combined were about as frequent in cases (7.1%) as in controls (6.3%). Secondly, 53 members of 3 families having a high incidence of breast cancer were c-Ha-ras-1 genotyped. None of 10 affected members was found to carry a rare c-Ha-ras-1 allele. The only c-Ha-ras-1 allele common to 11 affected members was a 6.8-kb allele which is found in 72% of the controls. Furthermore, this allele was found with equal frequency in affected and non-affected family members.

Adult↗
PubMed1989

A study of familial hypercholesterolaemia in Iceland using RFLPs.

We have studied 17 unrelated families from Iceland who have familial hypercholesterolaemia (FH), using three different restriction fragment length polymorphisms (RFLPs) of the LDL receptor gene. In one family FH was caused by a 2 kb deletion in the LDL receptor gene in the region of exons 9 to 10. The PvuII (intron 15), NcoI (exon 18), and ApaLI (intron 15) RFLPs were used to determine the haplotypes associated with the defective LDL receptor gene in Iceland. Genotypes were determined in 77 subjects from these 17 families, both FH and non-FH. A rare new NcoI RFLP was detected in three subjects. Among the patients, at least four different haplotypes were observed indicating that FH in Iceland is caused by at least four different mutations and is a heterogeneous disease, even in the small, geographically isolated population of Iceland.

Adult↗
PubMed1987

Specific polypeptide differences in normal versus malignant human breast tissues by two-dimensional electrophoresis.

Postmitochondrial and cytosolic polypeptides were extracted from human breast tumors and non-malignant breast tissue and analyzed using high resolution two-dimensional polyacrylamide gel electrophoresis (2D-PAGE). Approximately 800-1000 postmitochondrial and 600-800 silver stained cytosolic polypeptides were detected over the pH range of 4.8 to 7.5 and molecular weight range of 18-120 kDa. The 2D-PAGE patterns of polypeptides from normal and malignant tissue were very similar, although both qualitative and quantitative polypeptide differences were noted. Six cytosolic polypeptides (pI/molecular weight X 10(-3) 5.20/80 kDa, 5.75/43, 6.25/40, 5.43/35, 5.45/34.5, 5.50/34 and 6.15/24 were expressed only in malignant tissues. One constitutive polypeptide, 7.25/52, was not detected in any of the malignant tissue samples. Quantitatively, marked differences in spot density were noted in polypeptides localized mainly in the molecular weight ranges of 22-40 kDa and pI ranges of 5.65-7.00. A general increase in polypeptide expression was noted in malignant tissues as compared to normal. Twenty-two polypeptides were significantly and consistently increased in tumor samples while only one polypeptide was decreased. One polypeptide, p24 (6.15/24) was expressed in greatest concentrations in tumors which also expressed the greatest estrogen receptor content. Expression of p24 was markedly reduced in normal tissue and malignant tissues expressing low levels of estrogen and progesterone receptors.

Biomarkers, Tumor↗
PubMed1986

Catabolite repressive effects of 5-thio-D-glucose on Saccharomyces cerevisiae.

The effect of the glucose analogue 5-thio-D-glucose (5TG) on the yeast Saccharomyces cerevisiae was studied. Derepression of mitochondrial respiratory chain cytochromes, alcohol dehydrogenase (isoenzyme II), NADH dehydrogenase and maltase was inhibited by 0.5-2 mM-5TG. Growth rate was only slightly affected. Ethanol was efficiently produced with 2 mM-5TG in medium initially containing 0.25% glucose. Mutants resistant to the growth inhibitory effects of 5TG on glycerol medium showed resistance to the catabolite repressing effects of glucose. Other mutants, known to be catabolite repression resistant, showed resistance to 5TG. The analogue seems to inhibit derepression of glucose repressible enzymes with greater potency than glucose itself.

Cytochromes↗
PubMed1985

Suppression of temperature sensitive mutations in oncogene-related CDC genes in Saccharomyces cerevisiae by catabolite repression resistance and cytoplasmic petite mutations.

The "start" cell division control genes CDC36 and CDC28 have been reported to contain a certain sequence homology to tissue oncogenes (ets and some protein kinase encoding oncogenes respectively). Here we report that temperature sensitive mutations in these genes are suppressed in cytoplasmic "petite" mutants and catabolite repression resistant mutants.

Genes, Fungal↗