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Biomedical subjects

A M Dunning

Publications and source records attributed to A M Dunning.

14 recordsLinked to original sources
PubMed1999

Identification of a C/G polymorphism in the promoter region of the BRCA1 gene and its use as a marker for rapid detection of promoter deletions.

Reduced expression of BRCA1 has been implicated in sporadic breast cancer, although the mechanisms underlying this phenomenon remain unclear. To determine whether regulatory mutations could account for the reduced expression, we screened the promoter region by sequencing in 20 patients with sporadic disease. No mutations were detected; however, a new polymorphism consisting of a C-to-G base change within the beta-promoter was identified, with the frequency of the G allele being 0.34. Close to complete linkage disequilibrium was found between this marker and the Pro871 Leu polymorphism, situated in exon 11, which has previously been shown not to be associated with breast or ovarian cancer. This indicates that the C/G polymorphism is also unlikely to play a role in either disease. However, the strength of linkage disequilibrium between these markers permitted their use for rapid screening for genomic deletions within BRCA1. A series of 214 cases with familial breast cancer were analysed using this approach; 88/214 were heterozygous for the promoter polymorphism, thereby excluding a deletion in this region. Among the remaining patients, one hemizygous case reflecting a promoter deletion was successfully identified. Therefore, this study indicates that deletions within the beta-promoter region of BRCA1 are an uncommon event in familial breast cancer. Furthermore, it suggests that mutations within the BRCA1 promoter are unlikely to account for the reported decreased expression of BRCA1 in sporadic disease.

Adenocarcinoma↗
PubMed1998

No association between a polymorphism in the steroid metabolism gene CYP17 and risk of breast cancer.

A recent study showed an association between a single base substitution, T-->C, in the promotor region of the CYP17 gene, the risk of breast cancer and age at menarche in Asian, African-American and Latino women from California and Hawaii. The C allele was associated with increased risk of breast cancer, significantly so for patients presenting with advanced disease, whereas the TT genotype was associated with later age at menarche in control subjects. We attempted to confirm these findings in a large case-control study in East Anglia, England (835 cases and 591 control subjects). We found no evidence of an increased risk of breast cancer [odds ratio (OR) 1.10, confidence interval (CI) 0.89-1.37] or advanced breast cancer (OR 0.88, CI 0.38-2.01) in C allele carriers, nor any association between age at menarche and genotype. We conclude that these alleles do not significantly alter breast cancer risk in the English population.

Aged↗
PubMed1997

Common BRCA1 variants and susceptibility to breast and ovarian cancer in the general population.

Most multiple case families of young onset breast cancer and ovarian cancer are thought to be due to highly penetrant mutations in the predisposing genes BRCA1 and BRCA2. However, these mutations are uncommon in the population and they probably account for only a few percent of all breast cancer incidence. A much larger fraction of breast cancer might, in principle, be due to common variants which confer more modest individual risks. There are several common polymorphisms in the BRCA1 gene which generate amino acid substitutions. We have examined the frequency of four of these polymorphisms: Gln356Arg, Pro871Leu, Glu1038Gly and Ser1613Gly in large series of breast and ovarian cancer cases and matched controls. Due to strong linkage disequilibrium, these four sites generate only three haplotypes with a frequency > 1.3%. The most common haplotypes, defined by the alleles Gln356Pro871Glu1038Ser1613 and Gln356Leu871Gly1038Gly1613, have frequencies of 0.57 and 0.32 respectively, and these frequencies do not differ significantly between patient and control groups. Thus the most common polymorphisms of the BRCA1 gene do not make a significant contribution to breast or ovarian cancer risk. However, our data suggest that the Arg356 allele may have a different genotype distribution in breast cancer patients from that in controls (Arg356 homozygotes are more frequent in the control groups, P = 0.01), indicating that it may be protective against breast cancer. If this finding can be confirmed, it may provide an insight into the structural features of the BRCA1 protein that are important for its function.

Adult↗
PubMed1995

Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation.

Mutations in the BRCA1 gene, discovered in 1994, are associated with an 80-90% lifetime risk of breast cancer. We have analysed 60 families with a history of breast and/or ovarian cancer for germline mutations in BRCA1. Twenty-two different mutations were detected in 32 families (53%), of which 14 are previously unreported. We observed a significant correlation between the location of the mutation in the gene and the ratio of breast to ovarian cancer incidence within each family. Our data suggest a transition in risk such that mutations in the 3' third of the gene are associated with a lower proportion of ovarian cancer. Haplotype analysis supports previous data which suggest some BRCA1 mutation carriers have common ancestors; however, we have found at least two examples where recurrent mutations appear to have arisen independently.

BRCA1 Protein↗
PubMed1993

A postulated phylogenetic tree for the human apolipoprotein B gene: unpredicted haplotypes are associated with elevated apo B levels.

Using published data on seven polymorphic sites in the human apolipoprotein B (apo B) gene, it is possible to postulate a model phylogenetic tree for this gene, covering the time since the divergence of human beings from other primates. This simple model assumes no obligatory recombination events or multiple occurrences of the same mutation. This model was tested in two samples of Swedish individuals consisting of 143 young, myocardial infarction patients and 90 healthy, age-matched, control individuals. All the haplotypes postulated in the simple model were observed unequivocally. However, in addition, three unpredicted haplotypes were unambiguously observed and a further nine, much rarer haplotypes were deduced to occur in these samples. The frequencies of the haplotypes postulated in the model do not differ between the patient and control samples, however most of the unpredicted haplotypes occur more frequently in the patient group than in the controls. Two of these unpredicted haplotypes, defined by the combination of the Antigen group (a) epitope and the presence of the XbaI cutting site, were associated with raised serum apo B levels in the control group and significantly elevated levels in the patient group. We propose that these observations explain in part the consistent association reported between the XbaI polymorphic site in the apo B gene and levels of plasma lipids.

Amino Acid Sequence↗
PubMed1992

Genetic relationship between the 3'-VNTR and diallelic apolipoprotein B gene polymorphisms: haplotype analysis in individuals of European and south Asian origin.

The genetic relationship amongst apolipoprotein B (apo B) gene polymorphisms (signal peptide insertion/deletion (Leu-Ala-Leu-16/-14), XbaI (Thr2488), EcoRI (Glu4154----Lys), Asn4311----Ser, 3'-VNTR) has been investigated in samples of South Asian (Indian) and Swedish individuals. The frequency distribution of alleles at all these sites was found to be significantly different between the South Asian and the Swedish samples (deletion allele: 0.20 v. 0.31, X+ (presence of XbaI cutting site): 0.29 v. 0.55, R- (absence of EcoRI cutting site): 0.11 v. 0.19, Ser4311: 0.45 v. 0.19). The distribution of allele frequencies at the VNTR site was bimodal in both populations. However, in South Asians, the most common allele was a 35 repeat unit allele, whilst in the Swedish sample, and in all other reports from Caucasian samples the 37 repeat unit allele was the most frequent (South Asian v. Swedish: 35 allele: 0.36 v. 0.19, 37 allele: 0.25 v. 0.48). Furthermore, four new alleles at the apo B gene 3'-VNTR site (15, 17, 32, 38 repeat unit alleles) were observed in South Asians, of which two (15 and 17 repeat unit alleles) were well outside the bimodal distribution. In both samples, strong linkage disequilibrium and allelic association were detected between alleles at the 3'-VNTR and each of the other sites, and also between the ins/del and XbaI sites and between the XbaI and Asn4311----Ser sites. The same five common haplotypes as defined by ins/del, XbaI, EcoRI and Asn4311----Ser were found to be present in both samples comprising 97 and 99% of the haplotypes observed in the South Asian and Swedish samples respectively. Detailed analysis revealed the predominant occurrence of certain 3'-VNTR alleles on specific haplotypes and demonstrates the usefulness of the VNTR site for haplotyping and representative association studies. A model for the evolutionary relationship of the major haplotypes including the 3'-VNTR site is presented. These findings support a mechanism of replication slippage as a major factor for the generation of new alleles at the apo B 3'-VNTR locus rather than unequal crossing over.

Adult↗
PubMed1992

Two amino acid substitutions in apolipoprotein B are in complete allelic association with the antigen group (x/y) polymorphism: evidence for little recombination in the 3' end of the human gene.

We report the identification of an A-to-G base change, in exon 29 of the apolipoprotein B (apo B) gene, that results in the substitution of serine for asparagine at residue 4311 of mature apo B100. In a recent publication, Huang et al. have reported a C-to-T base change in exon 26 that causes the substitution of leucine for proline at residue 2712 of apo B. We have found complete linkage disequilibrium between the alleles at both these sites and an immunochemical polymorphism of LDL designated antigen group (x/y) (Ag(x/y)) in a sample of 118 Finnish individuals. This implies that either one of these substitutions--or both of them combined--could be the molecular basis of the Ag(x/y) antigenic determinants, with the allele encoding serine4311 plus leucine2712 representing the Ag(x) epitope, and that encoding asparagine4311 plus proline2712 the Ag(y) epitope. In a sample of 90 healthy Swedish individuals the Leu2712/Ser4311 allele is associated both with reduced serum levels of LDL-cholesterol and apo B and with raised levels of HDL. However, these differences are of smaller effect than those associated with the XbaI RFLP of the apo B gene in this sample. We have also genotyped 523 individuals from European, Asian, Chinese, and Afro-Caribbean populations and have found complete association between the sites encoding residues 2712 and 4311 in all of these samples, although there are large allele frequency differences between these populations. In addition, there is strong linkage disequilibrium with allelic association between the alleles of these sites and those of the XbaI RFLP in all the populations examined. Taken together, these data suggest that, since the divergence of the major ethnic groups, there has been little or no recombination in the 3' end of the human apo B gene.

Adult↗
PubMed1991

Genetic evidence that the putative receptor binding domain of apolipoprotein B (residues 3130 to 3630) is not the only region of the protein involved in interaction with the low density lipoprotein receptor.

We have searched for sequence differences in the region of the apolipoprotein B (apo B) gene encoding amino acids 3130-3630 in eight individuals with reduced affinity of low density lipoprotein (LDL) for the normal LDL-receptor. All individuals were hypercholesterolaemic and were selected either on the basis of reduced fractional catabolic rate (FCR) of autologous LDL or substantially reduced binding of their LDL to normal LDL-receptors determined by an in vitro cell growth assay using the U937 macrophage-like cell line. Segments of the apo B gene were amplified by the polymerase chain reaction. Using a combination of cloning and sequencing the amplified fragment, together with chemical cleavage mismatch analysis, no sequence differences were identified in this region of the gene. We therefore conclude that variation outside the region of the apo B gene that codes for amino acids 3130-3630 must be responsible for the reduced LDL clearance in these patients.

Apolipoproteins B↗
PubMed1990

Familial defective apolipoprotein B-100: detection in the United Kingdom and Scandinavia, and clinical characteristics of ten cases.

Familial defective apolipoprotein B-100 (FDB) is a recently identified, dominantly inherited genetic disorder, which leads to increased serum concentration of low density lipoprotein (LDL) cholesterol with reduced affinity for the LDL receptor. This disorder is associated with a G to A mutation in exon 26 of the apolipoprotein B (apo B) gene which creates a substitution of glutamine for arginine in the codon for amino acid 3500. We have searched for this mutation in 374 unrelated individuals with hyperlipidaemia from the United Kingdom, and in 371 unrelated individuals with a primary clinical diagnosis of atherosclerosis from the United Kingdom and Scandinavia. Ten individuals, 9 from the U.K. and 1 from Denmark, were identified. The frequency of the mutation was 3% in individuals classified clinically as having familial hypercholesterolaemia (FH) and 3% in individuals with type IIa hyperlipidaemia without FH, and was not found in patients with types IIb and III hyperlipidaemia. The mutation was rare in individuals with a primary clinical diagnosis of atherosclerosis. Plasma lipid levels and clinical characteristics of the ten patients identified in the present study are similar to those reported for heterozygous FH. Thus, in our study, FDB is associated with moderate to severe hypercholesterolaemia, and appears to be a serious disorder causing premature cardiovascular disease. Individuals with this mutation can be identified unambiguously using routine molecular screening techniques.

Adult↗
PubMed1988

Relationships between DNA and protein polymorphisms of apolipoprotein B.

The associations between four restriction fragment length polymorphisms (RFLPs) of the gene for human apolipoprotein B (apo B) and five antigen group (Ag) protein-polymorphisms of apo B have been investigated in 24 unrelated Finnish individuals. In this sample a complete correlation exists between the EcoRI RFLP and the Ag(t/z) polymorphism. There is strong association between the alleles of the XbaI RFLP and Ag(c/g) and a weaker one of the same XbaI site with Ag(x/y). Linkage disequilibrium is observed between the PvuII RFLP and the Ag(a1/d) polymorphism. These associations confirm that the Ag variants are true protein sequence polymorphisms of apo B.

Apolipoproteins B↗
PubMed1988

Association between epitopes detected by monoclonal antibody BIP-45 and the XbaI polymorphism of apolipoprotein B.

An epitope of Apolipoprotein B (ApoB), recognised by a monoclonal antibody BIP-45, is associated with the development of ischaemic heart disease (Duriez et al. 1988). We have examined the genetic relationships between this epitope and three Restriction Fragment Length Polymorphisms (RFLPs) of the gene for ApoB detected with the enzymes EcoRI, PvuII and XbaI in a sample of 53 unrelated individuals from France. There is an association between binding affinity to BIP-45 and the XbaI RFLP; the 8.6 kb XbaI allele (absence of cutting site) being associated with low-affinity binding to BIP-45. In this sample of individuals there is no significant association between serum cholesterol levels and BIP-45 binding affinity, but there is a significant correlation between serum cholesterol levels and XbaI genotype, with individuals of the genotype X1X1 having the highest and those with the genotype X2X2 having the lowest levels of serum cholesterol. This suggests that variation at the ApoB locus may be involved independently in the determination of serum lipid levels and in the development of ischaemic heart disease.

Adult↗