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Biomedical subjects

P M Brett

Publications and source records attributed to P M Brett.

At least 19 recordsLinked to original sources
PubMed2005

Functional gene polymorphisms in aggressive and chronic periodontitis.

There is strong evidence that genetic as well as environmental factors affect the development of periodontitis, and some suggestion that aggressive and chronic forms of the disease share the same genetic predisposition. This study addresses the hypothesis that there are both shared and unique genetic associations in these forms of periodontitis. A sample of 51 patients with aggressive disease, 57 patients with chronic disease, and 100 healthy controls was recruited for this study. Ten functional polymorphisms in 7 candidate genes were genotyped. The results show statistically significant (p <or= 0.05) differences between genotype frequencies in aggressive and controls (IL-1B +3954 & IL-6 -174); chronic and controls (IL-6 -174 & VDR -1056); chronic and aggressive periodontitis (IL-1A -889); and periodontitis as a whole and controls (VDR -1056, TLR-4 399 & IL-6 -174). These results suggest that there are in fact both shared and unique genetic associations in aggressive and chronic periodontitis.

Alleles↗
PubMed2004

Gene polymorphisms in pro-inflammatory cytokines are associated with systemic inflammation in patients with severe periodontal infections.

The inflammatory response to chronic infections such as periodontitis may be central to the systemic implications of these diseases. This study examined the possible association between specific gene polymorphisms and the systemic inflammatory response in individuals suffering from severe generalized periodontitis. Ninety-four subjects with periodontitis were genotyped for polymorphisms in IL-1A (-889), IL-1B (-511, +3954), TNF-A (-308), IL-6 (-174) and TLR4 (-299, -399) genes. We found that the genotypes for IL-1A or IL-6 are associated with higher levels of serum IL-6 (P < 0.03) and serum CRP (P < 0.05), similarly the TNF-A genotype is associated with higher levels of serum IL-6 (P < 0.05) after correction for age, body mass index, gender, ethnicity and cigarette smoking. Systemic inflammatory responses are higher in severe periodontitis patients carrying rare alleles for functional inflammatory gene polymorphisms. These results suggest that cytokine genotypes are important determinants of the systemic inflammatory response in subjects with periodontitis. Genetic polymorphism therefore, may in part explain the reported association between periodontitis and systemic disease.

Base Sequence↗
PubMed2004

Roughness response genes in osteoblasts.

Titanium (Ti) and Ti alloys are widely used as dental and orthopedic implants, but the effects of the surface characteristics of these materials, including roughness, on the response of target tissues in vivo are not well understood. The present study has therefore examined the effects of a moderately rough (sand-blasted, acid-etched; SLA) Ti surface, a highly rough (plasma-sprayed; TPS) surface, and a smooth surface (SMO) on bone cells in vitro. X-ray photoelectron spectroscopy showed that these surfaces had similar surface chemistry, while scanning electron microscopy suggested that the SLA provided a transiently less biocompatible surface, with initially less well-attached cells. SLA also delayed bone cell growth compared with SMO, whereas the TPS surface elicited the greatest increase in cell numbers. In addition, expression profiling using the ATLAS gene array showed marked differences in gene responses after 3 h of incubation; this increased further after 24 h, with TPS generating the largest number of up- and down-regulated genes compared with SLA and SMO. A number of osteoblast genes were also identified as 'roughness' genes on the basis of their similar response on SLA and TPS, compared with SMO. These findings show, for the first time, that the surface roughness of Ti has a profound effect on the profile of genes expressed by bone cells and suggest that improvements in the biological activity and possibly the clinical efficacy of these materials could be achieved by selective regulation of gene expression mediated via modification of surface roughness.

Adult↗
PubMed2004

Periodontitis and systemic inflammation: control of the local infection is associated with a reduction in serum inflammatory markers.

Severe periodontitis is associated with elevated inflammatory markers in otherwise healthy populations. However, the nature of this association has not been determined. Our aim was to assess whether the degree of response to periodontal therapy was associated with changes in serological markers of systemic inflammation. Ninety-four systemically healthy subjects with severe generalized periodontitis participated in a prospective six-month blind intervention trial. Periodontal parameters and inflammatory markers [C-reactive Protein (CRP) and Interleukin-6 (IL-6)] were evaluated prior to and 2 and 6 mos after delivery of standard non-surgical periodontal therapy. Six months after treatment, significant reductions in serum IL-6 (p < 0.001, median decrease 0.2 ng/L, 95% CI 0.1-0.4 ng/L) and CRP (p < 0.0001, median decrease 0.5 mg/L, 95% CI 0.4-0.7) were observed. Decreases in inflammatory markers were significant in subjects with above average clinical response to periodontal therapy after correction for possible confounders. Periodontitis may add to the systemic inflammatory burden of affected individuals.

Aggregatibacter actinomycetemcomitans↗
PubMed2002

Expression profiling of periodontal ligament cells stimulated with enamel matrix proteins in vitro: a model for tissue regeneration.

Several studies have examined the role of enamel matrix proteins in root formation and periodontal regeneration, although most of these have focused on a few specific genes which had previously been implicated. However, recent advances in expressional profiling have made it possible to examine the range of genetic responses involved in these processes. In the present experiments, we have therefore utilized this technique to determine the effects of enamel matrix proteins on the gene activities of periodontal ligament cells in vitro. Such cells were found to have an elevated level of RNA synthesis compared with control cells. Moreover, hybridization of the cDNA prepared from this RNA to gene array filters showed that there was differential expression of 121 genes, most of which had not previously been associated with periodontal regeneration. Some of these selective changes in gene activity might thus reflect the fundamental events that underlie periodontal development.

Adult↗
PubMed2000

A genome-wide family-based linkage study of coeliac disease.

The susceptibility to develop coeliac disease (CD) has a strong genetic component, which is not entirely explained by HLA associations. Two previous genome wide linkage studies have been performed to identify additional loci outside this region. These studies both used a sib-pair design and produced conflicting results. Our aim is to identify non-MHC genetic loci contributing to coeliac disease using a family based linkage study. We performed a genome wide search in 16 highly informative multiply affected pedigrees using 400 microsatellite markers with an average spacing of 10 cM. Linkage analysis was performed using lod score and model free methods. We identified two new potential susceptibility loci with lod scores of 1.9, at 10q23.1, and 16q23.3. Significant, but lower lod scores were found for 6q14 (1.2), 11p11 (1.5), and 19q13.4 (0.9), areas implicated in a previous genome wide study. Lod scores of 0.9 were obtained for both D78507, which lies 1 cM from the gammaT-cell receptor gene, and for D2S364, which lies 12 cM from the CTLA4 gene.

Abatacept↗
PubMed2000

Coeliac disease and Down syndrome: associations not due to genetic linkage on chromosome 21.

BACKGROUND: Individuals with Down syndrome have an increased prevalence of coeliac disease (CD). The HLA region accounts for only 30% of the heritability of CD, and segregation analyses have suggested the involvement of at least one other non-HLA gene. Distribution of known HLA susceptibility types in Down syndrome and normal populations are similar and do not explain the difference in disease frequency. This study tests the hypothesis that the association between these disorders is due to a susceptibility gene for coeliac disease being present on chromosome 21. METHODS: We studied 21 families multiply affected with CD, none of whom had Down syndrome. The typing information of six microsatellite markers across chromosome 21 was used to test linkage. RESULTS: Negative results from lod score and model-free linkage analysis were obtained, providing no support for genetic linkage of coeliac disease to chromosome 21 in this population. CONCLUSIONS: The high prevalence of coeliac disease in Down syndrome is not due to an increased copy number of a polymorphic susceptibility gene on chromosome 21.

Celiac Disease↗
PubMed1999

Common HLA alleles, rather than rare mutants, confer susceptibility to coeliac disease.

Coeliac Disease (CD) is a gluten sensitive enteropathy characterised by villous atrophy and crypt cell hyperplasia. It has a very strong HLA class II association to the DQ locus. The nature of the involvement of the DQ locus in the susceptibility to CD has been examined by tissue culture experiments, association and peptide binding studies. We examined the role of the DQ molecules in the pathogenesis from the perspective of a genetic family study. Using flanking microsatellite markers to the class II region of the MHC to establish the parental origin of the susceptibility DQ alleles, we have evidence suggesting that the HLA association is probably due to the necessity to have these DQ alleles in order to express CD and there is no support for the presence of a rare mutation within the DQ alleles nor any rare HLA-linked gene nearby in linkage disequilibrium with the DQ locus. This approach is applicable to other diseases demonstrating strong association with common alleles, and can be used to predict whether screening the region for rare mutations is likely to be worthwhile.

Alleles↗
PubMed1999

Family linkage study of the T-cell receptor genes in coeliac disease.

BACKGROUND: The susceptibility to coeliac disease is genetically determined by possession of certain HLA DQ alleles, together with a one or more non-HLA genes. The central role of the T-cell receptor in disease pathogenesis makes the T-cell receptor genes strong candidates as disease susceptibility genes, and previous studies had provided equivocal ambiguous results. METHODS: A pedigree based genetic linkage study was used to determine if any of the T-cell receptor genes have a role in the genetic aetiology of coeliac disease. Intragenic microsatellite markers were used to study T-cell receptor alpha, beta, and delta, while gamma was studied using two flanking microsatellites D7S484 and D7S629. RESULTS: Conventional linkage analysis was performed using the MLINK computer package. Model-free linkage analysis was performed using MFLINK. No evidence of linkage between coeliac disease and the T-cell receptor genes was found in these pedigrees. CONCLUSIONS: Mutations in the T-cell receptor genes are not implicated in the genetic aetiology of coeliac disease.

Base Sequence↗
PubMed1998

A pedigree-based linkage study of coeliac disease: failure to replicate previous positive findings.

Coeliac Disease (CD) is a gluten sensitive enteropathy characterised by villous atrophy and crypt cell hyperplasia. There is a tight HLA association between CD and the HLA DQ alleles DQA1*0501, DQB1*0201 (DQ2), arranged in either cis- or trans- configuration, are found in 98.9% of cases in Northern European populations and 80% in Greeks and Ashkenazi Jews resident in Israel. We have previously shown that the HLA alleles and CD do not co-segregate in families multiply affected with CD, suggesting that the HLA association is entirely due to the necessity to have these normal DQ alleles for CD to manifest, and that the main genetic predisposition lies at a locus other than the MHC. It is therefore possible to conduct genetic linkage studies in order to isolate the non HLA genes which predispose to CD. Recently a group conducted a genome screen for the non HLA genes in an affected sib-pair analysis and identified four non HLA loci with positive lod scores. We examined these loci using a pedigree based linkage study. Our pedigree sample consisted of a cohort of 21 families with 60 affected individuals and 125 unaffected family members. We used 11 microsatellite markers at the loci implicated and analysed the genotype data using both MLINK and MFLINK to detect linkage. The MLINK and MFLINK analyses did not provide any evidence to support the earlier findings, although the difficulties involved in analysing complex diseases mean that one cannot be certain that these regions do not harbour susceptibility loci, at least in some families.

Celiac Disease↗
PubMed1997

Neuroreceptor subunit genes and the genetic susceptibility to Gilles de la Tourette syndrome.

Segregation studies have shown that Gilles de la Tourette Syndrome (GTS) is probably transmitted as an autosomal dominant gene disorder and can therefore be studied by classical linkage analysis to identify susceptibility loci. Many neurotransmitter systems have been implicated in the etiology of GTS. Most recently the alpha-1 subunit of the glycine receptor etiologically responsible for hyperekplexia has been hypothesized as the cause of the susceptibility to GTS. Because of this and the high concentration of other neuroreceptor genes at 5q33-35, it was decided to study this region and the associated gene cluster on chromosome 4p12-16 in a large British kindred multiply affected with GTS and chronic motor tics. The genotypes of the microsatellite markers at these loci were determined by polymerase chain reaction. The allele data were analyzed using both parametric and nonparametric methods. Approximate multipoint maps were constructed across the regions of interest using FASTLINK. All of the lod scores produced were negative, showing no evidence of linkage to GTS in the family studied. The multipoint maps showed good exclusion across these regions. The glycine receptor gene responsible for hyperekplexia and the other neuroreceptor genes examined in this paper are not involved in the etiology of GTS in this large pedigree.

Alleles↗
PubMed1997

Optimization of liposome mediated transfection of a neuronal cell line.

A cell line derived from sensory neurons was transfected with high efficiency using cationic liposomes, formulated from 3 beta [N-(N',N'-dimethylaminoethane)carbamoyl]-cholesterol (DC-Chol) and dioleoyl L-alpha-phosphatidylethanolamine (DOPE). This is the first time that cationic liposomes of this type have been reported to transfect a neuronal cell line. We used a reporter gene construct expressing beta-galactosidase under the control of the cytomegalovirus immediate early promoter and routinely observed transfection efficiencies > 40%. Parameters affecting transfection efficiency were examined and the ratio of DNA to liposome proved to be crucial. Liposome formulation procedures and cell transfection protocols devised here will be used as a basis for further in vivo and in vitro work.

Animals↗
PubMed1996

Linkage analysis and exclusion of regions of chromosomes 3 and 8 in Gilles de la Tourette syndrome following the identification of a balanced reciprocal translocation 46 XY, t(3:8)(p21.3 q24.1) in a case of Tourette syndrome.

Gilles de la Tourette syndrome (GTS) and related disorders such as chronic multiple tics and obsessive compulsive behaviour are likely to be genetically transmitted with a Mendelian autosomal dominant mode of transmission. Following our discovery of a patient with GTS who also carried a balanced translocation 46 XY, t(3:8) (p21.3 q24.1), a linkage study of several families was performed covering the areas on chromosomes 3 and 8 implicated by the cytogenetic abnormality in this unique GTS patient. A positive multipoint lod score of 2.9 was obtained on chromosome 3 with markers at the loci RAF1, THRB and D3S11. Subsequently, the genetic map of this region was improved and new polymorphic markers close to our original three markers were identified. With the new map the maximum two-point lod with any marker was reduced to 1.77 at RAF1, and the FASTMAP approximate multipoint lod excluded the likely region of the breakpoint. After constructing a somatic cell hybrid, the original three markers were mapped relative to the break point of the translocation and to other new markers. It was confirmed that the original markers were at least 20 cM away from the position of the break point. In addition, we traced further family members of our translocation GTS proband, and identified affected individuals who did not possess the translocation. We concluded that the translocation was not responsible for the GTS symptoms in our affected proband.

Chromosome Mapping↗
PubMed1996

Genetic and immunological markers in pouchitis.

OBJECTIVES: Previous studies of the interleukin-1 receptor antagonist (IL-1RN) have found an increased frequency of the associated variable number tandem repeat (VNTR) allele 2 for ulcerative colitis (UC) and further evidence has been reported that this allele is associated with increased severity of several other inflammatory conditions. The HLA type of UC patients has also been implicated in the extent of disease as has the presence of perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA). We therefore decided to test the hypothesis that the p-ANCA, HLA type or the presence of the IL-1RN allele 2 in patients who received a restorative proctocolectomy for UC had an effect on the risk of developing pouchitis. PATIENTS: We determined the genotypes of the IL-1RN and HLA DR beta and DQ beta loci for 28 subjects with previous UC and a pouch with no evidence of pouchitis for a minimum of 2 years after formation of an ileo-anal reservoir (mean 6.3 years; range 2-17 years) and 25 subjects with previous UC and pouchitis confirmed by strict histological examination of pouch mucosal biopsy. The IL-1RN genotypes were also determined for 86 healthy controls and 61 unrelated patients with familial adenomatous polyposis (FAP). The p-ANCA status was determined for all 25 pouchitis subjects but only 23/28 non-pouchitis subjects, with 15 unaffected subjects as a negative control. METHODS: The HLA haplotypes of the UC groups were determined by polymerase chain reaction sequence-specific primer (PCR-SSP) typing and the IL-1RN genotypes were determined by PCR and agarose gel electrophoresis. The p-ANCA status was determined by indirect immunofluorescence. RESULTS: A chi 2 of 5.686 with 1 degree of freedom and a P value of 0.0171 using Yates' correction was obtained by comparing the IL-1RN allele frequencies of the combined UC groups to the FAP controls, and a chi 2 of 6.801 with 1 degree of freedom and a P value of 0.0091 comparing the pouchitis group to the FAP controls. The HLA haplotype frequencies did not vary significantly between groups nor did they correlate with p-ANCA status. There were also no significant associations of the p-ANCA status and pouchitis. CONCLUSION: There is an increased frequency of IL-1RN allele 2 in UC, with the majority of the association arising from the pouchitis group, suggesting that the presence of allele 2 in patients with UC affects the disease outcome. However, the HLA frequencies and p-ANCA status do not have any significant associations.

Adult↗
PubMed1995

The genetic susceptibility to Gilles de la Tourette syndrome in a large multiple affected British kindred: linkage analysis excludes a role for the genes coding for dopamine D1, D2, D3, D4, D5 receptors, dopamine beta hydroxylase, tyrosinase, and tyrosine hydroxylase.

Segregation analyses have shown that Gilles de la Tourette Syndrome (GTS) is transmitted as an autosomal dominant gene disorder indicating that classical linkage analysis should be able to identify susceptibility loci. Previous studies of GTS have included investigations of neuroreceptor function, neurotransmitters, and their metabolites as well as neurotransmitter-related enzymes in an attempt to determine the pathophysiology of GTS. The neurotransmitter systems most often thought to be involved in GTS include those involving adrenaline, noradrenaline, and dopamine. We have carried out research to test the hypothesis that genes encoding proteins in the catecholamine pathways may contribute to the genetic etiology of GTS. Polymorphic markers at or near the D1, D2, D3, D4, D5 neuroreceptor gene loci as well as at the genes encoding dopamine beta hydroxylase (DBH), tyrosinase (TY) and tyrosine hydroxylase (TH) were studied in one large multiple affected pedigree. The linkage results of this investigation exclude a major role of these candidate genes in the etiology of GTS in the pedigree.

Chromosome Aberrations↗
PubMed1995

Exclusion of the 5-HT1A serotonin neuroreceptor and tryptophan oxygenase genes in a large British kindred multiply affected with Tourette's syndrome, chronic motor tics, and obsessive-compulsive behavior.

OBJECTIVE: Previous studies have demonstrated a relationship between obsessive-compulsive disorder or behavior and Gilles de la Tourette syndrome. It has been hypothesized that the serotonergic system is implicated in the etiology of obsessive-compulsive disorder. Therefore, the authors investigated whether genetic variation in a serotonergic receptor and a modifying enzyme were associated with Tourette's syndrome. METHOD: A linkage analysis using DNA and blood group markers was carried out in a large British kindred multiply affected with Tourette's syndrome, chronic motor tics, and obsessive-compulsive behavior. RESULTS: There was no evidence to support the hypothesis that genetic variation in the serotonin 5-HT1A receptor and tryptophan oxygenase genes causes susceptibility to Tourette's syndrome and chronic multiple tics. CONCLUSIONS: The results eliminate two possible candidate genes from having a role in the pathophysiology of Tourette's syndrome.

Female↗
PubMed1994

Genomic cloning and localization by FISH and linkage analysis of the human gene encoding the primary subunit NMDAR1 (GRIN1) of the NMDA receptor channel.

A cDNA clone of the NMDAR1 (isoform E) has been used to screen both lambda and cosmid genomic libraries. A genomic phage clone was identified and sequenced and was found to contain some of the 3' coding regions of the GRIN1 gene. This clone was used to localize the gene using fluorescent in situ hybridization (FISH) to normal chromosomes, and also to a lymphoblastoid cell line containing a translocation involving chromosomes 9 and 15. FISH localized the gene to chromosome 9q34.3. The clone was used to screen a panel of genomic DNAs cut with 20 restriction enzymes. A VNTR sequence 5' to the gene, which was polymorphic for a number of restriction enzymes, was detected. A PvuII fragment of the genomic clone was found to detect the VNTR on Southern hybridization. The polymorphic VNTR marker was mapped against chromosome 9q34 markers using linkage analysis in the CEPH families. The GRIN1 gene was linked to D9S7 with a maximum lod score of 20.09 at zero recombination fraction in males and 0.03% recombination in females.

Alleles↗