An association analysis of candidate genes on chromosome 15 q11-13 and autism spectrum disorder.
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Autistic Disorder↗
Biomedical subjects
S Curran
Publications and source records attributed to S Curran.
Liver fatty acid binding protein expression in colorectal neoplasia.
Liver fatty acid binding protein is a member of the fatty acid binding group of proteins that are involved in the intracellular transport of bioactive fatty acids and participate in intracellular signalling pathways, cell growth and differentiation. In this study we have used proteomics and immunohistochemistry to determine the changes in liver fatty acid binding protein in colorectal neoplasia. Comparative proteome analysis of paired samples colorectal cancer and normal colon identified consistent loss of liver fatty acid binding protein (L-FABP) in colorectal cancer compared with normal colon. To identify the changes in liver fatty acid binding protein expression during colorectal cancer development and progression the cell-specific expression of L-FABP was determined by immunohistochemistry in a series of colorectal cancers and colorectal adenomas. Decreased L-FABP immunoreactivity was significantly associated with poorly differentiated cancers (P<0.001). In colorectal adenomas there was a significant trend towards decreased staining of L-FABP in the larger adenomas (P<0.001). There was consistent L-FABP immunostaining of normal surface colonocytes. This study demonstrates that loss of L-FABP occurs at the adenoma stage of colorectal tumour development and also indicates that L-FABP is a marker of colorectal cancer differentiation.
Adenoma↗
Haplotype analysis of SNAP-25 suggests a role in the aetiology of ADHD.
Several lines of evidence suggest a role for SNAP-25 (synaptosomal-associated protein of 25 kDa) in the genetic aetiology of ADHD. Most notable is the coloboma mouse mutant, which displays spontaneous hyperactivity and is hemizygous for a deletion spanning this gene. We have screened the SNAP-25 gene using denaturing high-performance liquid chromatography and sequencing, and genotyped six polymorphic single-nucleotide polymorphisms and two microsatellites in a clinically ascertained sample of 188 probands. Several markers were found to show association with ADHD, both individually and in combination with other markers to form multimarker haplotypes. Analyses of transmission by parental sex suggested that the association of SNAP-25 with ADHD is largely due to transmission of alleles from paternal chromosomes to affected probands, suggesting that this locus may be subject to genomic imprinting. Overall our data provide some evidence for a role of this gene in ADHD, although the precise causal functional variant is yet to be ascertained.
Attention Deficit Disorder with Hyperactivity↗
Regulatory CD8+ T cells fine-tune the myelin basic protein-reactive T cell receptor V beta repertoire during experimental autoimmune encephalomyelitis.
A significant number of self-reactive T cell clones escape thymic negative selection and are released into the periphery, where some are potentially pathogenic. The clonal expansion of self-reactive T cells is known to be limited during initial antigen encounter by apoptotic or anergic mechanisms, regulatory CD4+ T cells, and cytokines. Here we report that superimposed on these mechanisms, during the evolution of autoimmunity in experimental autoimmune encephalomyelitis (EAE), CD8+ T cells are induced, which fine-tune the peripheral self-reactive T cell receptor (TCR) repertoire. We assayed the myelin basic protein-reactive TCR repertoire in naive, EAE-recovered mice as well as EAE-recovered mice depleted of CD8+ T cells by TCRV beta surface expression, complementarity-determining region 3 length distribution, and complementarity-determining region 3 sequencing analysis. In EAE-recovered mice, certain myelin basic protein-reactive CD4+V beta 8.2+ clones are significantly decreased and this decrease is not observed if CD8+ T cells were depleted from these mice. The clones that persist in CD8+ T cell-intact mice are highly diverse in contrast to the clones expanded in CD8+ T cell-depleted mice, which are dominated by the significant outgrowth of a few clones. Importantly, the T cell clones that expand in the absence of CD8+ T cell control are enriched in potentially pathogenic self-reactive T cell clones capable of inducing EAE in vivo.
Adoptive Transfer↗
The dopamine transporter gene is associated with attention deficit hyperactivity disorder in a Taiwanese sample.
Genetic variation of the dopamine transporter gene (DAT1) is of particular interest in the study of attention-deficit hyperactivity disorder (ADHD), since stimulant drugs interact directly with the transporter protein. Association between ADHD and the 10-repeat allele of a 40-bp VNTR polymorphism that lies within the 3'-UTR of DAT1 was first reported in 1995, a finding that has been replicated in at least six independent samples from Caucasian populations. We analysed the DAT1 polymorphism in a sample of 110 Taiwanese probands with a DSM-IV diagnosis of ADHD and found evidence of increased transmission of the 10-repeat allele using TRANSMIT (chi(2)=10.8, 1 d.f., p=0.001, OR=2.9, 95% CI 1.4-6.3). These data give rise to a similar odds ratio to that observed in Caucasian poplulations despite a far higher frequency of the risk allele in this Taiwanese population; 82.3% in the un-transmitted parental alleles and 94.5% in the ADHD probands. These data support the role of DAT1 in ADHD susceptibility among Asian populations.
Adolescent↗
Evaluation of the epidermal growth factor receptor (EGFR) in colorectal tumours and lymph node metastases.
Overexpression of the epidermal growth factor receptor (EGFR) often correlates with an aggressive tumour phenotype and poor prognosis. To examine the relevance of EGFR in colorectal cancer, we determined the expression of EGFR protein in 249 colorectal adenocarcinomas and 42 lymph node metastases using immunohistochemistry. Moreover, we investigated a (CA)(n) dinucleotide repeat polymorphism of the EGFR gene in a subset of 114 tumours. High levels of EGFR protein were observed in 123/249 (49.4%) samples. EGFR expression in colorectal carcinomas correlated with differentiation grade (P=0.014). However, there were no associations with Dukes' stage, site, patient age or gender. EGFR protein expression did not influence survival in this colorectal cancer patient cohort (P>or=0.05). Expression was not identical in paired colorectal tumours and lymph node metastases, with only 17/42 (40.5%) samples showing equivalent EGFR levels (P>0.05). The distribution of the (CA)(n) dinucleotide repeat alleles in colorectal adenocarcinomas was not associated with EGFR protein expression (P>0.05). These results indicate that while EGFR overexpression is a common event in colorectal carcinogenesis, it does not influence patient prognosis.
Adenocarcinoma↗
Serotonergic system and attention deficit hyperactivity disorder (ADHD): a potential susceptibility locus at the 5-HT(1B) receptor gene in 273 nuclear families from a multi-centre sample.
Attention deficit hyperactivity disorder (ADHD) is a highly heritable and heterogeneous disorder, which usually becomes apparent during the first few years of childhood. Imbalance in dopamine neurotransmission has been suggested as a factor predisposing to ADHD. However, evidence has suggested an interaction between dopamine and serotonin systems in the pathophysiology of the disorder. Studies using selective agonists of the different 5-HT receptors microinjected into selected brain structures have shown a positive modulating effect on the functional activities of the mesotelencephalic dopaminergic system. This suggests that some of the genetic predisposition to ADHD might be due to DNA variation at serotonin system genes. In this study, we investigated polymorphisms in HTR(1B) and HTR(2A) (which encode the serotonin receptors 5-HT(1B) and 5-HT(2A) respectively) in a European ADHD sample. Using haplotype based haplotype relative risk (HHRR) and transmission disequilibrium test (TDT) analyses, we observed significant preferential transmission of the allele 861G of the HTR(1B) in the total sample (for HHRR; chi(2) = 7.4, P = 0.0065 and TDT; (chi(2) = 6.4, P = 0.014). Analysis of HTR(2A) failed to reveal evidence of association or linkage between the His452Tyr polymorphism and ADHD in the total sample. However, a significantly increased transmission of the allele 452His was observed in the Irish sample alone (chi(2) = 4.9, P = 0.026). These preliminary data suggest an important role for the serotonin system in the development of ADHD. Further studies, preferentially including different ethnic groups are required to substantiate these findings.
Attention Deficit Disorder with Hyperactivity↗
No association between CHRNA7 microsatellite markers and attention-deficit hyperactivity disorder.
Attention-deficit hyperactivity disorder (ADHD) is a highly heritable, common psychiatric disorder of childhood that probably involves several genes. There are several lines of evidence suggesting that the nicotinic system may be functionally significant in ADHD. First, nicotine promotes the release of dopamine and has been shown to improve attention in adults with ADHD, smokers, and nonsmokers. Second, ADHD is a significant risk factor for early initiation of cigarette smoking in children and maternal cigarette smoking appears to be a risk factor for ADHD. Finally, animal studies in rats and monkeys also suggest that nicotine may be involved in attentional systems and locomotor activity. The nicotinic system has previously been studied in schizophrenia where the neuronal nicotinic acetylcholine receptor alpha 7 subunit gene (CHRNA7) has been implicated in decreased P50 inhibition and attentional disturbances in patients with schizophrenia and in many of their nonschizophrenic relatives. Three known microsatellite markers (D15S165, D15S1043, and D15S1360) near the nicotinic acetylcholine alpha 7 receptor gene, CHRNA7, were studied in 206 ADHD parent-proband trios of children aged 5-16 with ADHD according to DSM-IV criteria. Children with known major medical or psychiatric conditions or mental retardation (IQ < 70) were excluded from the study. Markers D15S165 and D15S1360 were in linkage disequilibrium. The extended Transmission Disequilibrium Test analyses demonstrated no evidence that variation at the microsatellite markers D15S1360, D15S1043, and D15S165 influences susceptibility to ADHD. However, it remains possible that the CHRNA7 gene and other nicotinic system genes may be involved in conferring susceptibility to ADHD.
Adolescent↗
Colorectal cancer genomics: evidence for multiple genotypes which influence survival.
Colorectal cancer (CRC) is a leading cause of cancer death and the mechanism for variable outcome in this disease is not yet fully understood. It is hypothesized that differences in the genetic make-up of tumours may be partially responsible for the differences observed in survival among same staged individuals for this disease. In this study the tumour genomes of 29 consecutive patients undergoing surgery for Dukes' C CRC were assessed by comparative genomic hybridization (CGH). In addition, the CGH profiles from the tumours were compared with those from eight colorectal cell lines. Great variation in genetic grade (all detectable aberrations i.e., loss + gain) was observed in 29 Dukes' C colorectal tumours by CGH (median four aberrations per tumour, range 0-20). Gain was found in 76% and loss in 41% of tumours. The most frequently observed regions of gain were 13q (27.6%), 20q (27.6%), 7p (24.1%), 8q (24.1%), and 1q (20.7%) and loss were 18q (31%), 4q (20.7%), 17p (20.7%), 18p (20.7%), and 15q (20.1%). None of these specific genomic aberrations were associated with patient survival. However, patients with more than two aberrations had a better survival than patients with fewer regions of loss and gain (P = 0.02). CRC cell lines had similar regions of loss or gain as the tumours. However, the frequency of genomic aberrations was much greater in the CRC cell lines. Although genomic change in CRC is relevant to the survival of patients with Dukes' C CRC, careful analysis is required to identify cell lines which are representative models of CRC genomics.
Aged↗
QTL association analysis of the DRD4 exon 3 VNTR polymorphism in a population sample of children screened with a parent rating scale for ADHD symptoms.
Current developments in molecular genetics have led to a rapid increase in research aimed at the identification of genetic variation that influences complex human phenotypes. One phenotype that has aroused a great deal of interest is the behavioral trait hyperactivity and the related clinical disorder attention-deficit hyperactivity disorder (ADHD). The driving force behind the molecular genetic research in this area is the overwhelming evidence from quantitative genetic studies that show high heritablility (h(2) = 0.7-0.9) for the behaviors characterizing the diagnosis of ADHD, whether the disorder is viewed as a categorical entity or a continuous trait. To date, molecular studies have aimed at identifying susceptibility genes for ADHD, defined using operational diagnostic criteria, and have focused on variation within genes that regulate dopamine neurotransmission. Several studies report ADHD to be associated with the 7-repeat allele of a 48 bp repeat polymorphism (DRD4-7) in exon 3 of the dopamine D4 receptor gene (DRD4). In this study, we take a dimensional perspective of ADHD and examine the relationship of this DRD4 polymorphism in a sample of children selected from the general population on the basis of high and low scores on the five ADHD items of the Strengths and Difficulties Questionnaire (SDQ) as rated by their parents. We found a significant relationship between DRD4-7 and high-scoring individuals [chi-square = 8.63; P = 0.003; OR = 2.09 (95% CI 1.24 < OR < 3.54), F-statistic = 7.245; P = 0.008].
Adolescent↗
Correlations between motor persistence and plasma levels in methylphenidate-treated boys with ADHD.
Following a 0.9 mg/kg methylphenidate loading dose, serial plasma level determinations, self-scored mood ratings, and measures of motor persistence were gathered on eight previously unmedicated boys with attention deficit disorder with hyperactivity (ADHD) during a 9-h period. The measures were repeated using the same loading dose after 6 months of maintenance treatment with methylphenidate (1.3 mg/kg x d). Kinetic-dynamic modelling suggests inverse correlative relationships between motor performance errors and plasma levels. Pharmacokinetic parameters did not change between acute and maintenance drug treatment phases, and there was no evidence of long-term tolerance.
Adolescent↗
Attention deficit hyperactivity disorder (ADHD) and the dopamine D4 receptor gene: evidence of association but no linkage in a UK sample.
Recent studies report association and linkage between attention deficit hyperactivity disorder (ADHD) and the 7-repeat allele of a 48 base-pair repeat in the dopamine D4 receptor gene (DRD4). We examined the frequency of this allele in a sample of probands with DSM-IV ADHD using a case-control design, as well as the transmission disequilibrium test (TDT) and haplotype-based haplotype relative risk (HHRR) in the subset of probands with DNA available from both parents. One hundred and thirty-two ADHD probands were compared with 189 controls (chi(2) = 6.17, 1 df, P = 0.01, OR = 1.73, 95% CI = 1.11--2.71). A total of 85 complete trios were available for within-family tests of association and linkage. Fifty-two heterozygous parents carrying one copy of the 7-repeat were informative for the TDT (29 transmitted vs 23 non-transmitted, chi(2) = 0.69). Analysis of the entire sample of 132 probands using TRANSMIT provided no additional evidence for excess transmission of the 7-repeat allele (58 transmitted vs 54 non-transmitted). HHRR gave similar results. We conclude that the case-control findings are likely to be falsely positive, resulting from genetic stratification. However we can not rule out alternative explanations of low statistical power and gene-environment correlation.
Alleles↗
Association study of a dopamine transporter polymorphism and attention deficit hyperactivity disorder in UK and Turkish samples.
Molecular genetic studies in attention deficit hyperactivity disorder (ADHD) have focussed on candidate genes within the dopamine system, which is thought to be the main site of action of stimulant drugs, the primary pharmacological treatment of the disorder. Of particular interest are findings with the dopamine transporter gene (DAT1), since stimulant drugs interact directly with the transporter protein. To date, there have been eight published association studies of ADHD with a 480 base-pair allele of a variable number tandem repeat (VNTR) polymorphism in the 3'-untranslated region of the gene, five that support an association and three against. We have analysed the same VNTR marker in a dataset of UK Caucasian children and an independent dataset of Turkish Caucasian children with DSM-IV ADHD, using the transmission disequilibrium test (TDT). Results from the UK (chi(2) = 8.97, P = 0.001, OR = 1.95), but not the Turkish sample (chi(2) = 0.93, P = 0.34) support association and linkage between genetic variation at the DAT1 locus and ADHD. When considered alongside evidence from other published reports, there is only modest evidence for the association, consistent with a very small main effect for the 480-bp allele (chi(2) = 3.45, P = 0.06, OR = 1.15), however we find significant evidence of heterogeneity between the combined dataset (chi(2) = 22.64, df = 8, P = 0.004).
3' Untranslated Regions↗
Rural emergency medicine.
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Emergency Medicine↗
Low faecal elastase 1 concentrations in type 2 diabetes mellitus.
BACKGROUND: Previous studies have suggested an association between impaired pancreatic exocrine function and diabetes, but the evidence is weak because the invasive nature of the tests used to define exocrine function has led to small studies on selected patients. The availability of faecal elastase 1 as a non-invasive test has aided the detection of impaired exocrine function in population studies. We describe the association between levels of faecal elastase 1 and Type 2 diabetes. METHODS: 544 Type 2 diabetic patients (age: 63 +/- 8 years) were randomly selected from local diabetes registers in Cambridgeshire, UK and individually matched for age, sex and practice to 544 controls in whom diabetes was excluded by HbA1c measurement. RESULTS: Faecal elastase 1 concentrations were significantly lower in cases than controls (median: cases 308 microg/g; controls 418 microg/g; P < 0.01). Low levels of faecal elastase 1 (< 100 microg/g) were found in 11.9% of cases and 3.7% of controls (age-sex-adjusted odds ratio; 95% CI: 3.6; 2.2-6.2). After adjustment for potential confounding factors, the OR was 4.5 (2.6-8.3). Among patients with diabetes, poor glycaemic control (HbA1c > or = 7%) was associated with a higher risk of low elastase 1 level (OR 5.6; 1.5-37). No significant association was found with diabetes duration, peripheral neuropathy, alcohol intake, or prior gastrointestinal diseases. CONCLUSIONS: Faecal elastase 1 concentrations are lower in Type 2 diabetic patients than in non-diabetic controls, suggesting the co-existence of diabetes and impaired pancreatic exocrine function. Among the diabetic patients, the risk of having low elastase 1 levels was associated with glycaemic control.
Aged↗
Application of laser capture microdissection and proteomics in colon cancer.
AIMS: Laser capture microdissection is a recent development that enables the isolation of specific cell types for subsequent molecular analysis. This study describes a method for obtaining proteome information from laser capture microdissected tissue using colon cancer as a model. METHODS: Laser capture microdissection was performed on toluidine blue stained frozen sections of colon cancer. Tumour cells were selectively microdissected. Conditions were established for solubilising proteins from laser microdissected samples and these proteins were separated by two dimensional gel electrophoresis. Individual protein spots were cut from the gel, characterised by mass spectrometry, and identified by database searching. These results were compared with protein expression patterns and mass spectroscopic data obtained from bulk tumour samples run in parallel. RESULTS: Proteins could be recovered from laser capture microdissected tissue in a form suitable for two dimensional gel electrophoresis. The solubilised proteins retained their expected electrophoretic mobility in two dimensional gels as compared with bulk samples, and mass spectrometric analysis was also unaffected. CONCLUSION: A method for performing two dimensional gel electrophoresis and mass spectrometry using laser capture microdissected tissue has been developed.
Colon↗
"The psychiatrist will be with you in a day or two". Unnecessary delays in assessing the mentally ill in police custody in Scotland.
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Decision Making↗
Approaches to gene mapping in complex disorders and their application in child psychiatry and psychology.
BACKGROUND: Twin studies demonstrate the importance of genes and environment in the aetiology of childhood psychiatric and neurodevelopmental disorders. Advances in molecular genetics enable the identification of genes involved in complex disorders and enable the study of molecular mechanisms and gene--environment interactions. AIMS: To review the role of molecular genetics studies in childhood behavioural and developmental traits. METHOD: Molecular approaches to complex disorders are reviewed, with examples from autism, reading disability and attention-deficit hyperactivity disorder (ADHD). RESULTS: The most robust finding in ADHD is the association of a variable number tandem repeat polymorphism in exon 3 of the DRD4 gene. Other replicated associations with ADHD are outlined in the text. In autism, there is a replicated linkage finding on chromosome 7. Linkage studies in reading disability have confirmed a locus on chromosome 6 and strongly suggest one on chromosome 15. CONCLUSIONS: In the next 5--0 years susceptibility genes for these disorders will be established. Describing their relationship to biological and behavioural function will be a far greater challenge.
Attention Deficit Disorder with Hyperactivity↗