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Biomedical subjects
D Clayton
Publications and source records attributed to D Clayton.
Patterns of disease in concordant parent-child pairs with multiple sclerosis.
BACKGROUND: Although the exact etiology of MS remains elusive, there is good evidence that genetic factors play an important role. These factors are likely to be polygenic, exerting both independent and interactive effects on the expression of MS. They may determine susceptibility and/or shape the clinical course. METHODS: The authors studied clinical phenotype in 245 concordant parent-child pairs recruited from a national register of familial disease over a 10-year period. Data were examined in order to determine the effect of parental sex on expression of disease in the offspring. RESULTS: Allowing for the observed sex ratio of 2.6 F:1 M in this group of patients, sex pairings of parents and offspring were close to those expected. When assessed independently there was no evidence that either the sex of the affected offspring or the line of inheritance influenced disability, age at onset, or disease course. However, trends were observed toward greater disability and an increased frequency of primary progressive disease in offspring of affected fathers and an earlier age at onset in offspring of affected mothers. The highest mean Expanded Disability Status Scale score was observed in male offspring of affected fathers (5.64) and this group was also more likely to have primary progressive disease (OR 1.92). Thirty-one percent of families had an additionally affected offspring with no preferential maternal or paternal transmission. CONCLUSIONS: In offspring of concordant parent-child families with MS who are at high risk of inheriting increased numbers of susceptibility genes there is no evidence for a parent of origin effect distorting sex ratios in affected offspring, but parent of origin may influence disability and disease course as well as increasing the risk to additional offspring within the same family. The mechanism of these effects is not clear but may result from interactions between genes encoded at different loci (epistasis), which each independently influence susceptibility and phenotype.
Adolescent↗
A genome screen for multiple sclerosis in Italian families.
We have screened the whole genome for linkage in 40 Italian multiplex families with multiple sclerosis using 322 markers. The GENEHUNTER-PLUS program was used to analyse these data and revealed eight regions of potential linkage where the lod score exceeds the nominal 5% significance level (0.7). No region of linkage with genome-wide significance was identified and none of the markers showed evidence of statistically significant transmission disequilibrium. Overall these results have refined the linkage data relating to this disease in Italians modestly supporting some previously identified areas of interest and helping to exclude others.
Genetic Testing↗
No association between multiple sclerosis and the Notch3 gene responsible for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
The clinical and radiological overlap between multiple sclerosis and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; MIM 125310) raises the possibility of diagnostic confusion and suggests that pleiotropic effects of the Notch3 gene might include influencing susceptibility to multiple sclerosis. To investigate these possibilities three microsatellites markers closely flanking the Notch 3 gene in 745 simplex families with multiple sclerosis were genotyped and exon 3 and exon 4 of the gene were directly sequenced in a subset of the index members from these families (n=93). No evidence for association was found in any of the three markers and none of the commoner mutations causing CADASIL were found in the sequenced patients.
Adult↗
Parkinson's disease is not associated with the combined alpha-synuclein/apolipoprotein E susceptibility genotype.
A recent study showed significant association of sporadic Parkinson's disease with a polymorphism within the alpha-synuclein gene and closely linked DNA markers on chromosome 4q and the APOE epsilon4 allele. A combined alpha-synuclein/APOE-epsilon4 genotype increased the relative risk of developing Parkinson's disease 12-fold. We failed to confirm this association in a much larger sample of histopathologically proven cases of Parkinson's disease and controls.
Alleles↗
Population norms for the MMSE in the very old: estimates based on longitudinal data. Mini-Mental State Examination.
OBJECTIVE: To report the percentile distribution of Mini-Mental State Examination (MMSE) scores in older people by age, sex, and education level, estimated from longitudinal data, after correcting for loss due to dropout. METHODS: The Cambridge City over 75 Cohort is a population-based study of a cohort of 2106 subjects age 75 years and older at study entry followed up over 9 years. At each of the four waves, cognitive function was assessed using MMSE. Based on these data, the relationship between age and MMSE score was modeled. Percentile distributions by age, sex, and education level were provided using inverse probability weighting to correct for dropouts. RESULTS: Performance on MMSE was related to age in men and women. In women, at age 75, MMSE score ranged from 21 (10th percentile) to 29 (90th percentile). At age 95, the range was 10 (10th percentile) to 27 (90th percentile). The upper end of MMSE distribution was slightly modified with age, whereas the lower end of the distribution was very sensitive to age effect. A similar pattern was observed in both sexes. CONCLUSION: These findings provide norms for MMSE scores in subjects age 75 years and older from longitudinal population-based data. Such norms can be used as reference values to determine where an individual's score lies in relation to his or her age, sex, and education level.
Aged↗
Three-dimensional NMR structure of the sixth ligand-binding module of the human LDL receptor: comparison of two adjacent modules with different ligand binding specificities.
The sixth ligand-binding module of the low-density lipoprotein receptor contributes to the binding of apolipoprotein B100-containing lipoproteins. 1H NMR spectroscopy, DYANA and X-PLOR structure calculations were used to determine that this module has a well defined structure with a backbone conformation similar to other modules. Structures from calculations that simulated the presence of a calcium ion showed increased resolution without large increases in energy, increased deviations from idealised geometry or violations of experimental constraints. Investigation of the surface properties of this module indicates there are significant differences from the fifth module, which binds apolipoprotein E-containing lipoproteins in addition to apolipoprotein B100-containing lipoproteins.
Algorithms↗
Interleukin 1 receptor antagonist (IL-1ra) in multiple sclerosis.
The autoimmune nature of multiple sclerosis introduces cytokine genes as logical candidates for the loci determining susceptibility to the disease, and/or influencing disease progression. Working on this principle, several groups have investigated the relevance of polymorphism in the interleukin 1 receptor antagonist gene (IL1RN) but with conflicting results. In an effort to clarify this situation, we typed the functionally significant variable number of tandem repeat (VNTR) polymorphism from intron 2 of IL1RN in 536 simplex families with multiple sclerosis. In order to improve the information extracted from these families, we also typed a closely mapped single nucleotide polymorphism (SNP) from the promoter of IL1B (the gene for IL-1beta). Disease associations were assessed by transmission disequilibrium testing (TDT), alone and after haplotype construction. There was highly significant (P</=2.48.10(-16)) linkage disequilibrium (LD) between the two polymorphisms studied, illustrating that LD adjacent to an SNP can be considerably more extensive than has recently been suggested. None of the alleles from the VNTR, the SNP or their haplotype showed statistically significant evidence for association. We stratified patients for current disability status but using this manoeuvre found no evidence that either of the polymorphisms influences disease severity. Combining the available data on the IL1RN VNTR suggests that any effect of this gene on susceptibility to multiple sclerosis, or its progression is, at best, small.
Adult↗
Caloric restriction prevents age-related deficits in LTP and in NMDA receptor expression.
A major focus of aging research has been the search for treatments that will prevent or ameliorate the memory deficits associated with aging. One paradigm, lifelong caloric restriction, has been reported to reduce some of the effects of aging. In the current report, we examined the effects of this treatment on age-related deficits in LTP, a putative cellular building block for memory formation. We report here that lifelong caloric restriction completely prevents the age-related deficit in LTP. In addition, we report that there is a dramatic decrease in the expression of the NMDA receptor subunit NR1 in aged rats and this age-related defect is also prevented by caloric restriction. These data provide a molecular and cellular mechanism by which life long caloric restriction may ameliorate some of the cognitive deficits associated with the aging process.
Aging↗
Polymorphism at NRAMP1 and D2S1471 loci associated with juvenile rheumatoid arthritis.
OBJECTIVE: To examine the role of NRAMP1 in susceptibility to juvenile rheumatoid arthritis (JRA). METHODS: DNA from 119 JRA patients (72 pauciarticular, 47 polyarticular) and 111 healthy controls from Latvia was genotyped for a functional repeat polymorphism in the promoter of NRAMP1 and a linked (<150 kb) microsatellite D2S1471. The findings were compared with those from HLA-DQ alleles typed previously. Chi-square analyses were performed using the Mantel-Haenszel test and stratification according to pure Latvian or pure Russian descent. Haplotype analysis was performed using the Associate program to implement the expectation-maximization algorithm based on the gene-counting technique. RESULTS: Allele 3 at NRAMP1 conferred increased risk (odds ratios [ORs] 2.26, 2.31, and 2.19; P = 0.0006, 0.003, and 0.019) of disease in the JRA, pauciarticular, and polyarticular patient groups, respectively. Allele 2 conferred protection (OR 0.44, 0.43, and 0.46). Alleles at D2S1471 that conferred susceptibility (6 and 12) or protection (11) did so only when on a haplotype with alleles 3 or 2, respectively, at NRAMP1. Allele 3 at NRAMP1 was additive with HLA-DQ7 for susceptibility (OR 3.71, 3.71, and 4.02), and allele 2 at NRAMP1 was additive with HLA-DQ5 for protection (OR 0.19, 0.08, and 0.12). CONCLUSION: The NRAMP1 allele conferring susceptibility to JRA drives high levels of NRAMP1 expression, while the allele associated with protection drives low levels. These 2 alleles are inversely associated with susceptibility to infectious disease, consistent with their maintenance in populations through balancing selection.
Adolescent↗
Autoimmune disease in first-degree relatives of patients with multiple sclerosis. A UK survey.
Previous studies examining an association with other autoimmune diseases have suggested the existence of a generalized autoimmune diathesis in patients with multiple sclerosis. We investigated the prevalence of autoimmune disease in first-degree relatives of probands with multiple sclerosis using a case-control method. The results show an excess of autoimmune disease within these families, but no significant association was seen with non-autoimmune diseases. The higher risk in multiplex than simplex families suggests an effect of genetic loading. While the increase in risk applies to each autoimmune disease, autoimmune thyroid disease (and Graves' disease in particular) contributes disproportionately to the excess risk. There was no increase in autoimmune disease within patients with multiple sclerosis themselves when compared with the index controls or population data. We conclude that autoimmune disease is more common in first-degree relatives of patients with multiple sclerosis and hypothesize that common genetic susceptibility factors for autoimmunity co-exist with additional disease specific genetic or environmental factors, which determine clinical phenotype in the individual.
Adolescent↗
A genome-wide search for susceptibility loci to human essential hypertension.
We undertook a systematic search of the entire human genome with the affected sibling-pair model to identify major susceptibility loci to essential hypertension. Affected nuclear families (n=263) were recruited and divided according to definite or probable genetic contribution to hypertension depending on number of hypertensive siblings. The largest nuclear families were first screened with a set of microsatellite markers. Regions on the genome with P<0.05 were tested against the second set of smaller families. An exclusion map was generated to identify regions in which hypertension-causing genes are unlikely to reside. Sibling-pair linkage analysis identified a single locus on chromosome 11q (P<0.004) in the first pass. A second pass with nuclear families that had only affected sibling pairs was, as expected, insufficient to support linkage to 11q. Multipoint exclusion-linkage analysis showed that 3 genetic loci are necessary to explain familial aggregation of essential hypertension. Our preliminary findings suggest that no single region within the human genome contains genes with a major contribution to essential hypertension. We show that the disease is indeed polygenic, with each gene providing a relatively small risk. Our exclusion map will help future investigators to concentrate on areas likely to contain these genes. The region on chromosome 11 is the first to point to a new candidate gene for hypertension that has arisen out of a genome search, but replication of these results at a higher significance is necessary before positional cloning can be justified.
Aged↗
The effect of respiratory therapist-initiated treatment protocols on patient outcomes and resource utilization.
CONTEXT: Physicians frequently prescribe respiratory treatments to hospitalized patients, but the influence of such treatments on clinical outcomes is difficult to assess. OBJECTIVE: To compare the clinical outcomes of patients receiving respiratory treatments managed by respiratory care practitioner (RCP)-directed treatment protocols or physician-directed orders. DESIGN: A single center, quasi-randomized, clinical study. SETTING: Three internal medicine firms from an urban teaching hospital. PATIENTS: Six hundred ninety-four consecutive hospitalized non-ICU patients ordered to receive respiratory treatments. MAIN OUTCOME MEASURES: Discordant respiratory care orders, respiratory care charges, hospital length of stay, and patient-specific complications. Discordant orders were defined as written orders for respiratory treatments that were not clinically indicated as well as orders omitting treatments that were clinically indicated according to protocol-based treatment algorithms. RESULTS: Firm A patients (n = 239) received RCP-directed treatments and had a statistically lower rate of discordant respiratory care orders (24.3%) as compared with patients receiving physician-directed treatments in firms B (n = 205; 58.5%) and C (n = 250; 56.8%; p < 0.001). No statistically significant differences in patient complications were observed. The average number of respiratory treatments and respiratory care charges were statistically less for firm A patients (10.7 +/- 13.7 treatments; $868 +/- 1,519) as compared with patients in firms B (12.4 +/- 12.7 treatments, $1,124 +/- 1,339) and C (12.3 +/- 13.4 treatments, $1, 054 +/- 1,346; p = 0.009 [treatments] and p < 0.001 [respiratory care charges]). CONCLUSIONS: Respiratory care managed by RCP-directed treatment protocols for non-ICU patients is safe and showed greater agreement with institutional treatment algorithms as compared with physician-directed respiratory care. Additionally, the overall utilization of respiratory treatments was significantly less among patients receiving RCP-directed respiratory care.
Adult↗
No evidence for association of multiple sclerosis with the complement factors C6 and C7.
Four genome screens in multiple sclerosis have been completed and each has identified evidence for linkage in the pericentromeric region of chromosome 5. This region encodes a number of candidate genes including those for the complement components C6, C7 and C9. We have used a multiplexed oligoligation assay (OLA) to test single nucleotide polymorphisms (SNPs) from the C6 and C7 genes for evidence of association with multiple sclerosis in our sibling pair families. There was no statistically significant difference in the allele frequencies of these polymorphisms in the index cases from our families when compared with locally derived controls. No evidence for transmission distortion was seen with any of the polymorphisms, or with the haplotype built from the three SNPs from the C7 gene. Despite offering themselves as potential candidates these complement genes appear not to confer susceptibility to multiple sclerosis.
Autoimmune Diseases↗
A screen of candidates from peaks of linkage: evidence for the involvement of myeloperoxidase in multiple sclerosis.
We tested 11 microsatellite markers for evidence of transmission distortion in 744 trio families with multiple sclerosis. Ten of the markers lie within or near to candidate genes selected on the basis that they map within the regions of potential linkage identified in our previously reported linkage genome screen, while the eleventh is an anonymous marker which had previously shown modest evidence for transmission distortion in our sibling pair families. Only the marker related to the myeloperoxidase (MPO) gene revealed tentative evidence for linkage disequilibrium and further work on this gene is clearly needed in order to resolve the status of this region in conferring susceptibility to multiple sclerosis.
Adult↗
Dibutyryl cyclic AMP-induced process formation in astrocytes is associated with a decrease in tyrosine phosphorylation of focal adhesion kinase and paxillin.
Focal adhesion kinase (FAK or pp125FAK) is a cytosolic protein tyrosine kinase which plays an important role in integrin-mediated signal transduction. Adhesion of cells to the substratum correlates with an increase in tyrosine phosphorylation of FAK as well as an associated protein, paxillin. In this report we show that the tyrosine phosphorylation of FAK and paxillin are decreased during dibutyryl cyclic AMP-induced (dB-cAMP) process formation in astrocytes. When astrocytes in suspension are treated with dB-cAMP, no alteration in morphology or tyrosine phosphorylation is observed, suggesting that both phenomena are linked and adhesion dependent. Furthermore, genistein, a tyrosine kinase inhibitor, can induce process formation in such cells, underscoring the significance of protein tyrosine kinases in maintaining the morphology of adherent cells. Finally, endothelin-1, a vasopeptide which is known to inhibit process formation in astrocytes, inhibited the tyrosine dephosphorylation of proteins associated with dB-cAMP treatment. These results suggest that the formation of asymmetric processes in astrocytes results from a coordinated set of alterations in the actin cytoskeleton as well as the adhesion of the cell to the substratum. Modification of the properties of such molecules is required for process formation and the dynamic modulation of astrocytic morphology in vitro and in vivo.
Actins↗
Exploring the dense mapping of a region of potential linkage in complex disease: an example in multiple sclerosis.
In 1996 we reported the results of a genome screen in multiple sclerosis, in which potential linkage was identified in a total of twenty regions, including the centromeric region of chromosome 5. In order to investigate the efficiency of typing dense arrays of markers in regions of potential linkage, we have typed an additional nineteen microsatellite markers from this chromosome 5 region (D5S623 - D5S428) in the same sibling pair families. The mean additional information extracted per marker typed declined with increasing map density, while inaccuracies in the mapping and the density of genotyping errors increased. Our empirical results suggest that, in linkage-based experiments, there is a limit to the benefits that are gained from typing additional markers in the same families. Increasing map density up to the 2.5-5 cM level efficiently extracts valuable extra information; however, beyond this level efficiency declines while the confounding effects of mapping and genotyping errors accumulate. We, therefore, recommend that extra markers typed in linkage studies be limited to this level of resolution. Mapping regions beyond this density should only be initiated when searching for linkage disequilibrium.
Chromosome Mapping↗
Evidence that allelic variants of the spinocerebellar ataxia type 2 gene influence susceptibility to multiple sclerosis.
Expanded CAG trinucleotide repeats are known to be responsible for five of the autosomal dominant spinocerebellar ataxias (SCA1, SCA2, SCA3, SCA6, and SCA7). We have typed each of these repeats in 226 multiple sclerosis sibling pair families. No expanded repeats were seen, indicating an absence of SCA phenocopies in clinically defined familial multiple sclerosis. However, transmission disequilibrium testing for these repeats demonstrated significant excess transmission of the 22 repeat length allele of the SCA2 gene (P=4. 4E-06) in multiple sclerosis patients. This observation is consistent with pleiotropic effects of the SCA2 gene, with a non-dynamic mutation/polymorphism contributing epistatically to susceptibility in multiple sclerosis.
Alleles↗