Biomedical subjects

D Clayton

Publications and source records attributed to D Clayton.

At least 19 recordsLinked to original sources

PubMed1998

The Sardinian IDDM study: 1. Epidemiology and geographical distribution of IDDM in Sardinia during 1989 to 1994.

Analysis of the geographical variation of risk for a disease is a key issue in descriptive epidemiology and may provide useful suggestions for planning further studies to identify the underlying causes. We adopted a Bayesian approach to investigate the geographical distribution of insulin-dependent diabetes mellitus (IDDM) incidence rate across Sardinia. Data on incidence of IDDM in children aged under 15 years (619 IDDM cases) in Sardinia was obtained by the Sardinian Eurodiab ACE register. The overall completeness of ascertainment was: 91.3%. The average yearly standardized incidence rate for the years 1989-1994 was 33.24 per 100000 (95% C.I. 30.60, 35.88), which is the second highest in Europe after Finland. Sex and age-specific risks were higher in males than in females. Considering the variation of IDDM risk according to the age at diagnosis, the risk profile increased up to the 13th year of age for both sexes, being steeper in males. The degree of geographical variation in IDDM risk was small with a slight difference between the highest and the lowest standardized rate across the map. Indeed, even the municipalities at lowest risk in Sardinia showed a risk higher than most European countries. The Sardinian population is genetically atypical, characterized by genetic homogeneity and marked susceptibility to autoimmune diseases. Our finding of a small geographical variation within the island coupled with a marked temporal trend previously observed in data on military conscripts could be interpreted as evidence of a relatively recent environmental aetiological factor that was uniformly distributed across the island and had its effect in a genetically predisposed population.

Age Factors↗

PubMed1998

The genetics of multiple sclerosis: principles, background and updated results of the United Kingdom systematic genome screen.

Genetic susceptibility to multiple sclerosis is implicated on the basis of classical family studies and phenotype analyses. The only reproducible legacy from the candidate gene approach has been the discovery of population associations with alleles of the major histocompatibility complex. Systematic genome scanning has since been applied using a panel of anonymous markers to identify areas of linkage in co-affected siblings. Here, we describe the principles of genome screening and update the UK survey of multiple sclerosis. This identified 20 regions of potential interest, but in none was there unequivocal linkage. In theory, attempting to replicate these findings in a second set of sibling pair families is the most appropriate way to distinguish true from false positives, but unfortunately the number of families required to do this reliably is prohibitively large. We used three approaches to increase the definition achieved by the screen: (i) the number of sibling pairs typed in an identified region of potential linkage was extended; (ii) the information extraction was increased in an identified region; and (iii) a search was made for missed regions of potential linkage. Each of these approaches has considerable limitations. A chromosome-by-chromosome account is given to direct future searches. Although an additional marker placed distal to the 'hit' on chromosome 14q increased linkage in this area, and typing extra sibling pairs increased linkage on chromosomes 6p and 17q, evidence for linkage was more commonly reduced and no additional regions of interest were found. A further refinement of the genome screen was undertaken by conditioning for the presence of HLA-DR15. This produced a surprising degree of segregation among the regions of interest, which divided into two distinct groups depending on DR15 sharing: the DR15-sharing cohort comprised loci on chromosomal areas 1p, 17q and X; and the DR15-non-sharing cohort was made up of loci on 1cen, 3p, 7p, 14q and 22q. This result further highlights the genetic complexity of multiple sclerosis. What can now be inferred is that a gene of major effect is excluded from 95% of the genome and one with a moderate role from 65%, whereas genes which make a very small biological contribution cannot be discounted from any region. The available results suggest that multiple sclerosis depends on independent or epistatic effects of several genes each with small individual effects, rather than a very few genes of major biological importance.

Genetic Linkage↗

PubMed1998

Positive association of tyrosine hydroxylase microsatellite marker to essential hypertension.

Despite advances in the understanding of monogenic hypertensive disorders, the genetic contribution to essential hypertension has yet to be elucidated. The position of tyrosine hydroxylase (TH) as the rate-limiting enzyme in catecholamine biosynthesis renders it a candidate gene for the etiology of hypertension. The TH gene contains an internal, informative microsatellite marker (TCAT)9. We undertook (1) an association study in a group of well-characterized hypertensive subjects (HT) and control subjects (NT) and (2) an affected sibling pair (ASP) study using sibships from our local family practices. Two hundred twenty-seven hypertensive patients (pretreatment systolic/diastolic blood pressure [BP] range, 139/94 to 237/133 mm Hg; age range [SD], 30 to 71 [8.5] years) were age- and gender-matched with 206 control subjects (BP range, 96/62 to 153/86 mm Hg; age range, 40 to 70 [7.6] years). One hundred thirty-six affected sibling pairs were recruited for our linkage study; 73 young borderline hypertensive subjects (YHT) (pretreatment BP range, 123/76 to 197/107 mm Hg; age range, 20 to 51 [9.4] years) were also recruited in whom recent pretreatment norepinephrine and epinephrine levels were available. All subjects were white. The TH short tandem repeat (STR) was amplified using specific polymerase chain reaction cycling conditions in all subjects, and products were run on an ABI 373A sequencer. TH alleles were assigned using Genescan and Genotyper software. Five TH alleles were present and designated A through E. Allele frequencies in the NT population (A, B, C, D, and E: 0.24, 0.17, 0.13, 0.20, and 0.26, respectively) were significantly different from the HT cohort (A, B, C, D, and E: 0.24, 0.19, 0.11, 0.11, and 0.35, respectively), P<0. 0005 (Pearson's test chi2=19.94; 4 df). The E allele appears overrepresented in the HT group, whereas the D allele appears to be overrepresented in the NT group. TH genotype frequencies were also significantly different between cases and controls (P<0.001; chi2=36. 57; 14 df). Both groups were in Hardy-Weinberg proportion. There was a trend (NS) for the D allele to be associated with a lower BP when BP was analyzed as a quantitative trait. ASP linkage data was analyzed using Splink, a nonparametric program. Expected values for sharing 0, 1, and 2 alleles (Z0, Z1, and Z2, respectively) may be expected to be 25%, 50%, and 25%, respectively, by chance (assuming identity by descent). These probabilities were calculated by Splink as 34, 68, and 34, respectively, and compared with observed values of 36.8, 67.9, and 31.3, respectively; thus, there was no excess sharing of TH alleles among affected sibling pairs (P=0.59; logarithm of odds ratio score, 0.0). TH allele frequencies in our YHT group (A, B, C, D, and E: 0.24, 0.20, 0.12, 0.15, and 0.29, respectively) were similar to those of our NT cohort (P>0.05). There was a trend for lower pretreatment plasma norepinephrine levels with the D allele in this YHT cohort. A common and potentially functional variant at codon 81(Val-->Met) within exon 2 of the TH gene (which we show to be in linkage disequilibrium with TH-STR) was also typed in our YHT but did not associate with catecholamine levels and is therefore unlikely to account for our findings with D and E TH-STR. In conclusion, the TH locus strongly associates with essential hypertension in a case-control model using well-characterized hypertensive and control groups. An ASP linkage model was negative, presumably because of lack of power. This study suggests that the TH gene, or a nearby gene, may be involved in the etiology of essential hypertension.

Adult↗

PubMed1997

Offspring recurrence rates and clinical characteristics of conjugal multiple sclerosis.

BACKGROUND: There has been no previous systematic study of conjugal multiple sclerosis. This study of conjugal pairs with complex traits investigated disease transmissibility and the genetic contribution to frequency and clinical course. METHODS: We studied 45 conjugal pairs concordant for multiple sclerosis from 58 pairs recorded in a national register of familial disease, 86 offspring of the 45 pairs were individually assessed for clinical evidence of neurological disease; those over age 16 underwent cranial magnetic resonance imaging. Clinical features were compared in 33 pairs in whom neither member had symptoms before they met. FINDINGS: Of the 86 offspring, five (6%) had clinically definite multiple sclerosis. A further five children had either characteristic imaging abnormalities or clinical symptoms consistent with demyelination, but did not meet the criteria for clinically definite disease. There was no evidence of clinical concordance, clustering at year of onset, or distortion of the expected pattern of age of onset in the second affected spouse from 33 pairs. The crude recurrence in children of conjugal pairs (1 in 17) is significantly higher than previously reported population-based risk for offspring of single affected parents (1 in 200). INTERPRETATION: Taken with the low prevalence of multiple sclerosis in the spouses of affected individuals, and the lack of concordance for age at onset in these families, the disparity in crude recurrence between children of conjugal pairs and those of single affected parents shows that the recurrence risk in children is determined by genetic factors inherited from both parents.

Adolescent↗

PubMed1997

Empirical genomewide significance levels established by whole genome simulations.

The advent of high-resolution genetic maps and semiautomated genotyping technology has opened the way for genome screening in genetically complex traits. Many such screens are now under way, or completed, most using multipoint nonparametric linkage analysis of affected sibling pairs. This type of linkage analysis uses all the available genotype information to calculate the maximum lod score (MLS) value at each point in the genome, and thereby generates MLS profiles along each chromosome. Any positive MLS values indicate potential linkage, but the peaks in these profiles, which may be referred to as "hits," identify the most likely locations of disease susceptibility genes. However, such analysis presents serious problems of multiple testing, and the assessment of the statistical significance of hits has become a contentious issue [Lander and Kruglyak (1995) Nat Genet 11:241-247; Curtis (1996) Nat Genet 12:356-357; Witte et al. (1996) Nat Genet 12:355-356]. Having recently completed a genome screen in multiple sclerosis, we decided to investigate the statistical properties of our study by simulation. We report here in detail the results of this simulation study. Our main conclusion is that, for the particular set of families and markers used in our screen, an MLS of 3.2 carries a genome-wide significance of 5% (that is, there is a 5% probability of observing at least one false hit, above this threshold in a complete genome screen). This value is closer to the familiar limit of 3.0, originally suggested by Morton [1955; Am J Hum Genet 7:277-318] than to the more stringent limit of 4.0 recently proposed by Lander and Kruglyak [1995; Nat Genet 11:241-247]. This is somewhat reassuring, in view of the very large sample sizes that would be necessary to achieve adequate power to detect linkage at the more stringent threshold.

Female↗

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↗

PubMed1997

Analysis of the candidate gene NRAMP1 in the first 61 ARC National Repository families for rheumatoid arthritis.

Maximum likelihood identity-by-descent (IBD) sib pair analysis using a 3 locus haplotype NRAMP1-IL8RB-VIL1, or NRAMP1 alone, provided preliminary evidence (maximum LOD score = 1.01, p = 0.024) for a gene in this region of human chromosome 2q35 contributing to susceptibility to rheumatoid arthritis (RA). Candidacy for NRAMP1 as the disease susceptibility gene was supported by a significant bias (p < 0.048) toward transmission of the NRAMP1 promoter region allele 3 in affected offspring.

Alleles↗

PubMed1996

The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis.

OBJECTIVE: Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant disorder. The 3 recognized subtypes include MEN 2A, characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (pheo), and hyperparathyroidism (HPT); MEN 2B, by MTC, pheo, and characteristic stigmata; and familial MTC (FMTC), by the presence of MTC only. The purpose of this study was to establish the relationship between specific mutations and the presence of certain disease features in MEN 2 which could help in clinical decision making. DESIGN: Correlative survey study of 477 MEN 2 families. SETTING: Eighteen tertiary referral centers worldwide. PATIENTS: A total of 477 independent MEN 2 families. MAIN OUTCOME MEASURES: Association between the position and type of germline mutation in the RET proto-oncogene and the presence or absence of MTC, pheo, HPT, and/or other features in a family. RESULTS: There is a statistically significant association between the presence of any mutation at a specific position (codon 634) and the presence of pheo and HPT. The presence of a specific mutation, CGC at codon 634, has yet to be associated with FMTC. Conversely, mutations at codons 768 and 804 are thus far seen only with FMTC, while codon 918 mutation is MEN 2B--specific. Rare families with both MEN 2 and Hirschsprung disease were found to have MEN 2-specific codon mutations. Patients with Hirschsprung disease presenting with such mutations should be monitored for the possible development of MEN 2 tumors. CONCLUSIONS: This consortium analysis suggests that genotype-phenotype correlations do exist and, if made reliably absolute, could prove useful in the future in clinical management with respect to screening, surveillance, and prophylaxis, as well as provide insight into the genetic effects of particular mutations.

Carcinoma, Medullary↗

PubMed1996

Childhood leukaemia in Europe after Chernobyl: 5 year follow-up.

The European Childhood Leukaemia - Lymphoma Incidence Study (ECLIS) is designed to address concerns about a possible increase in the risk of cancer in Europe following the nuclear accident in Chernobyle in 1986. This paper reports results of surveillance of childhood leukaemia in cancer registry populations from 1980 up to the end of 1991. There was a slight increase in the incidence of childhood leukaemia in Europe during this period, but the overall geographical pattern of change bears no relation to estimated exposure to radiation resulting from the accident. We conclude that at this stage of follow-up any changes in incidence consequent upon the Chernobyl accident remain undetectable against the usual background rates. Our results are consistent with current estimates of the leukaemogenic risk of radiation exposure, which, outside the immediate vicinity of the accident, was small.

Child↗

PubMed1996

A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22.

The population prevalence of multiple sclerosis is 0.1%; however, the risk of the disease in the siblings of affected individuals is very much higher at 3-5%. The importance of genetic factors in accounting for this increased risk is confirmed by the results of twin and adoption studies. Despite the evidence for a strong genetic effect, a weak major histocompatibility complex (MHC) association is the only consistently observed feature in the genetics of multiple sclerosis. Other candidates have been proposed, including genes encoding the immunoglobulin heavy chain, T cell receptor beta chain and APOC2, but none has yet been confirmed. Evidence for linkage and association to the myelin basic protein gene has been reported in a genetically isolated Finnish population, but it has not been possible to reproduce these results in other populations. We used a two-stage approach to search the human genome for the genes causing susceptibility to multiple sclerosis. Two principal regions of linkage are identified, chromosomes 17q22 and 6p21 (MHC). Our results are compatible with genetic models involving epistatic interaction between these and several additional genes.

Chromosome Mapping↗

PubMed1996

Age-adjusted recurrence risks for relatives of patients with multiple sclerosis.

Familial aggregation is a cardinal epidemiological feature of multiple sclerosis, but few investigators have systematically examined recurrence risks for relatives of affected individuals in the United Kingdom. As part of a cross-sectional study of multiple sclerosis in Cambridgeshire, pedigree details were taken on 674 probands. Sex-specific, crude and age-adjusted recurrence risks were assessed amongst relatives of probands, applying a statistical model based on the observed age at onset of affected individuals and providing risks for clinical counselling. Details on year of birth, present age or age at death, and disease status were available on 11 391 relatives of successive probands. Nineteen percent of patients reported an additionally affected relative; 128 non-proband affected relatives were identified and the highest risk was observed for sisters. There was a systematic reduction in relative risk with genetic distance from the proband and no preferential recurrence for maternal or paternal relatives.

Adult↗

PubMed1996

Linkage of rheumatoid arthritis to the candidate gene NRAMP1 on 2q35.

The macrophage resistance gene NRAMP1 regulates priming/activation of macrophages for enhanced TNF alpha, IL 1 beta, and MHC class II expression. Since all of these functions are of potential importance in the induction or maintenance or both of autoimmune disease, samples from the Arthritis and Rheumatism Council's repository of multicase rheumatoid arthritis families were typed for a dinucleotide repeat in the NRAMP1 promoter region and four other 2q34 (TNP1) or 2q35 (IL8R, VIL1, DES) marker genes. Identity by descent (IBD) sib pair analysis using a three locus haplotype NRAMP1-IL8RB-VIL1, or NRAMP1 alone, provided preliminary evidence (maximum lod score = 1.01, p = 0.024) for a gene in this region contributing to suceptibility to rheumatoid arthritis. Candidacy for NRAMP1 as the disease susceptibility gene was supported by a significant bias (p = 0.048) towards transmission of the NRAMP1 promoter region allele 3 in affected offspring.

Arthritis, Rheumatoid↗

PubMed1996

CAMPATH-IH in multiple sclerosis.

In a pilot study, seven patients with multiple sclerosis were treated with CAMPATH-IH which targets the CD52 antigen present on lymphocytes and monocytes. There was a substantial reduction in disease activity as measured by gadoliunium-enhancing lesions on MRI. Encouraged by this result a further seven patients have been treated with CAMPATH-IH; four also received anti-CD4 antibody. Lymphopaenia developed rapidly and was sustained for at least one year. In 12 patients, the first infusion of antibody was characterised by significant exacerbation or re-awakening of pre-existing symptoms lasting several hours. These clinical effects of antibody treatment correlated with increased levels of circulating cytokines. Peak levels of tumour necrosis factor alpha (TNF alpha) and interferon gamma (IFN gamma) occurred at 2 h whereas the rise in interleukin-6 (IL-6) was significantly delayed and peaked at 4 h after starting antibody treatment. The neurological symptoms could not be attributed directly to pyrexia and were not provoked (in one patient) by an artificial rise in temperature. In the remaining two patients, a single pre-treatment with intravenous methylprednisolone (500 mg) prevented both the transient increase in neurological symptoms and the cytokine release. Our results suggest that soluble immune mediators contribute to symptom production in multiple sclerosis by directly or indirectly blocking conduction through partially demyelinated pathways.

Adrenal Cortex Hormones↗

PubMed1996

Clinical concordance in sibling pairs with multiple sclerosis.

As part of a linkage study, we obtained clinical, demographic, and genetic information on 210 families with siblings concordant for multiple sclerosis (MS). Twenty-eight pairs were excluded and information was incomplete in a further 16 pairs; intrafamilial comparisons of the clinical course are reported on the remaining 166 families (155 pairs and 11 trios) in whom complete data sets were available. The demographic characteristics were comparable to those of recently performed prevalence studies in the United Kingdom, supporting the application of results in these families for genetic linkage studies in MS. We observed no significant correlation for age at onset after correction for selection bias but found a minor correlation for year at onset, which we speculate is due to earlier recognition of symptoms in second affected siblings. There was no pair-wise concordance for presenting symptoms or disability at time of assessment. However, there was a strong correlation for disease course and to a lesser degree for gender. In addition, the familial recurrence rate was 33%, almost twice that previously recorded in a local prevalence study. These results suggest that the etiology of MS involves random exposure to an, as yet unidentified, environmental trigger and the clinical features of familial disease are modified by inherited factors. That the risk of developing MS is not spread uniformly among families has important implications for the counseling of individuals with familial disease.

Female↗

PubMed1995

Genome scan for association and linkage.

In this paper, a genome search is performed on the GAW Problem 1 data, in an attempt to determine which, if any, of the marker loci are associated and/or linked with the disease. Since there was no clear indication from the data of the likely mode of inheritance, methods were used which did not require such assumptions to be made. A two-stage procedure was used to test for association. Firstly a standard unmatched case-control test was applied to all the loci. The family-based method of Self et al. [1991] was then applied to those loci which gave a positive result in the first stage. This procedure correctly detected loci 1 and 2, and that disease risk was increased for homozygote carriers of the disease allele at each locus, although a false positive result was also found. The affected sib pair method of Holmans [1993] was also applied to the data, although the sample contained far too few sib-pairs for such an analysis to be effective. This analysis failed to find any of the disease loci.

Case-Control Studies↗

PubMed1995

Susceptibility to multiple sclerosis and the immunoglobulin heavy chain variable region.

A haplotype marker consisting of three biallelic restriction fragment length polymorphism (RFLP) loci from the VH-2 variable gene family was examined in 124 families with sibling pairs concordant for multiple sclerosis, 178 unrelated patients and 159 unaffected controls to investigate the role of the immunoglobulin heavy chain gene cluster in susceptibility to multiple sclerosis. Evidence for linkage was assessed using the affected sibling pair method of identity by descent, modified to allow for haplotype sharing on a probabilistic basis in families where haplotypes could not be assigned with certainty. The estimated probabilities of affected siblings sharing 0, 1 or 2 haplotypes were Z0 = 0.20, Z1 = 0.45, Z2 = 0.35. This deviation from the expected sharing probabilities of Z0 = 0.25, Z1 = 0.5, Z2 = 0.25 provides evidence for weak linkage (P < 0.05; equivalent to a lod score of 0.84); however, no significant allelic or haplotypic association was observed. Linkage without a population association suggests that a gene encoded on 14q confers susceptibility to multiple sclerosis, although this is not any of the existing VH-2 polymorphisms.

Alleles↗

PubMed1995

Multiple sclerosis and the HLA-D region: linkage and association studies.

Inheritance patterns of multiple sclerosis (MS) in multiplex families suggest a complex aetiology involving environmental and genetically determined components. The association between the HLA class II DR15, DQ6, Dw2 haplotype and MS has been well documented in patients with ancestral origins in Northern Europe. Conversely, linkage analysis of this region in multiplex families, derived from a population base, has generated negative results. Thus, given the Dw2 specificity association, evidence implicating this locus in disease susceptibility appears contradictory. We have collected and determined the HLA-DR and -DQ haplotypes of 115 sibling pairs with multiple sclerosis, and confirm a significant association with the Dw2-associated haplotype, both in index cases and their affected siblings compared with controls. However, using a sibling pair linkage analysis that restricts haplotype sharing probabilities to defined genetic models, we have not observed linkage of this region to susceptibility in MS. We discuss the basis for association and linkage and conclude that the DR15, DQ6, Dw2 haplotype does represent a susceptibility locus but its contribution to the pathogenesis is small; although it may interact epistatically with other susceptibility genes, this haplotype is not necessary for disease expression.

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↗