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Biomedical subjects

W O Cookson

Publications and source records attributed to W O Cookson.

At least 73 records · Page 4Linked to original sources
PubMed1996

Investigation of an interleukin-4 promoter polymorphism for associations with asthma and atopy.

The cytokine cluster located on chromosome 5 has been shown by linkage studies to play a role in the genetic determination of circulating immunoglobulin E (IgE) levels in atopic subjects. In the study presented here, the reported chromosome 5 linkage has been investigated in two sets of subjects. The first consisted of a general population sample of 230 nuclear families (n = 1004) from Busselton, a small West Australian country town. The second group consisted of 124 unrelated atopic asthmatics and 59 unrelated non-atopic, non-asthmatic controls, all resident in the Oxfordshire Regional Health Authority area in the United Kingdom. A previously reported interleukin-4 (II-4) promoter polymorphism (-590 C-->T) was analysed in these populations by a newly designed method of specific PCR amplification and BsmFI restriction endonuclease digestion. In the Busselton population the polymorphism was shown to be weakly associated with specific IgE to house dust mite (Mann-Whitney-U test, p = 0.013) and to wheeze (MWU test, p = 0.029), but not with specific IgE to grass pollen, total serum IgE, bronchial hyperresponsiveness, eosinophil count, or asthma. In the Oxfordshire subjects there were no statistically significant associations with any measure of asthma or atopy. These data show that the -590 C-->T II-4 promoter polymorphism is only weakly associated with certain measures of asthma and atopy in some subjects. It was specifically not associated with serum IgE concentration or asthma in either of the two groups in this study.

Adolescent↗
PubMed1995

Fc epsilon RI-beta polymorphism and risk of atopy in a general population sample.

OBJECTIVE: To establish the prevalence of Fc epsilon RI-beta polymorphisms Leu181 and Leu181/Leu183 on chromosome 11q13 in the general population and to examine whether when maternally inherited they confer a risk of atopy. DESIGN: A population based survey for measures of atopy (skin prick test reactions, specific IgE titres, total serum IgE concentration), bronchial hyperresponsiveness, and carriage of Fc epsilon RI-beta Leu181 and Leu181/Leu183. SETTING: The rural coastal town of Busselton, Western Australia. SUBJECTS: 1004 members of 230 two generation families identified through adults aged under 55. RESULTS: Fc epsilon RI-beta Leu181/Leu183 was identified in 45 subjects (4.5%). All 13 children who had inherited the variant maternally were atopic. Six had asthma and nine rhinitis. The odds ratio of a positive skin prick test reaction to house dust mite or grass pollen in these children compared with the other 523 children was 7.37 (95% confidence interval 1.62 to 33.60). The 95% confidence interval for the odds ratio of a positive specific IgE response (radio-allergosorbent test) was 3.00 to infinity, and the odds ratio for bronchial hyperresponsiveness was 3.70 (1.21 to 11.60). By contrast, the eight children who had derived the variant paternally had negative skin prick and radioallergosorbent test results and did not have increased bronchial responsiveness. CONCLUSION: Fc epsilon RI"' beta Leu181/Leu183 when inherited maternally identifies a genetic risk factor for atopy and bronchial hyperresponsiveness.

Adolescent↗
PubMed1995

A genetic map of chromosome 11q, including the atopy locus.

Atopy is a common and genetically heterogeneous syndrome predisposing to allergic asthma and rhinitis. A locus linked to the atopy phenotype has been shown to be present on chromosome 11q12-13. Linkage has only been seen in maternally derived alleles. We have constructed a genetic linkage map of the region, using 15 markers to span approximately 27 cM, and integrate previously published maps. Under a model of maternal inheritance, the atopy locus is placed within a 7-cM interval between D11S480 and D11S451. The interval contains the important candidate gene FCERIB.

Alleles↗
PubMed1995

The association of HLA-DR3 with specific IgE to inhaled acid anhydrides.

We have undertaken a case referent study of the association between HLA allele frequency and specific IgE antibody to acid anhydride-human serum albumin (AA-HSA) conjugates among acid anhydride workers. Thirty cases with radio-allergosorbent test score versus AA-HSA conjugates > 2 were compared with 30 referents without specific IgE selected from the same factory sites as the cases and matched for age, sex, duration of exposure, atopic status, and smoking habit. We found a significant excess of HLA-DR3 in the cases with specific IgE to acid anhydrides when compared with the referents (50% versus 14%, Fisher's statistic = 8.4; odds ratio = 6, p = 0.05 corrected). The excess of HLA-DR3 was particularly associated with IgE versus trimellitic anhydride, with HLA-DR3 present in eight of 11 workers with and in two of 14 referents without IgE (Fisher's statistic = 8.5, odds ratio = 16, p = 0.004). The proportion of HLA-DR3 among the phthalic anhydride workers was not different in those with IgE (two of 12) from their referents (two of 14). These findings suggest MHC II proteins are an important determinant of the specificity of the IgE response to an inhaled hapten.

Adolescent↗
PubMed1994

Association between atopy and variants of the beta subunit of the high-affinity immunoglobulin E receptor.

The beta-subunit of the high-affinity IgE receptor (Fc epsilon RI-beta) on chromosome 11 is maternally linked to atopy, the state of enhanced IgE responsiveness underlying allergic asthma and rhinitis. We have identified a common variant of Fc epsilon RI-beta, lle181Leu within the 4th transmembrane domain. Leu181 shows significant association with positive IgE responses in a random patient sample. Amongst 60 unrelated nuclear families with allergic asthmatic probands, Leu181 is identified in 10 (17%), is maternally inherited in each, and shows a strong association with atopy. Our data indicate that Fc epsilon RI-beta, subject to maternal modification, may be the atopy-causing locus on chromosome 11q.

Amino Acid Sequence↗
PubMed1994

A 2.8 Mb YAC contig in 11q12-q13 localizes candidate genes for atopy: Fc epsilon RI beta and CD20.

An important locus for Atopy (familial asthma, hay fever and eczema) has been localized to the 11q12-q13 region with the minimum recombination fraction around the CD20 gene. We have constructed a 2.8 megabase (Mb) Yeast Artificial Chromosome (YAC) contig of the candidate region using 15 STSs. A total of seven genes have been mapped within this interval in the order cen-OSBP-TCN1-GIF-Fc epsilon RI beta-CD20-CD5-PGA-q(ter) and can be covered by a minimum of eight YAC clones. Contig integrity was assayed with fluorescence in-situ hybridization (FISH) and the mapping of YAC ends on somatic cell and radiation hybrid panels. A long range restriction map of the contig has been constructed to establish the order of and distance between loci. Two promising candidates for the atopy locus, the beta subunit of the high affinity immunoglobulin E receptor (Fc epsilon RI beta) and CD20, a molecule involved in B cell differentiation, have been placed within the contig.

Antigens, CD↗
PubMed1994

HLA-DR and HLA-DP genotypes and immunoglobulin E responses to common major allergens.

In order to test for human histocompatibility leucocyte antigens (HLA) class II restriction of IgE responses, 431 subjects from 83 families were genotyped at the HLA-DR and HLA-DP loci and serotyped for IgE responses to six major allergens from common aero-allergen sources. A possible excess of HLA-DR1 was found in subjects who were responsive to Fel d I compared with those who were not (Odds Ratio (OR) = 2, P = 0.002), and a possible excess of HLA-DR4 was found in subjects responsive to Alt a I (OR = 1.9, P = 0.006). Increased sharing of HLA-DR/DP haplotypes was seen in sibling pairs responding to both allergens. Der p I, Der p II, Phl p V and Can f I were not associated with any definite excess of HLA-DR alleles. No significant correlations were seen with HLA-DP genotype and reactivity to any of the allergens. The results suggest class II HLA restriction is insufficient to account for individual differences in reactivity to common allergens.

Alleles↗
PubMed1993

Localisation of atopy and beta subunit of high-affinity IgE receptor (Fc epsilon RI) on chromosome 11q.

Atopy, a common familial syndrome underlying allergic asthma and rhinitis, is characterised by sustained immunoglobulin E (IgE) responses to common allergens. We have previously shown genetic linkage of atopy to the chromosome 11q13 marker D11S97 (pms51) through maternally derived alleles, but no likely candidate genes were known to lie near this marker. We have analysed maternally derived alleles from 155 sibling-pairs affected by atopy to seek evidence of linkage between the gene predisposing to atopy and other markers on chromosome 11q13. We found that the beta subunit of the high-affinity receptor for IgE (Fc epsilon RI-beta) also lies on chromosome 11q13, and that it is in close genetic linkage with the gene for atopy. The known roles of Fc epsilon RI in antigen-induced mast-cell degranulation and in the release of cytokines that enhance IgE production make the gene for its beta subunit a candidate for the chromosome 11 atopy locus.

Chromosome Mapping↗
PubMed1993

Radiographic abnormalities and mortality in subjects with exposure to crocidolite.

Plain chest radiographs from a one in six random sample of the workforce of the asbestos industry at Wittenoom, Western Australia between 1943 and 1966 have been classified for degree of profusion and pleural thickening by two independent observers according to the 1980 UICC-ILO Classification of Radiographs for the pneumoconioses to clarify the effect of degree of radiological abnormality on survival. A total of 1106 subjects were selected. Each subject's age, cumulative exposure to crocidolite, and time since first exposure were determined from employment records, the results of a survey of airborne concentrations of fibres > 5 mu in length conducted in 1966, and an exposure rating by an industrial hygienist and an ex-manager of the mine and mill at Wittenoom. By the end of 1986 193 subjects had died. Conditional logistic regression was used to model the relative risk of death in five separate case-control analyses in which the outcomes were deaths from: (1) all causes, (2) malignant mesothelioma, (3) lung cancer, (4) asbestosis, and (5) other causes excluding cancer and asbestosis. Up to 20 controls per case were randomly chosen from all men of the same age who were not known to have died before the date of death of the index case. After adjustment for exposure and time since first exposure, there were significant and independent effects of radiographic profusion and pleural thickening on all cause mortality. The effect of profusion was largely a result of the effect on mortality from malignant mesothelioma and asbestosis but not lung cancer. The effect of pleural thickening was greatest on mortality from other causes, mainly ischaemic heart disease. This study has shown that degree of radiographic abnormality has an independent effect on mortality from malignant mesothelioma, asbestosis, and all causes even after allowing for the effects of age, degree of exposure, and time since first exposure.

Asbestos, Crocidolite↗
PubMed1992

Maternal inheritance of atopic IgE responsiveness on chromosome 11q.

Atopy is a common familial state underlying allergic asthma and rhinitis. Lately, we have assigned a gene for atopy to chromosome 11q by linkage to the marker D11S97. Since previous studies have suggested that the risk of atopy is higher for children of atopic mothers than for those of atopic fathers, we sought differences between maternal and paternal patterns of transmission at the 11q13 locus among pairs of siblings in families affected by atopy. When we defined atopy as the presence of a positive skinprick test (greater than or equal to 2 mm) to any of a panel of common allergens, a higher than normal concentration of total serum IgE, or a positive radioallergosorbent test for a specific IgE, we found that 125 (62%) of the sibling-pairs affected by atopy shared the maternal 11q13 allele and 78 (38%) did not. This distribution differs significantly from the expected 50/50 distribution (p = 0.001). Of paternally derived alleles, 83 (46%) were shared and 96 (54%) were not (not significantly different from 50/50). The result was similar whatever definition of atopy was used and with other genetic markers on 11q. These findings show that transmission of atopy at the chromosome 11q locus is detectable only through the maternal line. The pattern of inheritance is consistent either with paternal genomic imprinting or with maternal modification of developing immune responses.

Alleles↗
PubMed1992

Factors confounding genetic linkage between atopy and chromosome 11q.

The results of testing for linkage between atopy and the chromosome 11 marker D11S97 is shown for all the 723 subjects genotyped by us up to January 1992. Lod score estimations were confounded by the high population prevalence of atopy, maternal inheritance of atopy at the 11q locus, genetic heterogeneity, and excess of atopy in families not ascertained through a single proband. Affected sib-pair analysis shows evidence for linkage which is not dependent on the definition of atopy or model specification. We suggest that presentation of sib-pair data will be suitable for meta-analysis of the different studies of genetic linkage and atopy.

Alleles↗
PubMed1992

Confirmation of genetic linkage between atopic IgE responses and chromosome 11q13.

Genetic linkage between atopic IgE responses and chromosome 11q13 (D11S97) has been previously reported in a limited number of extended families. Difficulties of phenotyping in the older family members, poor family structure in some families, and genetic heterogeneity were proposed as possible explanations for the variability in lod scores. To test this finding a second linkage study of 64 young nuclear families was undertaken and gave a two point lod score of 3.8 at theta = 0.07 (assuming theta m = theta f). A test of genetic heterogeneity in the nuclear families shows that atopic IgE responses are linked to this locus in 60 to 100% of families (approximate 95% confidence limits).

Adolescent↗
PubMed1992

Linkage analysis of glucokinase gene with NIDDM in Caucasian pedigrees.

NIDDM has a strong genetic component, as evidenced by the high level of concordance between identical twins. The nature of the genetic predisposition has remained largely unknown. Recently, the glucokinase gene locus on chromosome 7p has been shown to be linked to a subtype of NIDDM known as MODY in French and British pedigrees, and glucokinase mutations have been identified. To study the relationship between the glucokinase gene and NIDDM, we performed a linkage analysis in 12 Caucasian pedigrees ascertained through a proband with classical NIDDM. The LINKAGE program was used under four models, including autosomal dominant and recessive, with individuals with glucose intolerance counted as either affected or of unknown status. Linkage was significantly rejected with the dominant models (LOD scores -4.65, -4.25), and was unlikely with the recessive model when glucose intolerance was considered as affected (LOD score -1.38). These findings suggest that mutations in or near the glucokinase gene are unlikely to be the major cause of the inherited predisposition to NIDDM in Caucasian pedigrees, but do not exclude a role for this locus with a polygenic model, or a major role in some pedigrees.

Adult↗
PubMed1991

Relative risks of bronchial hyper-responsiveness associated with skin-prick test responses to common antigens in young adults.

We studied 143 young subjects by skin-prick testing to common allergens and by the measurement of non-specific bronchial responsiveness (NSBR). A logistic regression model showed a prevalence odds ratio (POR) for bronchial hyper-responsiveness (PD20 less than 10 mumol methacholine) in house dust positive subjects of 4.10 (95% CI 1.77-9.51, P less than 0.001), and in mould positive subjects 5.72 (95% CI 2.06-15.9, P less than 0.001): the PORs for epithelia (2.05, P = 0.12) and grasses (1.78, P = 0.19) were not significant. If bronchial reactivity was assessed as measurable (PD20 less than 102 mumol methacholine) or not, the POR for house-dust-positive subjects was 4.83 (95% CI 2.23-10.5, P less than 0.001), for moulds was 10.5 (95% CI 2.33-47.5, P less than 0.001), for epithelia was 4.79 (95% CI 1.91-12.0, P less than 0.001), and for grasses was 2.21 (95% CI 1.11-4.4, P = 0.022). The results show the risk of bronchial hyper-responsiveness is greater in subjects sensitive to house dust and mould than in those reactive to grasses, and suggests that the presence or absence of increased NSBR in atopic individuals may depend on the antigens to which they become sensitized.

Adolescent↗