Publications
396 results found
Palmer LJ, Paré PD, Faux JA, et al., 1997, Fc epsilon R1-beta polymorphism and total serum IgE levels in endemically parasitized Australian aborigines., Am J Hum Genet, Vol: 61, Pages: 182-188, ISSN: 0002-9297
Endemic helminthic infection is a major public-health problem and affects a large proportion of the world's population. In Australia, helminthic infection is endemic in Aboriginal communities living in tropical northern regions of the continent. Such infection is associated with nonspecific (polyclonal) stimulation of IgE synthesis and highly elevated total serum IgE levels. There is evidence that worm-infection variance (i.e., human capacity of resistance) and total serum IgE levels may be related to the presence of a major codominant gene. The beta chain of the high-affinity IgE receptor, Fc epsilon R1-beta, has been previously identified as a candidate for the close genetic linkage of the 11q13 region to IgE responses in several populations. We show a biallelic RsaI polymorphism in Fc epsilon R1-beta to be associated with total serum IgE levels (P = .0001) in a tropical population of endemically parasitized Australian Aborigines (n = 234 subjects). The polymorphism explained 12.4% of the total residual variation in serum total IgE and showed a significant (P = .0000) additive relationship with total serum IgE levels, across the three genotypes. These associations were independent of familial correlations, age, gender, racial admixture, or smoking status. Alleles of a microsatellite repeat in intron 5 of the same gene showed similar associations. The results suggest that variation in Fc epsilon R1-beta may regulate IgE-mediated immune responses in this population.
Dekker JW, Nizankowska E, Schmitz-Schumann M, et al., 1997, Aspirin-induced asthma and HLA-DRB1 and HLA-DPB1 genotypes., Clin Exp Allergy, Vol: 27, Pages: 574-577, ISSN: 0954-7894
BACKGROUND: Aspirin-induced asthma (AIA) affects one in 10 individuals with adult-onset asthma. It is not known if aspirin sensitivity is due to immune mechanisms or to interference with biochemical pathways. OBJECTIVE: The study aimed to test for possible involvement of the genes of the Major Histocompatibility Complex (MHC) in AIA. METHODS: HLA-DPB1 and HLA-DRB1 genotyping was carried out by DNA methods in 59 patients with positive challenge tests for AIA and in 48 normal and 57 asthmatic controls. RESULTS: The DPB1*0301 frequency was increased in AIA patients when compared with normal controls (19.5% vs 5.2%, Odds Ratio = 4.4, 95% Confidence Interval (CI) 1.6-12.1, P = 0.002), and compared with asthmatic controls (4.4%, OR = 5.3, 95% CI = 1.9-14.4, P = 0.0001). The frequency of DPB1*0401 in AIA subjects was decreased when compared with normal controls (28.8% vs 49.0%, OR = 0.42, 95% CI = 0.24-0.74, P = 0.003) and asthmatic controls (45.6%, OR = 0.48, 95% CI = 0.28-0.83, P = 0.008). The results remained significant when corrected for multiple comparisons. There were no significant HLA-DRB1 associations with AIA. CONCLUSION: The presence of an HLA association suggests that immune recognition of an unknown antigen may be part of the aetiology of AIA.
Faux JA, Moffatt MF, Lalvani A, et al., 1997, Sensitivity to bee and wasp venoms: Association with specific IgE responses to the bee and wasp venom and HLA DRB1 and DPB1, CLINICAL AND EXPERIMENTAL ALLERGY, Vol: 27, Pages: 578-583, ISSN: 0954-7894
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- Citations: 13
Moffatt MF, Cookson WO, 1997, Tumour necrosis factor haplotypes and asthma., Hum Mol Genet, Vol: 6, Pages: 551-554, ISSN: 0964-6906
Airway inflammation is a prominent feature of asthma. The pro-inflammatory cytokine Tumour Necrosis Factor shows constitutional variation in its level of secretion, which is linked to polymorphisms within the TNF gene complex and the surrounding MHC. In this study, 413 subjects in 88 nuclear families from a general population sample were examined for association with asthma and TNF polymorphisms. Ninety-two subjects were asthmatic, as defined by questionnaire. Asthma was significantly more common in subjects with allele 1 of the LT alpha NcoI polymorphism (LT alpha NcoI*1) (p = 0.005), and allele 2 of the TNF-308 polymorphism (TNF-308*2) (p = 0.004). The association was confined to the LT alpha NcoI*1/TNF-308*2 haplotype, so that it was not possible to differentiate between the effects of LT alpha NcoI and TNF-308 alleles. The HLA-DR locus was excluded as a cause of this association. The results suggest that genetic influences on inflammation may be important in the pathogenesis of asthma.
Cookson WO, Moffatt MF, 1997, Asthma: an epidemic in the absence of infection?, Science, Vol: 275, Pages: 41-42, ISSN: 0036-8075
Moffatt MF, Cookson WOCM, 1997, Linkage and candidate gene studies in asthma, ISSN: 1073-449X
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- Citations: 25
Moffatt MF, Schou C, Faux JA, et al., 1997, Germline TCR-A restriction of immunoglobulin E responses to allergen., Immunogenetics, Vol: 46, Pages: 226-230, ISSN: 0093-7711
Immunoglobulin E responses to known environmental antigens (allergens) may serve as a general model to investigate germline genetic restriction of the immune response. We have previously shown genetic linkage between IgE responses to major allergens and the T-cell receptor (TCR) A/D locus, but not to TCR-B, implying that elements in TCR A/D restrict the ability to react to specific antigens. We now show, in two sets of subjects from the same population, a strong allelic association between a VA8.1 polymorphism (VA8.1(*)2) and reactivity to Der p II, a major antigenic component of the house dust mite Dermatophagoides pteronyssinus. Association was also seen between Der p II IgE titres and HLA-DRB1(*)1501 alleles. Reactivity to Der p II was confined to subjects who were positive for VA8.1(*)2 and HLA-DRB1(*)1501, demonstrating germline HLA-DR and TCR-A interaction in restricting the response to exogenous antigen.
Daniels SE, Bhattacharrya S, James A, et al., 1996, A genome-wide search for quantitative trait loci underlying asthma, NATURE, Vol: 383, Pages: 247-250, ISSN: 0028-0836
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- Citations: 631
Walley AJ, Cookson WO, 1996, Investigation of an interleukin-4 promoter polymorphism for associations with asthma and atopy., J Med Genet, Vol: 33, Pages: 689-692, ISSN: 0022-2593
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.
Hill MR, Cookson WO, 1996, A new variant of the beta subunit of the high-affinity receptor for immunoglobulin E (Fc epsilon RI-beta E237G): associations with measures of atopy and bronchial hyper-responsiveness., Hum Mol Genet, Vol: 5, Pages: 959-962, ISSN: 0964-6906
The high affinity receptor for IgE (Fc epsilon RI) has a central role in mast cell degranulation and IgE mediated allergy. A systematic search through the coding regions of the beta subunit of Fc epsilon RI (Fc epsilon RI-beta) has identified a novel coding polymorphism in exon seven. An adenine to guanine substitution changes amino acid residue 237 from glutamic acid to glycine (E237G), in the cytoplasmic tail of the protein. E237G is predicted to introduce a hydrophobicity change within the C-terminus of Fc epsilon RI-beta. It is adjacent to the immunoreceptor tyrosine activation motif (ITAM), and may affect the intracellular signalling capacity of Fc epsilon RI. E237G was detected in 53 subjects from an Australian general population sample of 1004 individuals (5.3%). E237G positive subjects had a significantly elevated skin test response to grass (p = 0.0004) and house dust mite (p = 0.04), RAST to grass (p = 0.002) and bronchial reactivity to methacholine (p = 0.0009). The relative risk of individuals with E237G having asthma compared to subjects without the variant was 2.3 (95% CI 1.26-4.19; p = 0.005).
Moffatt M, Cookson W, 1996, Naked DNA: new shots for allergy?, Nat Med, Vol: 2, Pages: 515-516, ISSN: 1078-8956
Cookson W, 1996, Genetic factors in asthma., Pages: 55-60, ISSN: 0065-2598
Moffatt MF, Cookson WO, 1996, The genetics of specific allergy., Monogr Allergy, Vol: 33, Pages: 71-96, ISSN: 0077-0760
Cookson WO, 1995, 11q and high-affinity IgE receptor in asthma and allergy., Pages: 71-73, ISSN: 0954-7894
Hill MR, James AL, Faux JA, et al., 1995, Fc epsilon RI-beta polymorphism and risk of atopy in a general population sample., BMJ, Vol: 311, Pages: 776-779, ISSN: 0959-8138
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.
Hill MR, Cookson WO, 1995, Reply to “Atopy in Australia”, Nature Genetics, Vol: 10, ISSN: 1061-4036
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Young RP, Barker RD, Pile KD, et al., 1995, The association of HLA-DR3 with specific IgE to inhaled acid anhydrides., Am J Respir Crit Care Med, Vol: 151, Pages: 219-221, ISSN: 1073-449X
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.
DIZIER MH, HILL M, JAMES A, et al., 1995, DETECTION OF A RECESSIVE MAJOR GENE FOR HIGH IGE LEVELS ACTING INDEPENDENTLY OF SPECIFIC RESPONSE TO ALLERGENS, GENETIC EPIDEMIOLOGY, Vol: 12, Pages: 93-105, ISSN: 0741-0395
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- Citations: 50
Cookson W, 1994, Atopy: a complex genetic disease., Ann Med, Vol: 26, Pages: 351-353, ISSN: 0785-3890
Cookson W, 1994, The genetics of atopy., J Allergy Clin Immunol, Vol: 94, Pages: 643-644, ISSN: 0091-6749
Moffatt MF, Hill MR, Cornélis F, et al., 1994, Genetic linkage of T-cell receptor alpha/delta complex to specific IgE responses., Lancet, Vol: 343, Pages: 1597-1600, ISSN: 0140-6736
IgE responses to inhaled proteins underlie the clinical syndrome of allergic (atopic) asthma and rhinitis. We have investigated genetic linkage between specific IgE reactions to highly purified major allergens and the T-cell receptor (TCR) alpha and beta gene complexes on chromosome 14 and 7, respectively. Antigens tested included highly purified proteins from the housedust mite Dermatophagoides pteronyssinus, the domestic cat and dog, grass pollen, and the mould Alternaria alternata. Affected sibling-pair methods were used in two independent sets of families, one in the UK and one in Australia. No linkage of IgE serotypes to TCR-beta was detected, but significant linkage to TCR-alpha was seen in both family groups. For several of the IgE phenotypes investigated (positive responses to whole allergen sources or purified antigens or serum IgE above the 70th percentile in the population) the affected sibling-pairs showed significant sharing of TCR-alpha microsatellite alleles from both parents. The results show that a gene (or genes) in the TCR-alpha region modifies specific IgE responses.
Shirakawa T, Li A, Dubowitz M, et al., 1994, Association between atopy and variants of the beta subunit of the high-affinity immunoglobulin E receptor., Nat Genet, Vol: 7, Pages: 125-129, ISSN: 1061-4036
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.
Young RP, Dekker JW, Wordsworth BP, et al., 1994, HLA-DR and HLA-DP genotypes and immunoglobulin E responses to common major allergens., Clin Exp Allergy, Vol: 24, Pages: 431-439, ISSN: 0954-7894
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.
STAFFORD AN, RIDER SH, HOPKIN JM, et al., 1994, A 2.8 MB YAC CONTIG IN 11Q12-Q13 LOCALIZES CANDIDATE GENES FOR ATOPY - FC-EPSILON-RI-BETA AND CD20, HUMAN MOLECULAR GENETICS, Vol: 3, Pages: 779-785, ISSN: 0964-6906
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- Citations: 29
de Klerk NH, Musk AW, Cookson WO, et al., 1993, Radiographic abnormalities and mortality in subjects with exposure to crocidolite., Br J Ind Med, Vol: 50, Pages: 902-906, ISSN: 0007-1072
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.
SANDFORD AJ, SHIRAKAWA T, MOFFATT MF, et al., 1993, LOCALIZATION OF ATOPY AND BETA-SUBUNIT OF HIGH-AFFINITY IGE RECEPTOR (FC-EPSILON-RI) ON CHROMOSOME-11Q, LANCET, Vol: 341, Pages: 332-334, ISSN: 0140-6736
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- Citations: 259
Koerffy A, Polla BS, Philippe J, et al., 1993, [Asthma, allergy, current aspects. Report of the "3A" of 23 May 1992: genetics of asthma and atopy]., Pages: 55-60, ISSN: 0035-3655
Cookson WO, 1993, Genetic aspects of atopy., Monogr Allergy, Vol: 31, Pages: 171-189, ISSN: 0077-0760
Moffatt MF, Sharp PA, Faux JA, et al., 1992, Factors confounding genetic linkage between atopy and chromosome 11q., Clin Exp Allergy, Vol: 22, Pages: 1046-1051, ISSN: 0954-7894
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.
Cook JT, Hattersley AT, Christopher P, et al., 1992, Linkage analysis of glucokinase gene with NIDDM in Caucasian pedigrees., Diabetes, Vol: 41, Pages: 1496-1500, ISSN: 0012-1797
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.
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