Publications
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Moffatt MF, Schou C, Faux JA, et al., 2001, Association between quantitative traits underlying asthma and the HLA-DRB1 locus in a family-based population sample, EUROPEAN JOURNAL OF HUMAN GENETICS, Vol: 9, Pages: 341-346, ISSN: 1018-4813
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- Citations: 60
Cookson WO, Ubhi B, Lawrence R, et al., 2001, Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci., Nat Genet, Vol: 27, Pages: 372-373, ISSN: 1061-4036
We have carried out a genome screen for atopic dermatitis (AD) and have identified linkage to AD on chromosomes 1q21, 17q25 and 20p. These regions correspond closely with known psoriasis loci, as does a previously identified AD locus on chromosome 3q21. The results indicate that AD is influenced by genes with general effects on dermal inflammation and immunity.
Abecasis GR, Noguchi E, Heinzmann A, et al., 2001, Extent and Distribution of Linkage Disequilibrium in Three Genomic Regions., American Journal of Human Genetics, Vol: 68, Pages: 191-197, ISSN: 0002-9297
The positional cloning of genes underlying common complex diseases relies on the identification of linkage disequilibrium (LD) between genetic markers and disease. We have examined 127 polymorphisms in three genomic regions in a sample of 575 chromosomes from unrelated individuals of British ancestry. To establish phase, 800 individuals were genotyped in 160 families. The fine structure of LD was found to be highly irregular. Forty-five percent of the variation in disequilibrium measures could be explained by physical distance. Additional factors, such as allele frequency, type of polymorphism, and genomic location, explained <5% of the variation. Nevertheless, disequilibrium was occasionally detectable at 500 kb and was present for over one-half of marker pairs separated by <50 kb. Although these findings are encouraging for the prospects of a genomewide LD map, they suggest caution in interpreting localization due to allelic association.
Kurz T, Strauch K, Heinzmann A, et al., 2000, A European study on the genetics of mite sensitization, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 106, Pages: 925-932, ISSN: 0091-6749
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- Citations: 41
Cookson WO, Moffatt MF, 2000, Genetics of asthma and allergic disease., Hum Mol Genet, Vol: 9, Pages: 2359-2364, ISSN: 0964-6906
Atopic (allergic) asthma is the most common disease of childhood and is strongly genetic in origin. Many genome-wide screens for asthma and its associated traits have now been carried out, and genetic linkage has been consistently identified in several regions. It is probable that these loci contain major genes influencing atopy and asthma. Candidate genes have already been identified from the cytokine cluster on chromosome 5 and the MHC on chromosome 6. These complex regions contain more than one susceptibility locus for allergic disease. Other regions do not contain obvious candidate genes, and positional cloning of these loci is likely to identify novel disease pathways. Parent-of-origin effects are prominent at some of the loci and some also show linkage to other inflammatory immune diseases. Several single gene disorders are associated with allergic disease and on occasion are also linked to the same chromosomal regions. The positional cloning of asthma genes is now feasible.
Ober C, Moffatt MF, 2000, Contributing factors to the pathobiology. The genetics of asthma., Clin Chest Med, Vol: 21, Pages: 245-261, ISSN: 0272-5231
Markers in 19 chromosomal regions have shown some evidence of linkage to asthma, atopy, or related phenotypes in multiple independent genome-wide searches. Linkages to five of these regions (5q, 6p, 11q, 12q, and 13q) have also been reported in non-genome-wide screens. In addition, at least two independent studies have reported linkages to markers on 16p. Numerous candidate genes in these regions have shown varying levels of association to asthma or atopic phenotypes, potentially implicating them as disease susceptibility loci. These include the IL4, CD14, and B2ADR genes on 5q, the HLA-DRB1 and TNF genes on 6p, the FCERB1 and CC16 genes on 11q, and the IL4RA gene on 16p. It still remains to be determined whether polymorphisms in these genes account for the reported linkages in these regions. Studies are underway in laboratories around the world to identify the disease-causing variations in these genes that account for the linkages just discussed. Identifying specific genetic polymorphisms that influence asthma and atopic phenotypes will shed light on the molecular pathways involved in these complex disorders and provide a better understanding of the pathophysiology of asthma and atopy.
Moffatt MF, Traherne JA, Abecasis GR, et al., 2000, Single nucleotide polymorphism and linkage disequilibrium within the TCR alpha/delta locus., Hum Mol Genet, Vol: 9, Pages: 1011-1019, ISSN: 0964-6906
Much attention is being given to the identification of common disease genes through whole-genome linkage disequilibrium (LD) screens with single nucleotide polymorphisms (SNPs). Simulation studies have suggested that useful LD is unlikely to extend beyond 3 kb, and that > 500,000 SNPs may be needed for comprehensive coverage of the genome. The TCR alpha/delta locus on chromosome 14q contains many V, J and D segments that combine with constant domains to produce either an alpha or a delta chain of the T cell receptor. Multiple SNPs have been recognized within the V segments, and it has been suggested that variation within the locus may modify the course of autoimmune and allergic diseases. We have examined LD within an 850 kb section of the TCR alpha/delta locus on chromosome 14q by typing 24 V gene segment SNPs and two microsatellites. One hundred and fifty-nine nuclear and extended families were genotyped in order to derive haplotypes, and the pair-wise LD between SNPs was investigated in 600 haplotypes from unrelated individuals (the parents). The mean extent of useful LD was much greater than suggested by simulations: significant LD was relatively common at 250 kb and was detectable beyond 500 kb. The mean extent of LD was twice as far between alleles of low frequency than between common alleles. The distribution of LD was highly irregular and concentrated in three distinct islands. The results differ from those obtained by simulation, and if they are typical of other genomic regions, suggest that the minimum number of markers necessary for comprehensive LD mapping may be reduced by at least an order of magnitude.
Cookson WOC, Moffatt MF, 2000, Genetics of asthma and allergic disease, Human Molecular Genetics, Vol: 9, Pages: 2359-2364, ISSN: 0964-6906
Atopic (allergic) asthma is the most common disease of childhood and is strongly genetic in origin. Many genome-wide screens for asthma and its associated traits have now been carried out, and genetic linkage has been consistently identified in several regions. It is probable that these loci contain major genes influencing atopy and asthma. Candidate genes have already been identified from the cytokine cluster on chromosome 5 and the MHC on chromosome 6. These complex regions contain more than one susceptibility locus for allergic disease. Other regions do not contain obvious candidate genes, and positional cloning of these loci is likely to identify novel disease pathways. Parent-of-origin effects are prominent at some of the loci and some also show linkage to other inflammatory immune diseases. Several single gene disorders are associated with allergic disease and on occasion are also linked to the same chromosomal regions. The positional cloning of asthma genes is now feasible.
Moffatt MF, Cookson WO, 1999, Genetics of asthma and inflammation: the status., Curr Opin Immunol, Vol: 11, Pages: 606-609, ISSN: 0952-7915
Genome-wide screens are consistently finding linkage between asthma-associated traits and specific chromosomal loci. Several loci coincide with linkages to other inflammatory diseases, suggesting the presence of common pathways in their pathogenesis. Candidate-gene studies have found an association between a CD14 polymorphism and IgE levels, suggesting a mechanism for the increased prevalence of allergic disease. A polymorphism in Fc epsilon RI-beta shows parent-of-origin effects when associated with severe infantile eczema, further illustrating the complexity of gene-environment effects on the developing immune system.
Palmer LJ, Rye PJ, Gibson NA, et al., 1999, Association of FcepsilonR1-beta polymorphisms with asthma and associated traits in Australian asthmatic families., Clin Exp Allergy, Vol: 29, Pages: 1555-1562, ISSN: 0954-7894
BACKGROUND: Asthma is a genetically complex disease, and is characterized by elevated serum immunoglobulin E (IgE) levels, elevated blood eosinophil counts and increased airway responsiveness. Polymorphisms in the beta subunit of the high affinity receptor for IgE (FcepsilonR1-beta) have been previously associated with these phenotypes and with an increased risk of asthma. OBJECTIVE: To investigate the association of all known bi-allelic polymorphisms in FcepsilonR1-beta to asthma and quantitative traits associated with asthma in a selected sample of Australian asthmatic children and their nuclear families. METHODS: Australian Caucasian nuclear families (n = 134 subjects) were recruited on the basis of a child proband with current, severe, symptomatic asthma. The quantitative traits assessed included serum levels of total IgE and specific IgE to house dust mite and mixed grass, blood eosinophil counts and the dose-response slope of the forced expiratory volume in 1 s to histamine provocation. RESULTS: Neither the Leu181 nor the E237G mutations were detected in this population. Allele B of RsaI intron 2 (RsaI_in2*B) was significantly associated with physician-diagnosed asthma (ever) (P = 0.002). Alleles of both the RsaI_in2 and RsaI exon 7 (RsaI_ex7) polymorphisms were significantly associated with loge total serum IgE levels and the combined RAST index. RsaI_ex7 was also associated with loge blood eosinophil counts. These associations were independent of age, sex and familial correlations. CONCLUSION: This study supports a role for the FcepsilonR1-beta gene or a nearby gene in the pathogenesis of asthma.
Moffatt MF, James A, Ryan G, et al., 1999, Extended tumour necrosis factor/HLA-DR haplotypes and asthma in an Australian population sample., Thorax, Vol: 54, Pages: 757-761, ISSN: 0040-6376
BACKGROUND: Tumour necrosis factor (TNF) is a potent pro-inflammatory cytokine which is prominent in asthmatic airways. TNF shows genetic variations in secretion which are linked to polymorphisms in the TNF gene complex and the surrounding major histocompatibility (MHC) locus. These polymorphisms do not seem to be themselves functionally important. In these circumstances, the identification of disease associated haplotypes (combination of alleles on individual chromosomes) may narrow the search for polymorphisms which alter gene function. METHODS: TNF-308, LTalpha NcoI, and HLA-DRB1 polymorphisms were investigated for association with asthma, bronchial responsiveness, and medication use in 1004 subjects in 230 families from a general population sample. RESULTS: The common LTalpha NcoI*1/TNF-308*2/HLA-DRB1*03 haplotype, which was present in 11% of unrelated individuals, was weakly associated with asthma (OR = 1.38, p = 0.016, corrected for familial correlation). The rarer LTalpha NcoI*1/TNF-308*2/HLA-DRB1*02 haplotype, which was found in 0.6% of unrelated subjects, was more strongly associated with asthma (OR = 6.68, p = 0.002). This haplotype also showed association with bronchial hyperresponsiveness (OR = 21.9, p = 0. 0000) and the use of inhaled or oral steroids (OR 8.0, p = 0.04). CONCLUSIONS: The results of this study show only two extended TNF/HLA-DR haplotypes to be associated with asthma. The search for functional alleles responsible for an increased risk of asthma should concentrate on the LTalpha NcoI*1/TNF-308*2/HLA-DRB1*02 haplotype.
Moffatt MF, Cookson WO, 1999, Gene therapy for peanut allergy., Nat Med, Vol: 5, Pages: 380-381, ISSN: 1078-8956
Dizier MH, James A, Faux J, et al., 1999, Segregation analysis of the specific response to allergens: A recessive major gene controls the specific IgE response to timothy grass pollen, Genetic Epidemiology, Vol: 16, Pages: 305-315, ISSN: 0741-0395
Segregation analysis of the specific response to allergens (SRA) was performed in a sample of 234 randomly selected Australian families using the regressive models. Various SRA phenotypes were considered using broad and narrow definitions of these phenotypes, according to the type of test used, skin test or RAST test, and the specificity of the response to allergen. Strong evidence for familial dependencies among blood relatives was shown for most SRA phenotypes, especially when using a broad definition. There was no evidence for a Mendelian factor accounting for the familial transmission of these broadest phenotypes, which may involve multiple factors preventing the clear detection of a major effect with Mendelian transmission. However, segregation of a Mendelian recessive major gene was detected for one SRA sub- phenotype, the IgE response to a single allergen, Timothy grass pollen, measured by the RAST test. Identification of a specific SRA phenotype controlled by a major gene may have important implications for further linkage studies.
Dizier MH, James A, Faux J, et al., 1999, Segregation analysis of the specific response to allergens: a recessive major gene controls the specific IgE response to Timothy grass pollen., Genet Epidemiol, Vol: 16, Pages: 305-315, ISSN: 0741-0395
Segregation analysis of the specific response to allergens (SRA) was performed in a sample of 234 randomly selected Australian families using the regressive models. Various SRA phenotypes were considered using broad and narrow definitions of these phenotypes, according to the type of test used, skin test or RAST test, and the specificity of the response to allergen. Strong evidence for familial dependencies among blood relatives was shown for most SRA phenotypes, especially when using a broad definition. There was no evidence for a Mendelian factor accounting for the familial transmission of these broadest phenotypes, which may involve multiple factors preventing the clear detection of a major effect with Mendelian transmission. However, segregation of a Mendelian recessive major gene was detected for one SRA sub-phenotype, the IgE response to a single allergen, Timothy grass pollen, measured by the RAST test. Identification of a specific SRA phenotype controlled by a major gene may have important implications for further linkage studies.
Moffatt MF, Cookson WO, 1998, Gene identification in asthma and allergy., Int Arch Allergy Immunol, Vol: 116, Pages: 247-252, ISSN: 1018-2438
Asthma and atopy are due to the interaction between genetic and environmental factors. The genetic basis of asthma and atopy is becoming more certain, with the promise of improvements in the diagnosis and treatment of these disorders. A combination of candidate gene and positional cloning studies has already identified several genes which influence allergic disease. These genes predispose in general to atopy, or influence the specific IgE response to individual allergens, or enhance inflammation independently of atopic mechanisms. In addition to these known factors, the chromosomal localisation of other putative genes is becoming clear.
Cookson WO, Moffatt MF, 1998, Alchemy for asthma., Nat Med, Vol: 4, Pages: 500-501, ISSN: 1078-8956
Moffatt MF, Cookson WOCM, 1998, Maternal effects in atopic disease, Pages: 56-61, ISSN: 0960-2178
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- Citations: 97
Moffatt MF, Cookson WO, 1998, The genetics of asthma. Maternal effects in atopic disease., Clin Exp Allergy, Vol: 28 Suppl 1, Pages: 56-61, ISSN: 0954-7894
Moffatt MF, Cookson WOCM, 1998, The genetics of asthma and allergy, Revue Francaise d'Allergologie et d'Immunologie Clinique, Vol: 38, ISSN: 0335-7457
Cox HE, Moffatt MF, Faux JA, et al., 1998, Association of atopic dermatitis to the beta subunit of the high affinity immunoglobulin E receptor., Br J Dermatol, Vol: 138, Pages: 182-187, ISSN: 0007-0963
IgE dysregulation is a major pathogenic feature of atopic dermatitis and other IgE-mediated allergic diseases such as asthma and rhinitis. Allergen complexed to IgE binds to the high affinity receptor for IgE (Fc epsilon RI) on the surface of epidermal Langerhans cells, mast cells and basophils, triggering the release of inflammatory mediators. The beta subunit of Fc epsilon RI has been localized to human chromosome 11q12-13, and variants within this gene have been shown to associate with asthma and measures of atopy. We have tested several polymorphisms within Fc epsilon RI-beta for association to atopic dermatitis in a panel of 60 families (panel A), recruited through a proband with atopic dermatitis. The findings were tested in a second panel of families (panel B). Significant sharing of maternal alleles was seen for atopic dermatitis and allele 2 of RsaI intron 2 (RsaIvin2*2) (P = 0.0022) and allele 1 of RsaI exon 7 (RsaIvex7*1) (P = 0.0036) Fc epsilon RI-beta gene polymorphisms. These findings were replicated in Panel B, confirming the association of Fc epsilon RI-beta RsaI polymorphisms with atopic dermatitis. The combined significance of the association of atopic dermatitis to RsaI polymorphisms was P = 0.0002 (RsaIvin2*2) and P = 0.00034 (RsaIvex7*1). The polymorphisms also showed association with asthma: P = 0.0068 (RsaIvin2*2) and P = 0.018 (RsaIvex7*1). Polymorphisms within the Fc epsilon RI-beta gene are strongly associated with atopic dermatitis.
Wiltshire S, Bhattacharyya S, Faux JA, et al., 1998, A genome scan for loci influencing total serum immunoglobulin levels: possible linkage of IgA to the chromosome 13 atopy locus., Hum Mol Genet, Vol: 7, Pages: 27-31, ISSN: 0964-6906
Immunoglobulins play an essential part in the immune system, and immunoglobulin deficiencies can have profound medical consequences. The genetic control and regulation of the immunoglobulin response is therefore of interest. Previous investigations have identified a number of loci influencing total and specific IgE levels. In this study, 80 nuclear families have been examined for linkage of total serum IgA, IgG and IgM levels to a genome-wide panel of microsatellite markers. Potential quantitative trait loci influencing IgA levels have been identified on chromosomes 10 and 13, and possible loci influencing IgG levels were found on chromosomes 3 and 13. No significant linkages to IgM levels were found. The linkage of IgA on chromosome 13 was to a marker previously linked to IgE responses (atopy). Linkage to IgG was in the same region but to a more distal marker. None of the factors known to influence immunoglobulin expression map to the loci identified in the present study. These loci are therefore likely to contain previously unrecognized components of the immunoregulatory system.
Moffatt MF, Cookson WO, 1997, Linkage and candidate gene studies in asthma., Am J Respir Crit Care Med, Vol: 156, Pages: S110-S112, ISSN: 1073-449X
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.
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.
Moffatt M, Cookson W, 1996, Naked DNA: new shots for allergy?, Nat Med, Vol: 2, Pages: 515-516, ISSN: 1078-8956
Moffatt MF, Cookson WO, 1996, The genetics of specific allergy., Monogr Allergy, Vol: 33, Pages: 71-96, ISSN: 0077-0760
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