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1086 The effect of IL13 polymorphism in atopic dermatitis (AD) and high total serum IgE level
S370
Abstracts
1085
Interaction Between Loci on Chromosomes 1.29 and 17q Increases Susceptibility to Elevated Total IgE in Two Distinct Populations KC Barnes*, R Nickel*. RA Mathias*. LR Freidhoff, V Casolaro*. ML Stockton*, X Xue*, E Ehrlich*, RP Naidut. PN Lmettf, C Schou*. S-K Huang*, A Togias*, TH Beary* *Johns Hopkins Univ., Baltimore, MD tUniv. West Indies. Barbados Conventional approaches used to test models of inheritance and linkage have not been sufficient for understanding the complexity of the inflammatory and immunological network, and the ‘atopy’ phenotype(s) is’undoubtedly dependent upon many genes (polygenes). There is, therefore, potential value in considering the effects of two unlinked regions simultaneously for complex traits such as allergic airway disease. Using the new extension of GENEHUNTER, we evaluated whether conditioning on linkage evidence (non-parametric linkage [NPL] scores) in one region of the genome significantly alters evidence for linkage in a second region, which would constitute evidence for interaction between the two regions. In order to test the hypothesis that a locus on chromosome 12q21.31 interacts with an unlinked locus/loci on l7ql l.2-q21.2, we conducted multipoint allele-sharing analyses using NPL methods on 33 Afro-Caribbean families from Barbados (N=528 subjects) to test specifically for evidence of genegene interactions. We observed a significant correlation in linkage for individual families at D12Sl052 and Dl7Sl293 for elevated total IgE (baseline LOD=O. 19; conditioned LOD=2.17; 02=6.43), which was driven largely by one multiplex family (23 subjects, I6 affected individuals). A similar interaction was observed for Dl2S1052 and Dl7Sl299 (baseline LOD=0.39; conditioned LOD=2.18; 02=5.41). To replicate our findings in an independent population, we conducted two-point linkage analysis (SIBPAL) of l2q and l7q markers and multiplex families from the isolated Tangier Island, Virginia population (N=l05 subjects) and observed excessive allele-sharing at a marker near Dl2Sl052 (Dl2S313, PcO.05). but not at any of the l7q markers. Preliminary analyses on IBD sharing among all relative-pairs showed significant correlations between Dl2Sl052 and Dl7Sl293 I Dl7Sl299, which were stronger when restricted to those pairs with excess sharing at Dl2Sl052 (P
1088
The Effect of IL13 Polymorphism in Atopic Dermatitis (AD) and High Total Serum IgE Level X Liu*, R Nickelf#. K Beyert#, U Wahn#, L Freidhoff’f. J Forsterg. F Zeppl. V Wahn$. T Beaty*, SK Huangf *Department of Epidemiology, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD 21205 tDivision of Clinical Immunology, Johns Hopkins University, School of Medicine, Baltimore, MD 21224 $Department of Pediatrics, Humboldt University, Berlin, Germany BDepartment of Pediatrics, University Hospital Freiburg, Germany IDepartment of Pediatrics, University Hospital Mainz. Germany §Department of Pediatrics, University Hospital Dsseldorf, Germany
J ALLERGY CLIN IMMUNOL JANUARY 2000
The molecular genetic basis of allergic diseases is currently unclear, and IL13 has been shown to be important in the regulation of IgE synthesis and allergic inflammation. In a search for genetic polymorphism of the IL13 gene and possible association with atopic disease, we have conducted mutational analyses of the proximal promoter, the coding region and the 3’ untranslated region of IL13 gene by using Single-Stranded Conformation Polymorphism and DNA sequencing. We identified a coding-region polymorphism at bp-388 (388G-A), which results in a change in amino acid residue I29 from arginine to glutamine. Subsequently, we screened 604 children from the German Multicenter Allergy Study (MAS-90) for this polymorphism and performed two casecontrol studies for phenotypes AD (including1 87 patients with AD and 98 non-AD controls) and high IgE (including 100 high IgE cases and 1 I I low IgE controls). There are statistically significant association between the presence of -388A allele and these two phenotypes with ORs I .77 (95% CI: I .06-2.96; P=O.O3) for AD and 2.38 (95%CI: I .34-4.2; p=O.O026) for high IgE respectively. We conclude that this IL13 coding region variant may be involved in the pathogenesis of AD and high total serum IgE level.
1087
Genetic Variability at the Promoter Region of p2 Adrenoceptor Gene (ADRB2) and Bronchial Hyperresponsiveness (BHR): A Population Study M D’Amato*. L Ricci Vitiani*, S Boninif. P Matricardi.# *Institute of Cell Biology and of CNR. ‘iExperimental Medicine and *Lab. Immunology and Allergology-DASRS-RMAS, Rome, Italy The Bz adrenergic receptor gene (ADRBZ) is polymorphic and several studies have shown that the genetic variability at positions I6 (Arg/Gly) and 27 (Gln/Glu) can influence the outcome of the asthmatic phenotype. In a previous work. we described the haplotypic combinations of these two polimorphisms at a population level. in relation to a constant bronchial hyperresponsiveness (BHR), determined by a serial measurement of the response to a methacoline challenge provocation test. We found that the haplotype Glyl6-Gln27 was associated with bronchial hyperresponsiveness also after correction for other confounding variables, such as total and specific IgE levels, thus proposing this variant as an unrelated risk factor for the development of BHR. However, based on functional data previously obtained by other groups, a clear-cut explanation of the above mentioned association could not be provided. The level of expression of the SZ adrenoceptor is controlled in part by a short peptide encoded upstream the ADRB2 gene (beta upstream peptide, BUP). Recently, a polymorphism within BUP coding sequence has been described (Argl9uUPCysl9auP). which is in linkage disequilibrium with the aforementioned positions 16 and 27. and that was shown to influence the level of expression of the corresponding receptor. In this study, we sought to determine whethere this polymorphism could account for the association with BHR that we observed in our population. 5’-BUP polymorphism was typed by a PCR-RFLP method on all samples previously chracterized for positions I6 and 27 and, where possible, haplotypic combination for all three loci were determined. While both alleles showed comparable frequencies (ArgI9uoP 32% and Cysl9a’JP 68%, respectively), only three haplotypes were found among those that could be determined: Arg19aUP-
Abstracts
1085
Interaction Between Loci on Chromosomes 1.29 and 17q Increases Susceptibility to Elevated Total IgE in Two Distinct Populations KC Barnes*, R Nickel*. RA Mathias*. LR Freidhoff, V Casolaro*. ML Stockton*, X Xue*, E Ehrlich*, RP Naidut. PN Lmettf, C Schou*. S-K Huang*, A Togias*, TH Beary* *Johns Hopkins Univ., Baltimore, MD tUniv. West Indies. Barbados Conventional approaches used to test models of inheritance and linkage have not been sufficient for understanding the complexity of the inflammatory and immunological network, and the ‘atopy’ phenotype(s) is’undoubtedly dependent upon many genes (polygenes). There is, therefore, potential value in considering the effects of two unlinked regions simultaneously for complex traits such as allergic airway disease. Using the new extension of GENEHUNTER, we evaluated whether conditioning on linkage evidence (non-parametric linkage [NPL] scores) in one region of the genome significantly alters evidence for linkage in a second region, which would constitute evidence for interaction between the two regions. In order to test the hypothesis that a locus on chromosome 12q21.31 interacts with an unlinked locus/loci on l7ql l.2-q21.2, we conducted multipoint allele-sharing analyses using NPL methods on 33 Afro-Caribbean families from Barbados (N=528 subjects) to test specifically for evidence of genegene interactions. We observed a significant correlation in linkage for individual families at D12Sl052 and Dl7Sl293 for elevated total IgE (baseline LOD=O. 19; conditioned LOD=2.17; 02=6.43), which was driven largely by one multiplex family (23 subjects, I6 affected individuals). A similar interaction was observed for Dl2S1052 and Dl7Sl299 (baseline LOD=0.39; conditioned LOD=2.18; 02=5.41). To replicate our findings in an independent population, we conducted two-point linkage analysis (SIBPAL) of l2q and l7q markers and multiplex families from the isolated Tangier Island, Virginia population (N=l05 subjects) and observed excessive allele-sharing at a marker near Dl2Sl052 (Dl2S313, PcO.05). but not at any of the l7q markers. Preliminary analyses on IBD sharing among all relative-pairs showed significant correlations between Dl2Sl052 and Dl7Sl293 I Dl7Sl299, which were stronger when restricted to those pairs with excess sharing at Dl2Sl052 (P
1088
The Effect of IL13 Polymorphism in Atopic Dermatitis (AD) and High Total Serum IgE Level X Liu*, R Nickelf#. K Beyert#, U Wahn#, L Freidhoff’f. J Forsterg. F Zeppl. V Wahn$. T Beaty*, SK Huangf *Department of Epidemiology, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD 21205 tDivision of Clinical Immunology, Johns Hopkins University, School of Medicine, Baltimore, MD 21224 $Department of Pediatrics, Humboldt University, Berlin, Germany BDepartment of Pediatrics, University Hospital Freiburg, Germany IDepartment of Pediatrics, University Hospital Mainz. Germany §Department of Pediatrics, University Hospital Dsseldorf, Germany
J ALLERGY CLIN IMMUNOL JANUARY 2000
The molecular genetic basis of allergic diseases is currently unclear, and IL13 has been shown to be important in the regulation of IgE synthesis and allergic inflammation. In a search for genetic polymorphism of the IL13 gene and possible association with atopic disease, we have conducted mutational analyses of the proximal promoter, the coding region and the 3’ untranslated region of IL13 gene by using Single-Stranded Conformation Polymorphism and DNA sequencing. We identified a coding-region polymorphism at bp-388 (388G-A), which results in a change in amino acid residue I29 from arginine to glutamine. Subsequently, we screened 604 children from the German Multicenter Allergy Study (MAS-90) for this polymorphism and performed two casecontrol studies for phenotypes AD (including1 87 patients with AD and 98 non-AD controls) and high IgE (including 100 high IgE cases and 1 I I low IgE controls). There are statistically significant association between the presence of -388A allele and these two phenotypes with ORs I .77 (95% CI: I .06-2.96; P=O.O3) for AD and 2.38 (95%CI: I .34-4.2; p=O.O026) for high IgE respectively. We conclude that this IL13 coding region variant may be involved in the pathogenesis of AD and high total serum IgE level.
1087
Genetic Variability at the Promoter Region of p2 Adrenoceptor Gene (ADRB2) and Bronchial Hyperresponsiveness (BHR): A Population Study M D’Amato*. L Ricci Vitiani*, S Boninif. P Matricardi.# *Institute of Cell Biology and of CNR. ‘iExperimental Medicine and *Lab. Immunology and Allergology-DASRS-RMAS, Rome, Italy The Bz adrenergic receptor gene (ADRBZ) is polymorphic and several studies have shown that the genetic variability at positions I6 (Arg/Gly) and 27 (Gln/Glu) can influence the outcome of the asthmatic phenotype. In a previous work. we described the haplotypic combinations of these two polimorphisms at a population level. in relation to a constant bronchial hyperresponsiveness (BHR), determined by a serial measurement of the response to a methacoline challenge provocation test. We found that the haplotype Glyl6-Gln27 was associated with bronchial hyperresponsiveness also after correction for other confounding variables, such as total and specific IgE levels, thus proposing this variant as an unrelated risk factor for the development of BHR. However, based on functional data previously obtained by other groups, a clear-cut explanation of the above mentioned association could not be provided. The level of expression of the SZ adrenoceptor is controlled in part by a short peptide encoded upstream the ADRB2 gene (beta upstream peptide, BUP). Recently, a polymorphism within BUP coding sequence has been described (Argl9uUPCysl9auP). which is in linkage disequilibrium with the aforementioned positions 16 and 27. and that was shown to influence the level of expression of the corresponding receptor. In this study, we sought to determine whethere this polymorphism could account for the association with BHR that we observed in our population. 5’-BUP polymorphism was typed by a PCR-RFLP method on all samples previously chracterized for positions I6 and 27 and, where possible, haplotypic combination for all three loci were determined. While both alleles showed comparable frequencies (ArgI9uoP 32% and Cysl9a’JP 68%, respectively), only three haplotypes were found among those that could be determined: Arg19aUP-