Does genetic regulation of IgE begin in utero? Evidence from T H1/TH2 gene polymorphisms and cord blood total IgE

Xiumei Hong; Hui Ju Tsai; Xin Liu; Lester Arguelles; Rajesh Kumar; Guoying Wang; Nataliya Kuptsova-Clarkson; Colleen Pearson; Kathryn Ortiz; Anthony Bonzagni; Stephanie Apollon; Lingling Fu; Jacqueline A. Pongracic; Robert Schleimer; Patrick G. Holt; Howard Bauchner; Xiaobin Wang

doi:10.1016/j.jaci.2010.08.029

Does genetic regulation of IgE begin in utero? Evidence from T _H1/T_H2 gene polymorphisms and cord blood total IgE

Xiumei Hong, Hui Ju Tsai, Xin Liu, Lester Arguelles, Rajesh Kumar, Guoying Wang, Nataliya Kuptsova-Clarkson, Colleen Pearson, Kathryn Ortiz, Anthony Bonzagni, Stephanie Apollon, Lingling Fu, Jacqueline A. Pongracic, Robert Schleimer, Patrick G. Holt, Howard Bauchner, Xiaobin Wang^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

Abstract

Background: Elucidation of early life factors is critical to understand the development of allergic diseases, especially those manifesting in early life such as food allergies and atopic dermatitis. Cord blood IgE (CBIgE) is a recognized risk factor for the subsequent development of allergic diseases. In contrast with numerous genetic studies of total serum IgE in children and adults, limited genetic studies on CBIgE have been conducted. Objective: To test the associations between functional or tagging single nucleotide polymorphisms (SNPs) in genes involved in the T_H1/T_H2 pathway and CBIgE in a large US inner-city birth cohort. Methods: CBIgE, measured by Phadia ImmnunoCAP, was analyzed as a continuous and a binary variable. The association of each SNP with the 2 outcomes was tested using tobit and logistic regression models, respectively, with adjustment for pertinent covariates, ancestral proportion, and multiple testing. Ethnic heterogeneity and gene-gene interactions were also explored. Results: Three SNPs (rs1800925, rs2069743, and rs1295686) in the IL13 gene were significantly associated with CBIgE concentration (P ≤ 6 × 10^-4, FDR-corrected P < .05). These SNPs jointly influenced CBIgE in a dose-response manner (P for trend = 9 × 10^-8). Significant associations also were observed for SNPs in the IL-13 receptor α1 (rs5956080) and signal transducer and activator of transcription 6 (rs11172106) genes. Ethnicity-specific genetic effects were observed for SNPs in the IL5 and GATA3 genes. Several gene-gene interactions (including IL13-IL4 receptor and IL13-signal transducer and activator of transcription 6 interactions) were detected in relation to CBIgE. Conclusion: Our data demonstrated that multiple SNPs were individually and jointly associated with CBIgE, with evidence of gene-gene interactions and ethnic heterogeneity. These findings suggest that genetic regulation of IgE may begin in utero.

Original language	English (US)
Pages (from-to)	1059-1067.e1
Journal	Journal of Allergy and Clinical Immunology
Volume	126
Issue number	5
DOIs	https://doi.org/10.1016/j.jaci.2010.08.029
State	Published - Nov 2010

Funding

The parent study is supported in part by the March of Dimes PERI grants ( PI: X.W., 20-FY02-56 ), NIEHS ( PI: X.W., R21 ES011666 ), and NICHD ( PI: X.W., R01 HD041702 ). The follow-up study is supported in part by the Food Allergy Initiative and NIAID ( PI: X.W., R21AI079872 ). R.K. is supported by the NHLBI ( K23HL093023 ). X.L. has been supported by a career development award from the National Institutes of Health/Clinical and Translational Science Awards Program, Northwestern University ( KL2RR025740 ). X.L. also is supported by an NIAID grant ( R21AI087888 ). Disclosure of potential conflict of interest: R. Kumar has received research support from the National Heart, Lung, and Blood Institute . J. A. Pongracic has received research support from the National Institute of Allergy and Infectious Diseases and the Food Allergy Project . R. Schleimer has received research support from the National Institutes of Health . The rest of the authors have declared that they have no conflict of interest.

Keywords

Candidate gene
Cord blood IgE
Gene-gene interaction
Genetic association

ASJC Scopus subject areas

Immunology and Allergy
Immunology

Access to Document

10.1016/j.jaci.2010.08.029

Cite this

Hong, X., Tsai, H. J., Liu, X., Arguelles, L., Kumar, R., Wang, G., Kuptsova-Clarkson, N., Pearson, C., Ortiz, K., Bonzagni, A., Apollon, S., Fu, L., Pongracic, J. A., Schleimer, R., Holt, P. G., Bauchner, H., & Wang, X. (2010). Does genetic regulation of IgE begin in utero? Evidence from T _H1/T_H2 gene polymorphisms and cord blood total IgE. Journal of Allergy and Clinical Immunology, 126(5), 1059-1067.e1. https://doi.org/10.1016/j.jaci.2010.08.029

@article{5f6786d1b5e54d6a9cebdc2bfb63cd9d,

title = "Does genetic regulation of IgE begin in utero? Evidence from T H1/TH2 gene polymorphisms and cord blood total IgE",

abstract = "Background: Elucidation of early life factors is critical to understand the development of allergic diseases, especially those manifesting in early life such as food allergies and atopic dermatitis. Cord blood IgE (CBIgE) is a recognized risk factor for the subsequent development of allergic diseases. In contrast with numerous genetic studies of total serum IgE in children and adults, limited genetic studies on CBIgE have been conducted. Objective: To test the associations between functional or tagging single nucleotide polymorphisms (SNPs) in genes involved in the TH1/TH2 pathway and CBIgE in a large US inner-city birth cohort. Methods: CBIgE, measured by Phadia ImmnunoCAP, was analyzed as a continuous and a binary variable. The association of each SNP with the 2 outcomes was tested using tobit and logistic regression models, respectively, with adjustment for pertinent covariates, ancestral proportion, and multiple testing. Ethnic heterogeneity and gene-gene interactions were also explored. Results: Three SNPs (rs1800925, rs2069743, and rs1295686) in the IL13 gene were significantly associated with CBIgE concentration (P ≤ 6 × 10-4, FDR-corrected P < .05). These SNPs jointly influenced CBIgE in a dose-response manner (P for trend = 9 × 10-8). Significant associations also were observed for SNPs in the IL-13 receptor α1 (rs5956080) and signal transducer and activator of transcription 6 (rs11172106) genes. Ethnicity-specific genetic effects were observed for SNPs in the IL5 and GATA3 genes. Several gene-gene interactions (including IL13-IL4 receptor and IL13-signal transducer and activator of transcription 6 interactions) were detected in relation to CBIgE. Conclusion: Our data demonstrated that multiple SNPs were individually and jointly associated with CBIgE, with evidence of gene-gene interactions and ethnic heterogeneity. These findings suggest that genetic regulation of IgE may begin in utero.",

keywords = "Candidate gene, Cord blood IgE, Gene-gene interaction, Genetic association",

author = "Xiumei Hong and Tsai, {Hui Ju} and Xin Liu and Lester Arguelles and Rajesh Kumar and Guoying Wang and Nataliya Kuptsova-Clarkson and Colleen Pearson and Kathryn Ortiz and Anthony Bonzagni and Stephanie Apollon and Lingling Fu and Pongracic, {Jacqueline A.} and Robert Schleimer and Holt, {Patrick G.} and Howard Bauchner and Xiaobin Wang",

note = "Funding Information: The parent study is supported in part by the March of Dimes PERI grants ( PI: X.W., 20-FY02-56 ), NIEHS ( PI: X.W., R21 ES011666 ), and NICHD ( PI: X.W., R01 HD041702 ). The follow-up study is supported in part by the Food Allergy Initiative and NIAID ( PI: X.W., R21AI079872 ). R.K. is supported by the NHLBI ( K23HL093023 ). X.L. has been supported by a career development award from the National Institutes of Health/Clinical and Translational Science Awards Program, Northwestern University ( KL2RR025740 ). X.L. also is supported by an NIAID grant ( R21AI087888 ). Funding Information: Disclosure of potential conflict of interest: R. Kumar has received research support from the National Heart, Lung, and Blood Institute . J. A. Pongracic has received research support from the National Institute of Allergy and Infectious Diseases and the Food Allergy Project . R. Schleimer has received research support from the National Institutes of Health . The rest of the authors have declared that they have no conflict of interest. ",

year = "2010",

month = nov,

doi = "10.1016/j.jaci.2010.08.029",

language = "English (US)",

volume = "126",

pages = "1059--1067.e1",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Elsevier Inc.",

number = "5",

}

Hong, X, Tsai, HJ, Liu, X, Arguelles, L, Kumar, R, Wang, G, Kuptsova-Clarkson, N, Pearson, C, Ortiz, K, Bonzagni, A, Apollon, S, Fu, L, Pongracic, JA , Schleimer, R, Holt, PG, Bauchner, H & Wang, X 2010, 'Does genetic regulation of IgE begin in utero? Evidence from T _H1/T_H2 gene polymorphisms and cord blood total IgE', Journal of Allergy and Clinical Immunology, vol. 126, no. 5, pp. 1059-1067.e1. https://doi.org/10.1016/j.jaci.2010.08.029

TY - JOUR

T1 - Does genetic regulation of IgE begin in utero? Evidence from T H1/TH2 gene polymorphisms and cord blood total IgE

AU - Hong, Xiumei

AU - Tsai, Hui Ju

AU - Liu, Xin

AU - Arguelles, Lester

AU - Kumar, Rajesh

AU - Wang, Guoying

AU - Kuptsova-Clarkson, Nataliya

AU - Pearson, Colleen

AU - Ortiz, Kathryn

AU - Bonzagni, Anthony

AU - Apollon, Stephanie

AU - Fu, Lingling

AU - Pongracic, Jacqueline A.

AU - Schleimer, Robert

AU - Holt, Patrick G.

AU - Bauchner, Howard

AU - Wang, Xiaobin

N1 - Funding Information: The parent study is supported in part by the March of Dimes PERI grants ( PI: X.W., 20-FY02-56 ), NIEHS ( PI: X.W., R21 ES011666 ), and NICHD ( PI: X.W., R01 HD041702 ). The follow-up study is supported in part by the Food Allergy Initiative and NIAID ( PI: X.W., R21AI079872 ). R.K. is supported by the NHLBI ( K23HL093023 ). X.L. has been supported by a career development award from the National Institutes of Health/Clinical and Translational Science Awards Program, Northwestern University ( KL2RR025740 ). X.L. also is supported by an NIAID grant ( R21AI087888 ). Funding Information: Disclosure of potential conflict of interest: R. Kumar has received research support from the National Heart, Lung, and Blood Institute . J. A. Pongracic has received research support from the National Institute of Allergy and Infectious Diseases and the Food Allergy Project . R. Schleimer has received research support from the National Institutes of Health . The rest of the authors have declared that they have no conflict of interest.

PY - 2010/11

Y1 - 2010/11

N2 - Background: Elucidation of early life factors is critical to understand the development of allergic diseases, especially those manifesting in early life such as food allergies and atopic dermatitis. Cord blood IgE (CBIgE) is a recognized risk factor for the subsequent development of allergic diseases. In contrast with numerous genetic studies of total serum IgE in children and adults, limited genetic studies on CBIgE have been conducted. Objective: To test the associations between functional or tagging single nucleotide polymorphisms (SNPs) in genes involved in the TH1/TH2 pathway and CBIgE in a large US inner-city birth cohort. Methods: CBIgE, measured by Phadia ImmnunoCAP, was analyzed as a continuous and a binary variable. The association of each SNP with the 2 outcomes was tested using tobit and logistic regression models, respectively, with adjustment for pertinent covariates, ancestral proportion, and multiple testing. Ethnic heterogeneity and gene-gene interactions were also explored. Results: Three SNPs (rs1800925, rs2069743, and rs1295686) in the IL13 gene were significantly associated with CBIgE concentration (P ≤ 6 × 10-4, FDR-corrected P < .05). These SNPs jointly influenced CBIgE in a dose-response manner (P for trend = 9 × 10-8). Significant associations also were observed for SNPs in the IL-13 receptor α1 (rs5956080) and signal transducer and activator of transcription 6 (rs11172106) genes. Ethnicity-specific genetic effects were observed for SNPs in the IL5 and GATA3 genes. Several gene-gene interactions (including IL13-IL4 receptor and IL13-signal transducer and activator of transcription 6 interactions) were detected in relation to CBIgE. Conclusion: Our data demonstrated that multiple SNPs were individually and jointly associated with CBIgE, with evidence of gene-gene interactions and ethnic heterogeneity. These findings suggest that genetic regulation of IgE may begin in utero.

AB - Background: Elucidation of early life factors is critical to understand the development of allergic diseases, especially those manifesting in early life such as food allergies and atopic dermatitis. Cord blood IgE (CBIgE) is a recognized risk factor for the subsequent development of allergic diseases. In contrast with numerous genetic studies of total serum IgE in children and adults, limited genetic studies on CBIgE have been conducted. Objective: To test the associations between functional or tagging single nucleotide polymorphisms (SNPs) in genes involved in the TH1/TH2 pathway and CBIgE in a large US inner-city birth cohort. Methods: CBIgE, measured by Phadia ImmnunoCAP, was analyzed as a continuous and a binary variable. The association of each SNP with the 2 outcomes was tested using tobit and logistic regression models, respectively, with adjustment for pertinent covariates, ancestral proportion, and multiple testing. Ethnic heterogeneity and gene-gene interactions were also explored. Results: Three SNPs (rs1800925, rs2069743, and rs1295686) in the IL13 gene were significantly associated with CBIgE concentration (P ≤ 6 × 10-4, FDR-corrected P < .05). These SNPs jointly influenced CBIgE in a dose-response manner (P for trend = 9 × 10-8). Significant associations also were observed for SNPs in the IL-13 receptor α1 (rs5956080) and signal transducer and activator of transcription 6 (rs11172106) genes. Ethnicity-specific genetic effects were observed for SNPs in the IL5 and GATA3 genes. Several gene-gene interactions (including IL13-IL4 receptor and IL13-signal transducer and activator of transcription 6 interactions) were detected in relation to CBIgE. Conclusion: Our data demonstrated that multiple SNPs were individually and jointly associated with CBIgE, with evidence of gene-gene interactions and ethnic heterogeneity. These findings suggest that genetic regulation of IgE may begin in utero.

KW - Candidate gene

KW - Cord blood IgE

KW - Gene-gene interaction

KW - Genetic association

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