Polymorphisms related to ORMDL3 are associated with asthma susceptibility, alterations in transcriptional regulation of ORMDL3, and changes in T_H2 cytokine levels

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• 作者：Michaela Schedel ; PhD^b ; ^c ; Sven Michel ; PhD^a ; ^c ; Vincent D. Gaertner ; BSc^a ; Antoaneta A. Toncheva ; PhD^a ; ^c ; Martin Depner ; PhD^d ; Aristea Binia ; PhD^a ; ⁿ ; Maximilian Schieck ; PhD^a ; ^c ; Marie T. Rieger ; MD^d ; Norman Klopp ; PhD^e ; ^f ; Andrea von Berg ; MD^g ; Albrecht Bufe ; MD^h ; Otto Laub ; MD^d ; Ernst Rietschel ; MDⁱ ; Andrea Heinzmann ; MD^j ; Burkard Simma ; MD^k ; Christian Vogelberg ; MD^l ; Jon Genuneit ; MD^m ; Thomas Illig ; PhD^e ; ^f ; Michael Kabesch ; MD^a ; ^c ; ^{michael.kabesch@ukr.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Asthma ; association study ; polymorphism ; ORMDL3 ; chromosome 17q21 ; promoter activity ; TH2 cytokine ; upstream stimulatory factor ; transcriptional regulation
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2015
• 出版时间：October 2015
• 年：2015
• 卷：136
• 期：4
• 页码：893-903.e14
• 全文大小：2251 K

文摘

Chromosome 17q21, harboring the orosomucoid 1-like 3 (ORMDL3) gene, has been consistently associated with childhood asthma in genome-wide association studies.

Objective

We investigated genetic variants in and around ORMDL3 that can change the function of ORMDL3 and thus contribute to asthma susceptibility.

Methods

We performed haplotype analyses and fine mapping of the ORMDL3 locus in a cross-sectional (International Study of Asthma and Allergies in Childhood Phase II, n = 3557 total subjects, n = 281 asthmatic patients) and case-control (Multicenter Asthma Genetics in Childhood Study/International Study of Asthma and Allergies in Childhood Phase II, n = 1446 total subjects, n = 763 asthmatic patients) data set to identify putative causal single nucleotide polymorphisms (SNPs) in the locus. Top asthma-associated polymorphisms were analyzed for allele-specific effects on transcription factor binding and promoter activity in vitro and gene expression in PBMCs after stimulation ex vivo.

Results

Two haplotypes (H1 and H2) were significantly associated with asthma in the cross-sectional (P = 9.9 × 10⁻⁵ and P = .0035, respectively) and case-control (P = 3.15 × 10⁻⁸ and P = .0021, respectively) populations. Polymorphisms rs8076131 and rs4065275 were identified to drive these effects. For rs4065275, a quantitative difference in transcription factor binding was found, whereas for rs8076131, changes in upstream stimulatory factor 1 and 2 transcription factor binding were observed in vitro by using different cell lines and PBMCs. This might contribute to detected alterations in luciferase activity paralleled with changes in ORMDL3 gene expression and IL-4 and IL-13 cytokine levels ex vivo in response to innate and adaptive stimuli in an allele-specific manner. Both SNPs were in strong linkage disequilibrium with asthma-associated 17q21 SNPs previously related to altered ORMDL3 gene expression.

Conclusion

Polymorphisms in a putative promoter region of ORMDL3, which are associated with childhood asthma, alter transcriptional regulation of ORMDL3, correlate with changes in T_H2 cytokines levels, and therefore might contribute to the childhood asthma susceptibility signal from 17q21.