褪黑激素受体1A（MTNR1A）内的DNA甲基化介导了哮喘合并鼻炎病人父系基因遗传变异效应
2016/11/09
摘要
背景：哮喘和过敏性鼻炎（AR）是常见的过敏性并发症，有较强的遗传因素，可能与表观遗传密切相关。
目的:我们的目的是考虑到父亲遗传的影响，确定哮喘和过敏性鼻炎新的风险位点。
方法：我们进行了一系列的遗传分析，考虑到父亲遗传在哮喘家庭中的影响：（1）在 615个欧洲家庭中进行哮喘和过敏性鼻炎的全基因组连锁扫描（2）在162个法国遗传学和哮喘环境流行病学研究家庭中进行了覆盖重要连锁区域的1233个单核苷酸多态性（SNP）的关联分析，在154个Saguenay-Lac-Saint-Jean哮喘研究家庭中重复，和（3）在40个Saguenay-Lac-Saint-Jean哮喘家庭中进行了疾病与CpG 位点DNA甲基化(DNAm)显著的SNPs关联分析。
结果：我们发现4q35区域与哮喘合并过敏性鼻炎合并症是一个显著的父系连锁（AAR；P = 7.2×10（- 5））。对这个区域的关联分析强有力地证明了父系遗传的G等位基因rs10009104对AAR影响（P = 1.1×10（- 5），达到多重检验校正阈值）。这个父系遗传的等位基因也明显与cg02303933位点的DNA甲基化水平（P = 1.7×10（- 4））显著相关。在这个位点的DNA甲基化的差异介导了SNP-AAR之间的联系。
结论：通过整合遗传和表观遗传数据，我们发现在褪黑激素受体1A（MTNR1A）基因中不同的甲基化CpG位点介导了哮喘合并过敏性鼻炎合并症中父系遗传基因变异。该研究提供了表观遗传机制在呼吸道过敏性疾病患者中作用的新视角。
（苏欣 审校）
JAllergy Clin Immunol. 2016 Sep;138(3):748-53. doi: 10.1016/j.jaci.2015.12.1341. Epub 2016 Mar 30.
DNA methylation within melatonin receptor 1A (MTNR1A) mediates paternally transmitted genetic variant effect on asthma plus rhinitis.
Sarnowski C1, Laprise C2, Malerba G3, Moffatt MF4, Dizier MH1, Morin A5, Vincent QB6, Rohde K7, Esparza-Gordillo J8, Margaritte-Jeannin P1, Liang L9,Lee YA7, Bousquet J10, Siroux V11, Pignatti PF3, Cookson WO4, Lathrop M12, Pastinen T12, Demenais F1, Bouzigon E13.
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Abstract
BACKGROUND:Asthma and allergic rhinitis (AR) are common allergic comorbidities with a strong genetic component in which epigenetic mechanisms might be involved.
OBJECTIVE:We aimed to identify novel risk loci for asthma and AR while accounting for parent-of-origin effect.
METHODS:We performed a series of genetic analyses, taking into account the parent-of-origin effect in families ascertained through asthma: (1) genome-wide linkage scan of asthma and AR in 615 European families, (2) association analysis with 1233 single nucleotide polymorphisms (SNPs) covering the significant linkage region in 162 French Epidemiological Study on the Genetics and Environment of Asthma families with replication in 154 Canadian Saguenay-Lac-Saint-Jean asthma study families, and (3) association analysis of disease and significant SNPs with DNA methylation (DNAm) at CpG sites in 40 Saguenay-Lac-Saint-Jean asthma study families.
RESULTS:We detected a significant paternal linkage of the 4q35 region to asthma and allergic rhinitis comorbidity (AAR; P = 7.2 × 10(-5)). Association analysis in this region showed strong evidence for the effect of the paternally inherited G allele of rs10009104 on AAR (P = 1.1 × 10(-5), reaching the multiple-testing corrected threshold). This paternally inherited allele was also significantly associated with DNAm levels at the cg02303933 site (P = 1.7 × 10(-4)). Differential DNAm at this site was found to mediate the identified SNP-AAR association.
CONCLUSION:By integrating genetic and epigenetic data, we identified that a differentially methylated CpG site within the melatonin receptor 1A (MTNR1A) gene mediates the effect of a paternally transmitted genetic variant on the comorbidity of asthma and AR. This study provides a novel insight into the role of epigenetic mechanisms in patients with allergic respiratory diseases.
Copyright © 2016 American Academy of Allergy, Asthma & Immunology. All rights reserved.
KEYWORDS:DNA methylation; Linkage analysis; allergic rhinitis; asthma; genetic association study; parent-of-origin effect; positional cloning
JAllergy Clin Immunol. 2016 Sep;138(3):748-53. doi: 10.1016/j.jaci.2015.12.1341. Epub 2016 Mar 30.
