Oral contraceptives modify the effect of GATA3 polymorphisms on the risk of asthma at the age of 18 years via DNA methylation.
Oral contraceptives modify the effect of GATA3 polymorphisms on the risk of asthma at the age of 18 years via DNA methylation.
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DOI：
10.1186/1868-7083-6-17
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发表时间：
2014
影响因子：
5.7
通讯作者：
Karmaus W
中科院分区：
文献类型：
--
作者：
Guthikonda K;Zhang H;Nolan VG;Soto-Ramírez N;Ziyab AH;Ewart S;Arshad HS;Patil V;Holloway JW;Lockett GA;Karmaus W
女孩的哮喘患病率在青春期后增加。先前的研究已经发现了性激素和哮喘之间的联系，以及性激素和辅助性T 2 （Th2）哮喘典型免疫反应之间的联系。因此，我们假设外源性或内源性性激素暴露（分别以口服避孕药（OCP）的使用和月经初潮早期为代表）与Th2转录因子基因GATA3的DNA甲基化（DNA- m）有关，进而影响女孩哮喘的风险，可能与遗传变异相互作用。从英国怀特岛出生队列中随机选择245名18岁女性进行甲基化分析。使用ocp、初潮年龄和并发哮喘的信息通过问卷进行评估。使用Illumina Infinium HumanMethylation450头芯片测定全基因组DNA-M。在第一阶段，我们测试了性激素暴露与特定胞嘧啶-磷酸-鸟嘌呤（CpG）位点DNA-M遗传变异之间的相互作用。在第二阶段，我们确定这些CpG位点是否与GATA3的遗传变异相互作用，以解释哮喘的风险。分析了14个CpG位点的OCP使用与GATA3的7个单核苷酸多态性（snp）之间的相互作用（阶段1）。发现OCP使用与SNP rs1269486之间的相互作用与cg17124583的甲基化水平相关（P = 0.002，假发现率（FDR）调整P = 0.04）。同一CpG位点的DNA-M也受初潮年龄与rs1269486的交互作用影响（P = 0.0017）。在第二阶段，我们发现cg17124583修改了SNP rs422628与18岁哮喘风险的关联（P = 0.006， FDR调整P = 0.04）。相对于基因型AA，当甲基化水平从0.02增加到0.12时，AG基因型受试者的平均风险比（RR）从0.31 （95% CI: 0.10 ~ 0.8）增加到11.65 （95% CI: 1.71 ~ 79.5）。一个由GATA3基因的遗传变异、OCP的使用、月经初潮年龄和DNA-M组成的两阶段模型可以解释女性性激素如何增加青春期后哮喘的患病率。
The prevalence of asthma in girls increases after puberty. Previous studies have detected associations between sex hormones and asthma, as well as between sex hormones and T helper 2 (Th2) asthma-typical immune responses. Therefore, we hypothesized that exogenous or endogenous sex hormone exposure (represented by oral contraceptive pill (OCP) use and early menarche, respectively) are associated with DNA methylation (DNA-M) of the Th2 transcription factor gene, GATA3, in turn affecting the risk of asthma in girls, possibly in interaction with genetic variants. Blood samples were collected from 245 female participants aged 18 years randomly selected for methylation analysis from the Isle of Wight birth cohort, UK. Information on use of OCPs, age at menarche, and concurrent asthma were assessed by questionnaire. Genome-wide DNA-M was determined using the Illumina Infinium HumanMethylation450 beadchip. In a first stage, we tested the interaction between sex hormone exposure and genetic variants on DNA-M of specific cytosine-phosphate-guanine (CpG) sites. In a second stage, we determined whether these CpG sites interact with genetic variants in GATA3 to explain the risk of asthma. Interactions between OCP use and seven single nucleotide polymorphisms (SNPs) of GATA3 were analyzed for 14 CpG sites (stage 1). The interaction between OCP use and SNP rs1269486 was found to be associated with the methylation level of cg17124583 (P = 0.002, false discovery rate (FDR) adjusted P = 0.04). DNA-M of this same CpG site was also influenced by the interaction between age at menarche and rs1269486 (P = 0.0017). In stage 2, we found that cg17124583 modified the association of SNP rs422628 with asthma risk at the age of 18 years (P = 0.006, FDR adjusted P = 0.04). Subjects with genotype AG showed an increase in average risk ratio (RR) from 0.31 (95% CI: 0.10 to 0.8) to 11.65 (95% CI: 1.71 to 79.5) when methylation level increased from 0.02 to 0.12, relative to genotype AA. A two-stage model consisting of genetic variants in the GATA3 gene, OCP use, age at menarche, and DNA-M may explain how sex hormones in women can increase the asthma prevalence after puberty.
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影响因子：
4.4
作者：
Bibikova, Marina;Barnes, Bret;Shen, Richard
通讯作者：
Shen, Richard
影响因子：
2.8
作者：
Cai, Yeping;Zhou, Jiansheng;Webb, Dianne C.
通讯作者：
Webb, Dianne C.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
5.8
作者：
Kuan, Pei Fen;Wang, Sijian;Chu, Haitao
通讯作者：
Chu, Haitao
DOI：
10.1097/aci.0b013e32835ad0e7
发表时间：
2013-02
影响因子：
2.8
作者：
Karmaus W;Ziyab AH;Everson T;Holloway JW
通讯作者：
Holloway JW