Background

Within fossil- and solid-fuel dependent geographic locations, mechanisms of air pollution-induced asthma remains unknown. In particular, sources of greater genetic susceptibility to airborne carcinogen, namely, benzo[a]pyrene (B[a]P) has never been investigated beyond that of a few well known genes.

Objectives

To deepen our understanding on how the genotypic variations within the candidate genes contribute to the variability in the children's susceptibility to ambient B[a]P on doctor-diagnosed asthma.

Methods

Clinically confirmed asthmatic versus healthy control children (aged, 7–15) were enrolled from historically polluted and rural background regions in Czech Republic. Contemporaneous ambient B[a]P concentration was obtained from the routine monitoring network. The sputum DNA was genotyped for 95 genes. B[a]P interaction with SNPs was studied by two-stage, semi-agnostic screening of 621 SNPs.

Results

The median B[a]P within the highly polluted urban center was 8-times higher than that in the background region (7.8 vs. 1.1 ng/m³) during the period of investigation. Within the baseline model, which considered B[a]P exposure-only, the second tertile range was associated with a significantly reduced odds (aOR = 0.28) of asthma (95% CI, 0.16 to 0.50) compared to those at the lowest range. However, the highest range of B[a]P was associated with 3.18-times greater odds of the outcome (95% CI, 1.77 to 5.71). Within the gene-environment interaction models, joint occurrence of a high B[a]P exposure range and having a high-risk genotype at CTLA4 gene (rs11571316) was associated with 9-times greater odds (95% CI, 4.56–18.36) of the asthma diagnosis. Similarly, rs11571319 at CTLA4 and a high B[a]P exposure range was associated with a 8-times greater odds (95% CI, 3.95–14.27) of asthma diagnosis. Furthermore, having TG + GG genotypes on rs1031509 near STAT4 was associated with 5-times (95% CI, 3.03–8.55) greater odds of asthma diagnosis at the highest B[a]P range, compared to the odds at the reference range. Also CYP2E1 AT + TT genotypes (rs2070673) was associated with 5-times (95% CI, 3.1–8.8) greater odds of asthma diagnosis at the highest B[a]P exposure.

Conclusions

The children, who jointly experience a high B[a]P exposure (6.3–8.5 ng/m3) as well as susceptible genotypes in CTLA4 (rs11571316 and rs11571319), STAT4 (rs1031509), and CYP2E1 (rs2070673), respectively, are associated with a significantly greater odds of having doctor-diagnosed asthma, compared to those with neither risk factors.

中文翻译：

---

CTLA4，STAT4和CYP2E1多态性改变了周围环境苯并[ a ] P对哮喘的易感性^☆

背景

在依赖化石燃料和固体燃料的地理位置内，由空气污染引起的哮喘的机制仍然未知。尤其是，从未对空气传播致癌物具有更高遗传易感性的来源，即苯并[ a ] re（B [ a ] P）进行过研究，而仅是少数几个众所周知的基因。

目标

为了加深我们对候选基因内的基因型变异如何导致儿童对医生诊断为哮喘的环境B [ a ] P敏感性的变异性的理解。

方法

临床确诊的哮喘与健康对照儿童（7-15岁）来自捷克共和国历史上受污染的乡村地区。从常规监测网络获得了同期的环境B [ a ] P浓度。对痰液DNA进行了95个基因分型。通过两阶段，半不可知性筛选621个SNP，研究了B [ a ] P与SNP的相互作用。

结果

在调查期间，高污染城市中心的B [ a ] P的中位数比背景区域的中位数B [ a ] P高（7.8对1.1 ng / m ³）。在基线模型中，仅考虑B [ a ] P暴露，与最低范围相比，第二个三分位数范围与哮喘发生几率（aOR = 0.28）（95％CI，0.16至0.50）显着降低有关。但是，B [ a ] P的最高范围与结果的几率高3.18倍相关（95％CI，1.77至5.71）。在基因-环境相互作用模型中，高B [ a ] P暴露范围的联合发生并在CTLA4处具有高风险基因型基因（rs11571316）与哮喘诊断的9倍几率相关（95％CI，4.56–18.36）。同样，在CTLA4处的rs11571319和较高的B [ a ] P暴露范围与哮喘诊断的几率高8倍（95％CI，3.95–14.27）相关。此外，在STAT4附近的rs1031509上具有TG + GG基因型与最高B [ a ] P范围的哮喘诊断几率相比，在参考范围的几率高5倍（95％CI，3.03-8.55）。也CYP2E1 AT + TT基因型（rs2070673）中的溶液用5倍（95％CI，3.1-8.8）哮喘诊断人杰在最高B [关联一个]芘曝光。

结论

这些孩子分别经历了较高的B [ a ] P暴露（6.3–8.5 ng / m3）以及CTLA4（rs11571316和rs11571319），STAT4（rs1031509）和CYP2E1（rs2070673）的易感基因型。与没有危险因素的人相比，具有医生诊断的哮喘的几率要高得多。