BACKGROUND Because immune responses are sensitive to environmental changes that drive selection of genetic variants, we hypothesized that polymorphisms of some xenobiotic response and immune response genes may be associated with specific types of immune-mediated diseases (IMD), while others may be associated with IMD as a larger category regardless of specific phenotype or ethnicity. OBJECTIVE To examine transethnic gene-IMD associations for single nucleotide polymorphism (SNP) frequencies of prototypic xenobiotic response genes-aryl hydrocarbon receptor (AHR), AHR nuclear translocator (ARNT), AHR repressor (AHRR) - and a prototypic immune response gene, protein tyrosine phosphatase, non-receptor type 22 (PTPN22), in subjects from the Environmental Polymorphisms Registry (EPR). METHODS Subjects (n = 3731) were genotyped for 14 SNPs associated with functional variants of the AHR, ARNT, AHRR, and PTPN22 genes, and their frequencies were compared among African Americans (n = 1562), Caucasians (n = 1838), and Hispanics (n = 331) with previously reported data. Of those genotyped, 2015 EPR subjects completed a Health and Exposure survey. SNPs were assessed via PLINK for associations with IMD, which included those with autoimmune diseases, allergic disorders, asthma, or idiopathic pulmonary fibrosis. Transethnic meta-analyses were performed using METAL and MANTRA approaches. RESULTS ARNT SNP rs11204735 was significantly associated with autoimmune disease by transethnic meta-analyses using METAL (odds ratio, OR [95% confidence interval] = 1.29 [1.08-1.55]) and MANTRA (ORs ranged from 1.29 to 1.30), whereas ARNT SNP rs1889740 showed a significant association with autoimmune disease by METAL (OR = 1.25 [1.06-1.47]). For Caucasian females, PTPN22 SNP rs2476601 was significantly associated with autoimmune disease by allelic association tests (OR = 1.99, [1.30-3.04]). In Caucasians and Caucasian males, PTPN22 SNP rs3811021 was significantly associated with IMD (OR = 1.39 [1.12-1.72] and 1.50 [1.12-2.02], respectively) and allergic disease (OR = 1.39 [1.12-1.71], and 1.62 [1.19-2.20], respectively). In the transethnic meta-analysis, PTPN22 SNP rs3811021 was significantly implicated in IMD by METAL (OR = 1.31 [1.10-1.56]), and both METAL and MANTRA suggested that rs3811021 was associated with IMD and allergic disease in males across all three ethnic groups (IMD METAL OR = 1.50 [1.15-1.95]; IMD MANTRA ORs ranged from 1.47 to 1.50; allergic disease METAL OR = 1.58 [1.20-2.08]; allergic disease MANTRA ORs ranged from 1.55 to 1.59). CONCLUSIONS Some xenobiotic and immune response gene polymorphisms were shown here, for the first time, to have associations across a broad spectrum of IMD and ethnicities. Our findings also suggest a role for ARNT in the development of autoimmune diseases, implicating environmental factors metabolized by this pathway in pathogenesis. Further studies are needed to confirm these data, assess the implications of these findings, define gene-environment interactions, and explore the mechanisms leading to these increasingly prevalent disorders.

中文翻译：

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免疫介导的疾病与芳烃反应基因ARNT和PTPN22免疫调节基因的单核苷酸多态性之间的跨种族关联。

背景技术由于免疫应答对驱动选择遗传变异的环境变化敏感，因此我们假设某些异种应答和免疫应答基因的多态性可能与特定类型的免疫介导疾病（IMD）相关，而其他可能与IMD相关不论具体的表型或种族如何，都应作为较大的类别。目的探讨跨种族基因-IMD关联的原型异种生物应答基因-芳烃受体（AHR），AHR核转运子（ARNT），AHR阻遏物（AHRR）和原型免疫应答基因，蛋白质的单核苷酸多态性（SNP）频率来自环境多态性注册中心（EPR）的受试者中的22型非受体酪氨酸磷酸酶（PTPN22）。方法对对象（n = 3731）进行14种与AHR，ARNT，AHRR和PTPN22基因功能变异相关的SNP的基因分型，并在非裔美国人（n = 1562），高加索人（n = 1838）和西班牙裔（n = 331）有先前报告的数据。在这些基因型中，2015年EPR受试者完成了健康与暴露调查。通过PLINK评估了SNP与IMD的关联，其中包括患有自身免疫性疾病，过敏性疾病，哮喘或特发性肺纤维化的患者。跨种族荟萃分析使用METAL和MANTRA方法进行。结果使用金属（单数比，OR [95％置信区间] = 1.29 [1.08-1.55]）和MANTRA（OR范围为1.29至1.30）进行跨种族荟萃分析，ARNT SNP rs11204735与自身免疫疾病显着相关，而ARNT SNP rs1889740与金属引起的自身免疫性疾病显着相关（OR = 1.25 [1.06-1.47]）。对于白人女性，通过等位基因关联测试，PTPN22 SNP rs2476601与自身免疫性疾病显着关联（OR = 1.99，[1.30-3.04]）。在高加索人和高加索人中，PTPN22 SNP rs3811021与IMD（分别为OR = 1.39 [1.12-1.72]和1.50 [1.12-2.02]）和过敏性疾病（OR = 1.39 [1.12-1.71]和1.62 [1.19]显着相关。 -2.20]）。在跨种族的荟萃分析中，METAL与PTPN22 SNP rs3811021明显相关于IMD（OR = 1.31 [1.10-1.56]），METAL和MANTRA均表明rs3811021与所有三个族裔的男性IMD和过敏性疾病相关（IMD METAL OR = 1.50 [1.15-1.95]； IMD MANTRA OR的范围为1.47至1.50；过敏性疾病金属OR = 1.58 [1.20-2.08]；变态反应性疾病的ORTRA范围为1.55至1.59）。结论首次显示一些异种和免疫反应基因多态性在广泛的IMD和种族中具有关联。我们的研究结果还表明，ARNT在自身免疫性疾病的发展中发挥了作用，这牵涉到在发病机理中被该途径代谢的环境因素。需要进一步的研究来确认这些数据，评估这些发现的含义，定义基因与环境的相互作用，并探索导致这些日益普遍的疾病的机制。与广泛的IMD和种族建立联系。我们的研究结果还表明，ARNT在自身免疫性疾病的发展中发挥了作用，这牵涉到在发病机理中被该途径代谢的环境因素。需要进一步的研究来确认这些数据，评估这些发现的含义，定义基因与环境的相互作用，并探索导致这些日益普遍的疾病的机制。与广泛的IMD和种族建立联系。我们的研究结果还表明，ARNT在自身免疫性疾病的发展中发挥了作用，这牵涉到在发病机理中被该途径代谢的环境因素。需要进一步的研究来确认这些数据，评估这些发现的含义，定义基因与环境的相互作用，并探索导致这些日益普遍的疾病的机制。