Aryl Hydrocarbon Receptor Polymorphisms Research Articles

Association of the AhR, ARNT, and AhRR gene polymorphisms and cord blood AhR levels with elevated cord blood IgE susceptibility in Taiwan mother-infant pairs: a nested case–control study

ABSTRACT The roles of aryl hydrocarbon receptor (AhR), AhR-nuclear translocator (ARNT), and AhR repressor (AhRR) genes in the elevation of cord blood IgE (CbIgE) remained unclear. Our aims were to determine the polymorphisms of AhR, ARNT, and AhRR genes, cord blood AhR (CBAhR) level, and susceptibility to elevation of CbIgE. 206 infant-mother pairs with CbIgE>=0.35 IU/ml and 421 randomly selected controls recruited from our previous study. Genotyping was determined using TaqMan assays. Statistical analysis showed AhR rs2066853 (GG vs. AA+AG: adjusted OR (AOR)=1.5, 95%CI=1.10–2.31 and AOR=1.60, 95%CI=1.06–2.43, respectively) and the combination of AhR rs2066853 and maternal total IgE (mtIgE)>=100 IU/ml were significantly correlated with CbIgE>=0.35 IU/ml or CbIgE>=0.5 IU/ml. CBAhR in a random subsample and CbIgE levels were significantly higher in infants with rs2066853GG genotype. We suggest that infant AhR rs2066853 and their interactions with mtIgE>=100 IU/ml significantly correlate with elevated CbIgE, but AhRR and ARNT polymorphisms do not.

Association between altered tryptophan metabolism, plasma aryl hydrocarbon receptor agonists, and inflammatory Chagas disease.

Chagas disease causes a cardiac illness characterized by immunoinflammatory reactions leading to myocardial fibrosis and remodeling. The development of Chronic Chagas Cardiomyopathy (CCC) in some patients while others remain asymptomatic is not fully understood, but dysregulated inflammatory responses are implicated. The Aryl hydrocarbon receptor (AhR) plays a crucial role in regulating inflammation. Certain tryptophan (Trp) metabolites have been identified as AhR ligands with regulatory functions. We investigated AhR expression, agonist response, ligand production, and AhR-dependent responses, such as IDO activation and regulatory T (Treg) cells induction, in two T. cruzi-infected mouse strains (B6 and Balb/c) showing different polymorphisms in AhR. Furthermore, we assessed the metabolic profile of Trp catabolites and AhR agonistic activity levels in plasma samples from patients with chronic Chagas disease (CCD) and healthy donors (HD) using a luciferase reporter assay and liquid chromatography-mass spectrophotometry (LC-MS) analysis. T. cruzi-infected B6 mice showed impaired AhR-dependent responses compared to Balb/c mice, including reduced IDO activity, kynurenine levels, Treg cell induction, CYP1A1 up-regulation, and AhR expression following agonist activation. Additionally, B6 mice exhibited no detectable AhR agonist activity in plasma and displayed lower CYP1A1 up-regulation and AhR expression upon agonist activation. Similarly, CCC patients had decreased AhR agonistic activity in plasma compared to HD patients and exhibited dysregulation in Trp metabolic pathways, resulting in altered plasma metabolite profiles. Notably, patients with severe CCC specifically showed increased N-acetylserotonin levels in their plasma. The methods and findings presented here contribute to a better understanding of CCC development mechanisms and may identify potential specific biomarkers for T. cruzi infection and the severity of associated heart disease. These insights could be valuable in designing new therapeutic strategies. Ultimately, this research aims to establish the AhR agonistic activity and Trp metabolic profile in plasma as an innovative, non-invasive predictor of prognosis for chronic Chagas disease.

Investigating possible effects of aryl hydrocarbon receptor G1661A polymorphism on asthma severity in adults

Aryl hydrocarbon Receptor (AhR) is a ligand-activated transcription factor with an important role in lung health. The association of AhR polymorphisms with asthma severity has not been yet investigated. We analyzed the association of G1661A, the most prevalent polymorphism of AhR, with the asthma stages in a population-based study including 555 asthmatics (Intermittent: 93, Mild: 240, Moderate: 158, and Severe: 64). The SNP was genotyped using allele-specific PCR. Obtained data were analyzed using the Generalized-Ordered Logit Estimates. Genotypes GA (OR: 0.53, CI: 0.32-0.90, P=0.019) and AA (OR: 0.22, CI: 0.06-0.76, P=0.017) were associated with decreased risk of Severe, Moderate, Mild vs. Intermittent stage; and Severe, Moderate, vs. Mild, Intermittent stages respectively. However, Genotype GA (OR: 1.90, CI: 1.05-3.44, P=0.033), dominant model GA+AA (OR: 2.04, CI: 1.17-3.57, P=0.012), and allele A (OR: 1.68, CI: 1.06-2.66, P=0.027) were associated with increased risk of Severe stage vs. Moderate, Mild, Intermittent stages. Also, male sex and higher age were associated with an increased odds ratio for severe asthma. Furthermore, significant associations with asthma stages were found for the interactions of the SNP and sex, smoking, and alcohol consumption. In conclusion, we revealed that the mutant allele of AhR-G1661A may interact with independent variables and act as a protective factor against lower stages of asthma but it may increase the risk of severe asthma.

Association of aryl hydrocarbon receptor (AhR) serum level and gene rs10247158 polymorphism with anthropometric, biochemical parameters and food consumption in overweight/obese patients.

Aryl hydrocarbon receptor (AhR) plays a role in xenobiotic metabolism, which can be also activated by dietary patterns and components. AhR ligands in circulation are reported to induce weight gain, glucose intolerance and suggested to contribute to the development of obesity. In this study, we aimed to examine the relationship of the AhR gene and its polymorphisms with obesity and food consumption. The study was conducted with 117 individuals of whom 52 had a body mass index (BMI) of <25 (normal weight) and 65 had a BMI of ≥25 (overweight/obese). The distribution of the serum level and polymorphism (rs10247158) of the participants were determined in venous blood samples using the ELISA and PCR method. Body composition and skinfold thickness of the individuals were measured and their food consumption records were analysed in the BeBiS program. The serum AhR, HOMA-IR, fasting blood glucose and basal insulin levels were found to be significantly higher (P < .001); however, no relationship was found between AhR polymorphisms in the overweight/obese individuals. In the overweight/obese group, the serum AhR level had a negative correlation with potassium, coffee and alcohol consumption and a positive correlation with suprailiac skinfold thickness. Dietary patterns expected to be related with increased serum AhR levels, such as fat and derivatives, were not observed in overweight/obese group; on the other hand, there was a negative correlation in normal group. In our study, the serum AhR levels of the overweight/obese individuals were found to be significantly higher. Some dietary patterns were determined to be correlated with serum AhR levels in overweight/obese group. However, the results need to be confirmed for ethnic differences and larger samples.

Association of xenobiotic receptor polymorphisms with carbamazepine response in epilepsy patients

Drug-resistant epilepsy is a problem worldwide. Xenobiotic receptors may play a significant role in the establishment of resistance to antiepileptic agents. Previous studies have confirmed that the metabolism and efficacy of carbamazepine (CBZ) can be influenced by xenobiotic receptors, especially pregnaneXreceptor (PXR), constitutive androstane receptor (CAR), and aryl hydrocarbon receptor (AHR). Therefore, this study intends to elucidate the pharmacogenomic associations of polymorphisms of these xenobiotic receptors with the CBZ response in epilepsy patients, and these genetic data may be useful for the treatment of clinical prophylaxis and individualized treatment of intractable epilepsy. Adult patients with epilepsy who were on CBZ-based monotherapy and combination therapy (n=257) were genotyped, and the patients were divided into drug-responsive and drug-resistant groups according to the International League Against Epilepsy criteria. We sought to tag single-nucleotide polymorphisms (SNPs) of PXR, CAR and AHR that principally represent alleles associated with drug resistance risk; in addition, a gene interaction analysis reference panel was constructed for SNP-based imputation. No significant effects of PXR or AHR polymorphisms were observed. However, an interaction between the CAR rs2502815 variant and CBZ response was observed: in CBZ-based monotherapy and combination therapy patients, the GG genotype of the CAR rs2502815 variant (vs. wild-type homozygous) was independently associated with CBZ response after adjusting for variables [odds ratio (OR)=0.389, 95% confidence interval (CI) 0.203-0.743, p=0.004]. The results of the haplotype and gene interaction case-control analyses of the CBZ response were negative. Our results provide clinical data regarding the genetic possibilities of drug responses related to CAR variation in epilepsy patients. This study is the first to indicate a potentially relevant interaction between the CAR rs2502815 polymorphism and the CBZ response in epilepsy patients.

Lack of association between multiple polymorphisms in aryl hydrocarbon receptor (AhR) gene and cancer susceptibility

BackgroundThe aryl hydrocarbon receptor (AhR) is commonly known as an environmental sensor. Polymorphisms in AhR gene have been implicated in susceptibility to cancer. However, the results were controversial. This study was conducted to quantitatively summarize the association between AhR polymorphisms and cancer risk by meta-analysis.MethodsRelevant reports were searched in four databases (Embase, PubMed, Wanfang, and China National Knowledge Infrastructure). We used pooled odds ratio (OR) and 95% confidence interval (95% CI) to evaluate the strength of the association in both standard and cumulative meta-analysis. Subgroup and sensitivity analysis was also performed, and between-study heterogeneity and publication bias were checked.ResultsA total of seventeen studies referring to three AhR polymorphisms (rs2066853, rs7796976, and rs2074113) were identified, and 9557 cases and 10038 controls were included. There was no statistically significant association of AhR rs2066853 polymorphism with cancer risk in the overall population, and the negative results were repeated in subgroup analysis by the ethnicity and cancer type. Concerning AhR rs7796976 or rs2074113 polymorphism, no significant correlation was detected. Moreover, these non-significant findings were stable in sensitivity analysis, and the cumulative meta-analysis indicated a trend of no significant link between this three AhR polymorphisms and cancer risk as more data accumulated over time.ConclusionThis meta-analysis provides evidence that the rs2066853, rs7796976, or rs2074113 polymorphism in AhR gene is not a susceptible predictor of cancer. Further clinical and functional investigation between AhR polymorphisms and cancer susceptibility are needed.

Association of Crohn’s Disease with Aryl Hydrocarbon Receptor Gene Polymorphisms in Patients from Southeast China

ABSTRACTAims The aryl hydrocarbon receptor (AhR) plays a pivotal role in regulating the innate and the acquired immune systems. The present study aimed to investigate the association of Crohn’s disease (CD) with AhR polymorphisms in a cohort of patients from Southeast China.Methods An improved multiple ligase detection reaction technique was applied to examine the polymorphisms of rs2158041, rs2066853, and rs10249788 in 310 patients with CD and 573 controls.Results Compared to the controls, the variant allele (T) and genotype (CT+TT) of rs2158041 were less frequent in patients with CD (both p < 0.05). Similar conclusions were drawn from patients with ileal CD and with stricture CD as compared to the controls (all p < 0.0083). However, no significant differences were observed in allele and genotype frequencies of rs2066853 and rs10249788 between patients with CD and the controls (all p > 0.05). Although rs2158041 and rs10249788 were in complete linkage disequilibrium with rs2066853, respectively, only the frequency of haplotype (TG) formed by rs2158041 and rs2066853 was significantly lower in patients with CD than that in the controls (p < 0.05).Conclusions AhR (rs2158041) might be a susceptible locus for CD, especially for the two subtypes: ileal CD and stricture CD.

Traffic-related air pollution and eczema in the elderly: Findings from the SALIA cohort.

Childhood eczema results from an interplay of genetic and environmental factors including Traffic-Related Air Pollution (TRAP). In contrast, little is known about eczema in the elderly in general and its association with TRAP in particular. Animal experiments indicate that the arylhydrocarbon receptor (AHR) might link TRAP and eczema. We investigated (i) incidence and prevalence of eczema in elderly women, (ii) its association with long-term TRAP exposure and (iii) the effect modification by AHR polymorphism rs2066853. The study is based on the SALIA cohort. The women's average age was 55 years at baseline (1985-1994) and 74 years at follow-up (2008-2009) examination. Incidence and prevalence of eczema were assessed by an adapted version of the International Study of Asthma and Allergies in Childhood (ISAAC) symptom questionnaire. TRAP was determined using land-use regression models. Adjusted logistic regression models were used. After age 55, the incidence and prevalence of eczema symptoms were 7.9% and 8.8%, respectively. Significant associations (p < 0.05) were found between all parameters of TRAP at the baseline visit and eczema incidence. The risk was higher for minor allele carriers of rs2066853 e.g. NOx: OR = 3.75, p = 0.030 vs. OR = 1.34, p = 0.317 in non-carriers (p(interaction) = 0.122). These results indicate a high incidence for eczema in elderly women, which is associated with chronic exposure to TRAP and possibly mediated by AHR.

Predictive polymorphisms for breast cancer in postmenopausal Mexican women.

Several factors contribute to the increase in breast cancer (BC) incidence, such as lifetime exposure to estrogen, early menarche and older ages at first birth, menopause, and the increased prevalence of postmenopausal obesity. In fact, there is an association between an increased BC risk and elevated estrogen levels, which may be involved in carcinogenesis via the estrogen receptor alpha (ERα) encoded by the ESR1 gene. Interestingly, there is an antagonistic relationship between ERα and the aryl hydrocarbon receptor (AhR) in BC cells. Herein, we explore the combined effects of the ESR1 (XbaI, PvuII) and AhR polymorphisms on BC development in Mexican women according to their menopausal status. Investigation was performed using a cases and controls design. In a group of 96 cases diagnosed with BC and 111 healthy women, the single-nucleotide polymorphisms ESR1 (XbaI, PvuII) and AhR gene were identified by qPCR. Chi-square test or Fisher's exact test were used. Statistical analyses were conducted using the STATA statistical package (Version 10.1, STATA Corp., College Station, TX, USA). The G/G XbaI genotype was more prevalent in the cases than in the controls (P = 0.008). Moreover, Mexican women carrying the XbaI (wild type [WT]/G or G/G) ESR1 genotype have higher risk (12.26-fold) for developing postmenopausal BC than individuals carrying the WT/WT genotype. The presence of the G/G genotype of XbaI may be considered a susceptibility allele in Mexican women. Due to increased postmenopausal BC risk, the XbaI (WT/G or G/G) alleles may be used as a postmenopausal predictive factor for BC in Mexican women.

A Functional Aryl Hydrocarbon Receptor Genetic Variant, Alone and in Combination with Parental Exposure, is a Risk Factor for Congenital Heart Disease.

Recent experimental studies showed that ablation of the aryl hydrocarbon receptor (AhR) as well as its activation by exogenous ligands disrupt the molecular networks involved in heart formation and function, leading to congenital heart disease (CHD). However, no evidence is available about the role of AhR in humans. We assessed the prevalence of a functional AhR genetic variant (p.Arg554Lys) in CHD patients as well as its joint effects with parental exposure. A total of 128 CHD patients (76 males; age 6.2±6.7years) and 274 controls (160 males; age at birth) were genotyped for the AhR polymorphism by using the TaqMan® Drug Metabolism Genotyping assay. Both case and control parents completed a structured questionnaire on demographic, lifestyle and preconception exposures. Genotype (p=0.001) and allele (p<0.0001) distributions of AhR p.Arg554Lys differed significantly between patients and controls. A significant elevated CHD risk was found under dominant (OR=2.9, 95% CI 1.9-4.6, p<0.0001) and additive genetic models (OR=6.2, 95% CI 2-19, p=0.001). There was a significant interaction between 554-Lys allele and paternal smoking exposure (ORsmoking=1.6, 95% CI=0.9-2.9; ORallele=2.6, 95% CI=1.3-5; ORinteraction=4.9, 95% CI=2.4-9.9, p interaction<0.0001). Additionally, 554-Lys allele exacerbated the effect of maternal periconceptional exposure (ORexposure=1.6, 95% CI=0.8-3; ORallele=2.6, 95% CI=1.5-4.5; ORinteraction=5.7; 95% CI=2.6-12, p interaction<0.0001). Our findings showed that the AhR p.Arg554Lys polymorphism, alone and in combination with parental exposures, is associated with the CHD risk, highlighting the significant role of AhR in the cardiovascular development.

AhR expression and polymorphisms are associated with risk of coronary arterial disease in Chinese population

The aryl hydrocarbon receptor (AhR) mediates the control of environmental toxicity, and modulates the development and pathogenesis of the cardiovascular system. However, little is known about the role of AhR in coronary arterial disease (CAD) susceptibility. We therefore conducted a case-control study in a Chinese population, and assessed the potential association between AhR variants and CAD susceptibility. Compared with the controls, circulating AhR expression was found to be significantly increased in patients with CAD and its subtypes including ST-segment and non-ST-segment elevation myocardial infarction, and stable and unstable angina pectoris. Receiver operating characteristic (ROC) analysis to evaluate the effect of AhR on CAD progression showed it to be a potent biomarker for CAD. Genotype frequencies of AhR rs2066853 differed significantly between CAD and control subjects, while smoking and hyperlipidemia markedly promoted CAD risk relative to the AhR polymorphism. Moreover, a significant difference in AhR variant distribution was observed between the four CAD subtypes with different severities. The expression level and functional polymorphisms of circulating AhR may affect the susceptibility and progression of CAD in Chinese populations. This provides a novel view of the etiology and epidemiology of CAD, and will contribute to the diagnosis and therapy of this severe disease.

Comment to "Vitamin D Receptor Poly(A) Microsatellite Polymorphism and 25-Hydroxyvitamin D Serum Levels: Association with Susceptibility to Breast Cancer".

To the Editor, The article by Colagar et al. [1], in the latest issue of this journal, showed the relationship between the genetic polymorphism of vitamin D receptor (VDR), as a VDR polyA allele L microsatellite variants, serum level of 25(OH)D3 and risk of breast cancer. As in many other type of malignancies, low levels of 25(OH)D3, the main circulating form of vitamin D following dietary intake, has been associated with higher breast cancer susceptibility, particularly with plasmatic levels of 25(OH)D3 below 20 to 32 ng/mL [2]. Therefore, one of the major goal pursued by physicians endeavoured to prevent or fight cancer is to increase plasma bioavailability of 25(OH)D3 by increasing vitamin D intake or ameliorating its gut adsorption, supplementation protocol or pharmacokinetics [3]. However, the paper by Colagar appears to raise the same concern that I addressed in some recent papers of mine [4], namely that the preventive effect of vitamin D on cancer depends on the wide collection of factors including genetic polymorphism for VDR [1], for example, for breast cancer the different ability of individuals to respond to 1,25(OH)2D3 might depend on the Taq1 VDR polymorphism [5]. The individual genetic endowment to respond to vitamin D, in such a fashion able to assess its presumptive chemopreventive potential against some important malignancies such as breast cancer, should be a fundamental hallmark to arrange any vitamin D supplementation protocol [4]. Other genetic polymorhisms may be involved in the chemopreventive role of 25(OH)D3, for example those ones regarding P450 family of cytochromes [6], as interestingly CYP1A1 is involved in xenobiotic metabolism and is a VDR target [7], moreover CYP3A4 is a human microsomal 25(OH)D3 hydrolase [8]. Because of the genetic variability of VDR exising within the Causasian population, the authors discussed the controversial issue that any variant in VDR may influence the activity of vitamin D against tumors and their prevalence in the population [1]. Yet, some correlation exists between low levels of circulating 25(OH)D3 and frequency of breast cancer [2,9], which should suggest for an increase in vitamin D intake as a supplementation aid, but very few reports correlated positive outcomes for breast cancer incidence following vitamin D supplementation [3,10]. While several papers associated cancer risk with a low 25(OH) D3 plasma level, the reason of this insufficient bioavalailability is far to be elucidated. Cancer cells can promote the 25(OH) D3 enzymatic hydroxylation, contribuiting in the reduction of the level in the circulating form [11,12], The protective effect against breast cancer claimed by the authors [1] might derive from a wide panoply of variability, which may even involve P450 cytochromes and aryl hydrocarbon receptor polymorphism [13,14], though some contradictory evidence yet exists [15]. The conclusion which the authors reached assessed that breast cancer risk is related to low levels of the circulating metabolite 25(OH)D3 and to a favorable assessment of a VDR genetic polymorphism, particularly with poly(A) long (LL+LS) microsatellite alleles [1]. Interestingly, this genetic polymorhism was associated with breast cancer also in a Northern Indian population, nearby the Iranian regions from which the authors recruited their patients [16]. Interestingly, Fok1 polymorphism is a poly(A) microsatellite polymorphism, which was recently closely associated to breast cancer [17], although yet Fok1 is also a VDR polymorphism that has been associated with many other types of cancers [18] and even with pulmonary tuberculosis susceptibility [19]. The authors did not clarify which kind of VDR polymorphism, previously described in the literature, they reported in their paper. The genetic association of VDR polymorphism to several types of cancer makes particularly puzzling the role of the genetic variability of vitamin D enzymes and receptors in the presumptive chemopreventive role of 1,25(OH)2D3. HLA-aplotype genetic linkage may be a possible path to focus onto vitamin D action on tumors. Due to the strong association with tuberculosis (TB) susceptibility and Fok1 VDR polymorphism [19], a suggestion might come from the evidence that some HLA alleles, such as the aplotypes HLA-DRB1, HLA-DQB1 or more precisely DRB1*1101-1121-DQB1*05 are associated with TB as well as the polymorphic SNP variants Fok1, Bsm1, Apa1, and Taq1, some of which related to breast cancer [20]. The question is if some HLA aplotypes in linkage disequilibrium with VDR polymorphic genes may be used as genetic markers to evaluate the individual's vitamin D response against breast cancer [21]. This issue puts questions and concerns about the fundamental role of genetic determinants for ensuring vitamin D efficacy in counteracting cancer malignancy through its immune modulating and hormonal action.

AhR (Aryl Hydrocarbon Receptor) Polymorphisms: A Possible Role in TCDD (Dioxins)-AhR Binding and Carcinogenesis

Carcinogenicity of dioxins seems to be largely mediated by their binding to the aryl hydrocarbon receptor (AhR), a cytosolic transcriptional regulator of cell growth, differentiation, and migration. The most widely studied agonist of AhR, in the last thirty years, is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which also presents the highest binding affinity for this receptor. The activated ligand-AhR complex has been described to contribute in suppressing both humoral and cellular immune responses. Starting from the description of the main mechanisms underlying the physiological activation of AhR, the present review is aimed at evaluating a putative functional role of the intragenic AhR polymorphisms, which could greatly affect the functionality of the receptor by either inducing or contrasting its ligand-dependent activation. As consequence, this may participate in lowering or increasing the risk of cancer, particularly, in the most polluted areas.

Interactions between polymorphisms in the aryl hydrocarbon receptor signalling pathway and exposure to persistent organochlorine pollutants affect human semen quality.

Persistent organic pollutants (POPs) may affect male reproductive function. Many dioxin-like POPs exert their effects by activation of the aryl hydrocarbon receptor (AHR) signalling pathway. We analysed whether gene-environment interactions between polymorphisms in AHR (R554K) and AHR repressor (AHRR P185A) and serum levels of markers of POP exposure 1,1-bis-(4-chlorophenyl)-2,2-dichloroethene (p,p'-DDE) and 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) are associated with 21 parameters of male reproductive function in 581 proven-fertile European and Greenlandic men. In Greenlandic men, AHR variants significantly modified the association between serum levels of both p,p'-DDE and CB-153 and inhibin B levels, sperm chromatin integrity, and seminal zinc levels. In the total cohort, interactions between AHRR variants and serum levels of CB-153 were associated with sperm chromatin integrity and the expression of the pro-apoptotic marker protein Fas. The data indicate that susceptibility to adverse effects of POP exposure on male reproductive function is dependent on polymorphisms in genes involved in AHR signalling.

Influence of CYP1A1/CYP1A2 and AHR polymorphisms on systemic olanzapine exposure

Metabolism of the atypical antipsychotic olanzapine (OLA) is partially catalyzed by cytochrome P450 (CYP) 1A2, a target of aryl hydrocarbon receptor (AHR)-mediated induction. We investigated the influence of four cis-acting polymorphisms (rs2470893C>T and rs2472297C>T between CYP1A1 and CYP1A2 loci, and rs762551C>A and rs2472304A>G within CYP1A2) as well as one trans-acting polymorphism upstream of the AHR locus (rs4410790C>T) on interindividual variation in systemic OLA exposure. A cohort of 342 Caucasian psychiatric patients on long-term OLA treatment was genotyped using Illumina GoldenGate assays. The influence of haplotype and genotype was evaluated in terms of dose-adjusted steady-state serum concentrations (C/Ds) of OLA and the 4'-desmethyl OLA (DMO) to OLA ratio, a marker for CYP1A2-mediated metabolism of OLA. The CYP1A haplotype [rs2470893 (T)-rs2472297 (T)-rs762551 (A)] was associated with an increased DMO/OLA ratio and decreased C/Ds of OLA. This haplotype could not be tagged by rs762551 (A) but was tagged by rs2472297C>T, a single nucleotide polymorphism further identified as a significant covariate of the DMO/OLA ratio (P=0.0001) and OLA C/D (P=0.01). AHR rs4410790C>T influenced only the DMO/OLA ratio (P=0.02). Among nonsmokers, patients carrying rs2472297 (T) and homozygous for rs4410790 (C) [n=26; mean=0.22, 95% confidence interval (CI) 0.19-0.26] showed a 1.7-fold higher mean DMO/OLA ratio compared with those carrying rs4410790 (T) and homozygous for rs2472297 (C) (n=50; mean=0.13, 95% CI 0.12-0.16, P=0.0001), together with a nonsignificant decrease in the mean OLA C/D. The reported influence of CYP1A2*1F (also known as CYP1A2-163A, rs762551C>A) on systemic OLA exposure could not be verified. CYP1A1/CYP1A2 rs2472297C>T and AHR rs4410790C>T are potentially useful genetic markers associated with variability in CYP1A2-mediated metabolism, but are of minor quantitative importance for systemic OLA exposure.

Contributions of Aryl Hydrocarbon Receptor Genetic Variants to the Risk of Glioma and PAH-DNA Adducts

The aryl hydrocarbon receptor (AHR) gene is involved in the response to polycyclic aromatic hydrocarbon (PAH) exposure. To investigate the hypothesis that the genetic variants in the AHR gene might be a causal genetic susceptibility to PAH-DNA adduct formation and glioma risk, we conducted a case-control study of 384 glioma cases and 384 cancer-free controls to explore the association between six common single-nucleotide polymorphisms of the AHR gene and glioma risk. Using PAH-DNA adducts as biomarkers, we then evaluated the association between PAH-DNA adduct levels and glioma risk based on a tissue microarray including 11 controls and 77 glioma patients. We further explored the contributions of the glioma risk-associated AHR polymorphisms to the levels of PAH-DNA adducts in glioma tissues based on 77 glioma patients. We found that PAH-DNA adduct staining existed in normal brain tissues and grades I-IV gliomas, and the staining intensity was significantly associated with the glioma grade. Two AHR polymorphisms (rs2066853 and rs2158041) demonstrated significant association with glioma risk. Intriguingly, we also found statistically significant associations between these two variants and PAH-DNA adduct levels in glioma tissue. These data suggest the contributions of AHR rs2066853 and rs2158041 to glioma risk and the PAH-DNA adduct levels, which shed new light on gene-environment interactions in the etiology of glioma. Further studies with a larger sample size and ethnically diverse populations are required to elucidate the potential biological mechanism for, as well as the impact of, the susceptibility to glioma due to genetic variants of AHR.

The association of functional polymorphisms in the aryl hydrocarbon receptor ( AHR ) gene with the risk of vitiligo in Han Chinese populations

Vitiligo is an acquired depigmentation disorder resulting from selective destruction of melanocytes. The aryl hydrocarbon receptor (AHR) is vital to the regulation of melanogenesis and melanocyte proliferation and differentiation through modulating the expressions of melanogenesis-related genes. AHR mutations may negatively affect AHR proteins and its target genes. Therefore, we hypothesized that AHR polymorphisms might be involved in vitiligo by impacting the transcriptional activities of related genes as mentioned above. To evaluate the potential association between AHR polymorphisms and vitiligo susceptibility. We performed a hospital-based, case-control study of 1000 patients with vitiligo and 1000 vitiligo-free but age- and gender-matched controls. Two single nucleotide polymorphisms of the AHR gene (rs10249788 and rs2066853) were selected and genotyped using a polymerase chain reaction-restriction fragment length polymorphism method. A statistically significantly decreased risk of vitiligo was found to be associated with the TT and CT genotypes of rs10249788 [odds ratio (OR) 0·59, 95% confidence interval (CI) 0·38-0·93; P = 0·028 and OR 0·82, 95% CI 0·68-0·98; P = 0·032, respectively] as well as among subgroups: male, active, nonsegmental vitiligo, and onset age ≤ 20 years. Moreover, subjects with the combined (CT + TT)/GG genotype or T/G haplotype (rs10249788/rs2066853) showed a decreased risk for vitiligo (OR 0·57, 95% CI 0·37-0·87, P = 0·009 and OR 0·78, 95% CI 0·64-0·96, P = 0·033, respectively). These results suggest that the T allele of rs10249788 located in the promoter of the AHR gene is associated with a protective effect on vitiligo in Han Chinese populations.

Assessment of an Association between an Aryl Hydrocarbon Receptor Gene (AHR) Polymorphism and Risk of Male Infertility

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxicity of a variety of environmental chemicals, such as polycyclic aromatic hydrocarbons (PAHs) and dioxins. We hypothesized that polymorphisms of AHR may result in significant differences in sensitivity to toxic effects of PAHs or dioxins and contribute to susceptibility to male infertility. To address this possibility, we conducted a study including 580 idiopathic infertile subjects and 580 fertile controls to assess associations between the male infertility risk and six tagging single nucleotide polymorphisms of AHR gene. Additionally, correlations between AHR polymorphisms and sperm concentration, levels of DNA fragmentation, and benzo(a)pyrene diolepoxide (BPDE)-DNA adducts in sperm were determined in 420 patients. Genotypes were determined using the ABI OpenArray platform. Sperm DNA fragmentation was evaluated by terminal deoxyribonucleotidyl transferase (TdT)-mediated dUDP nick-end labelling (TUNEL) assay, and sperm BPDE-DNA adducts were measured by immunofluorescent assay using flow cytometry. We found that the G variant of rs2158041 was associated with significantly increased risk of male infertility (adjusted odds ratio 1.53, 95% confidence interval 1.21-1.93; p = 6.0 x 10⁻⁶; GA/AA vs. GG genotypes). Furthermore, patients with rs2158041 AA genotype showed a reduced sperm concentration. In addition, a gradual increase of sperm DNA fragmentation and sperm BPDE-DNA adducts was found among the three rs2158041 subgroups (GG → GA → AA), though the differences were not statistically significant. These results suggested that the AHR polymorphism might be associated with individual risk of male infertility in the Chinese population study.

Characterization of human aryl hydrocarbon receptor polymorphisms in MCF-7 breast cancer cells

Characterization of human aryl hydrocarbon receptor polymorphisms in MCF-7 breast cancer cells

Association of human aryl hydrocarbon receptor gene polymorphisms with risk of lung cancer among cigarette smokers in a Chinese population

Most of the carcinogenic effects of polycyclic aromatic hydrocarbons present in tobacco smoke are mediated by the aryl hydrocarbon receptor (AHR), a ligand-dependent transcription factor that regulates tobacco-induced expression of carcinogen metabolic enzymes. We hypothesized that genetic variations in AHR might confer individual susceptibility to lung cancer. Eight selected single-nucleotide polymorphisms in AHR were genotyped using the Illumina SNP genotyping BeadLab platform in a case-control study of 500 lung cancer patients and 517 cancer-free controls in a Chinese population. We found that significantly increased lung cancer risk was associated with heterozygous genotypes of rs2158041 (adjusted odds ratio=1.53 and 95% confidence interval=1.17-1.99 for GA, compared with the GG genotype) and rs7811989 (adjusted odds ratio=1.48 and 95% confidence interval=1.13-1.93 for GA, compared with the GG genotype), although these two single-nucleotide polymorphisms were in linkage disequilibrium. Furthermore, haplotype analysis revealed significant differences in haplotype distributions of AHR between cases and controls (Global P=1.38e-5). We also observed statistically significant interaction between the polymorphism rs2066853 (p.Arg554Lys) and cumulative cigarette smoking as a discrete or continuous variable (P=0.033 and 0.019, respectively), and the Lys/Lys genotype conferred an increased risk of lung cancer in the heavy smokers (adjusted odds ratio=3.36 and 95% confidence interval=1.07-10.55). These findings suggest that AHR polymorphisms and potential gene-smoking interaction may be involved in the etiology of lung cancer. Further large prospective studies with ethnically diverse populations and functional studies are warranted to validate these findings.