Hypomethylation of AHRR (cg05575921) Is Related to Smoking Status in the Mexican Mestizo Population.
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ABSTRACT:
SUBMITTER: Bravo-Gutierrez OA
PROVIDER: S-EPMC8391630 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundDNA methylation is associated with cancer, metabolic, neurological, and autoimmune disorders. Hypomethylation of aryl hydrocarbon receptor repressor (AHRR) especially at cg05575921 is associated with smoking and lung cancer. Studies on the association between AHRR methylation at cg05575921 and sources of polycyclic aromatic hydrocarbon (PAH) other than smoking are limited. The aim of our study was to assess the pattern of blood DNA methylation at cg05575921 in non-smoking Taiwanese adults living in areas with different PM2.5 levels.MethodsData on blood DNA methylation, smoking, and residence were retrieved from the Taiwan Biobank dataset (2008-2015). Current and former smokers, as well as individuals with incomplete information were excluded from the current study. The final analysis included 708 participants (279 men and 429 women) aged 30-70 years. PM2.5 levels have been shown to increase as one moves from the northern through central towards southern Taiwan. Based on this trend, the study areas were categorized into northern, north-central, central, and southern regions.ResultsLiving in PM2.5 areas was associated with lower methylation levels: compared with the northern area (reference area), living in north-central, central, and southern areas was associated with lower methylation levels at cg05575921. However, only methylation levels in those living in central and southern areas were significant (β = - 0.01003, P = 0.009 and β = - 0.01480, P < 0.001, respectively. Even though methylation levels in those living in the north-central area were not statistically significant, the test for linear trend was significant (P < 0.001). When PM2.5 was included in the regression model, a unit increase in PM2.5 was associated with 0.00115 (P < 0.001) lower cg05575921 methylation levels.ConclusionLiving in PM2.5 areas was inversely associated with blood AHRR methylation levels at cg05575921. The methylation levels were lowest in participants residing in southern followed by central and north-central areas. Moreover, when PM2.5 was included in the regression model, it was inversely associated with methylation levels at cg05575921. Blood methylation at cg05575921 (AHRR) in non-smokers might indicate different exposures to PM2.5 and lung cancer which is a PM2.5-related disease.
| S-EPMC6503351 | biostudies-literature
Project description:BackgroundPolycyclic aromatic hydrocarbon (PAH)-rich substances like cigarette smoke and PM2.5 induce aryl hydrocarbon receptor (AHR)-mediated aryl hydrocarbon receptor repressor (AHRR) methylation. AHRR cg05575921 and coagulation factor II (thrombin) receptor-like 3 (F2RL3) cg03636183 methylation patterns are well-established biomarkers for smoking. Even though AHRR cg05575921 methylation has recently been associated with PM2.5, the interaction between smoking and PM2.5 on AHRR methylation is yet to be fully explored. We evaluated AHRR and F2RL3 CpG sites to identify potential significant markers in relation to PM2.5 and smoking in Taiwanese adults.MethodsDNA methylation and smoking data of 948 participants aged 30-70 years were obtained from the Taiwan Biobank Database (2008-2015), while PM2.5 data were obtained from the Air Quality Monitoring Database (2006-2011).ResultsSmoking and PM2.5 were independently associated with hypomethylation (lower levels) of AHRR cg05575921, AHRR cg23576855, F2RL3 cg03636183, and F2LR3 cg21911711 after multiple-comparison correction (Bonferroni P < 0.00028409). Cg05575921 was the most hypomethylated AHRR CpG site, while cg03636183 was the most hypomethylated F2RL3 CpG site. Overall, cg05575921 was the most hypomethylated CpG site: β = - 0.03909, P < 0.0001; - 0.17536, P < 0.0001 for former and current smoking, respectively (P-trendsmoking < 0.0001) and - 0.00141, P < 0.0001 for PM2.5. After adjusting for F2RL3 cg03636183, smoking and PM2.5 remained significantly associated with cg05575921 hypomethylation: β - 0.02221, P < 0.0001; - 0.11578, P < 0.0001 for former and current smoking, respectively (P-trendsmoking < 0.0001) and - 0.0070, P = 0.0120 for PM2.5. After stratification by sex, smoking and PM2.5 remained associated (P < 0.05) with cg05575921 hypomethylation in both men (β = - 0.04274, - 0.17700, and - 0.00163 for former smoking, current smoking, and PM2.5, respectively) and women (β = - 0.01937, - 0.17255, and - 0.00105 for former smoking, current smoking, and PM2.5, respectively). After stratification by residential area, former and current smoking remained associated (P < 0.05) with cg05575921 hypomethylation: β = - 0.03918 and - 0.17536, respectively (P-trendsmoking < 0.0001). Living in the central and southern areas was also associated (P < 0.05) with cg05575921 hypomethylation: β = - 0.01356 and - 0.01970, respectively (P-trendarea < 0.0001).ConclusionSmoking and PM2.5 were independently associated with hypomethylation of cg05575921, cg23576855, cg03636183, and cg21911711. The most hypomethylated CpG site was cg05575921 and its association with smoking and PM2.5 was dose-dependent.
| S-EPMC7394684 | biostudies-literature
Project description:BackgroundPrior studies have shown that AHRR (cg05575921) hypomethylation may be a marker of smoking, lung cancer risk and potentially lung cancer survival (in some lung cancer subtypes). It is unknown if AHRR (cg05575921) hypomethylation is associated with reduced survival among lung cancer patients.MethodsIn bisulfite treated leukocyte DNA from 465 lung cancer patients from the Copenhagen prospective lung cancer study, we measured AHRR (cg05575921) methylation. 380 died during max follow-up of 4.4 years. Cox proportional hazard models were used to analyze survival as a function of AHRR (cg05575921) methylation.ResultsWe observed the expected inverse correlation between cumulative smoking and AHRR methylation, as methylation (%) decreased (Coefficient -0.03; 95% confidence interval, -0.04- -0.02, p = 8.6x10-15) for every pack-year. Cumulative smoking > 60 pack-years was associated with reduced survival (hazard ratio and 95% confidence interval 1.48; 1.05-2.09), however, AHRR (cg05575921) methylation was not associated with survival when adjusted for sex, body mass index, smoking status, ethnicity, performance status, TNM Classification, and histology type of lung cancer.ConclusionAHRR (cg05575921) methylation is linked to smoking but does not provide independent prognostic information in lung cancer patients.
| S-EPMC6366765 | biostudies-literature
Project description:There is a growing body of evidence demonstrating an association between smoking and DNA methylation. Accordingly, DNA methylation is now considered a promising biomarker of smoking exposure. We evaluated the relationship between methylation markers (AHRR and F2RL3) and urine cotinine as well as self-reported smoking status. DNA methylation levels of AHRR and F2RL3 in blood as well as urine cotinine were measured in 330 adults (46 to 87 years of age). Pyrosequencing was performed to measure DNA methylation of AHRR and F2RL3 associated with smoking exposure. The lung cancer risk associated with DNA methylation and urine cotinine was analyzed using logistic regression analysis. The AHRR and F2RL3 genes were significantly hypomethylated in current smokers compared to in individuals who have never smoked. An inverse relationship was observed between urine cotinine and methylation levels. Methylation of AHRR and F2RL3 distinguished current smokers from never-smokers with high accuracy. Logistic multivariate analysis showed that AHRR methylation is significantly associated with the risk of lung cancer (OR = 0.96, P = 0.011). Our study validated the smoking-associated DNA methylation markers reported in a Korean population-based cohort. In conclusion, DNA methylation of AHRR and F2RL3 provided accurate measures for smoking exposure. Methylation markers reflecting the long-term effect of smoking on the risk of lung cancer showed better performance in distinguishing former smokers from never-smokers.
| S-EPMC5409156 | biostudies-literature
Project description: Not available
| S-EPMC10397557 | biostudies-literature
Project description:Subclinical atherosclerosis (SA) is the presence of coronary calcification in the absence of cardiovascular symptoms, and it usually progresses to atherosclerotic disease. Studies have shown an association of osteoprotegerin gene (OPG) variants with calcification process in cardiovascular diseases; however, to this day there are no studies that evaluate individuals in the asymptomatic stage of atherosclerotic disease. Therefore, the purpose of this study was to analyze the association of four genetic variants and haplotypes of the OPG gene with the development of SA, through TaqMan genotyping assays. We also aimed to identify potential response elements for transcription factors in these genetic variants. The study included 1413 asymptomatic participants (1041 were controls and 372 were individuals with SA). The rs3102735 polymorphism appeared as a protective marker (OR = 0.693; 95% CI = 0.493-0.974; pheterozygote = 0.035; OR = 0.699; 95% CI = 0.496-0.985; pcodominant&nbsp;1 = 0.040) and two haplotypes were associated with SA, one as a decreased risk: GACC (OR = 0.641, 95% CI = 0.414-0.990, p = 0.045) and another as an increased risk: GACT (OR = 1.208, 95% CI = 1.020-1.431, p = 0.029). Our data suggest a lower risk of SA in rs3102735 C carriers in a representative sample of Mexican mestizo population.
| S-EPMC9221599 | biostudies-literature
Project description:While tobacco smoke exposure strongly influences DNA methylation and is causative in numerous human diseases, the underlying mechanistic links are obscure. Here we investigated genome-wide smoking-associated differentially methylated regions (SM-DMRs) using CD14 monocytes of smokers (n=47) and nonsmokers (n=46) from two independently recruited populations, the Multi-Ethnic Study of Atherosclerosis (MESA) and Clinical Research Unit (CRU) at NIEHS. We found that SM-DMRs preferentially occur at genomic regions with the characteristics of putative enhancer, open chromatin, and the enrichment of TF binding indicated by ENCODE/Roadmap Epigenome/BLUEPRINT datasets. Most of our selected candidate SM-DMRs identified in the two populations were also observed in other hematopoietic cell types (CD15 granulocytes, CD19 B cells, CD4 T cells, CD8 T cells, CD56 NK cells) and were successfully validated using a second method in an independently recruited group of subjects. Aryl-Hydrocarbon Receptor Repressor (AHRR) SM-DMR, located at an intragenic enhancer, was the most significantly affected DMR and we have previously reported that a methylation level of a CpG in this gene was associated with subclinical atherosclerosis. The AHRR DMR was also detected in saliva DNA and these results were highly correlated with effects in monocytes (r2 = 0.90), suggesting that saliva may provide a potential alternative, noninvasive source for biomarkers that use DNA. Mechanistically, our results suggested that AHRR SM-DMR upregulated AHRR mRNA through activating AHRR enhancer in monocytes of smokers but not in granulocytes, indicated by increased noncoding RNA. Taken together, our study suggests that cell type-specific activation of enhancers at SM-DMRs may represent a mechanism driving smoking-related disease.
2017-12-19 | GSE104700 | GEO
Project description:The Mexican population is characterized by high and particular admixture, and the picture of variants associated with disease remains unclear. Here we investigated the distribution of single nucleotide polymorphisms (SNPs) in the Mexican population. We focused on two non-synonymous and three synonymous SNPs in the beta-2 adrenergic receptor gene (ADRB2), which plays key roles in energy balance regulation. These SNPs were genotyped in 2,011 Mexican Amerindians (MAs) belonging to 62 ethnic groups and in 1,980 geographically matched Mexican Mestizos (MEZs). The frequency distribution of all five ADRB2 variants significantly differed between MAs, MEZs, and other continental populations (CPs) from the 1000 Genomes database. Allele frequencies of the three synonymous SNPs rs1042717A, rs1042718A, and rs1042719C were significantly higher in Mexican individuals, particularly among MAs, compared to in the other analyzed populations (P<0.05). The non-synonymous ADRB2 Glu27 allele (rs1042714G), which is associated with several common conditions, showed the lowest frequency in MAs (0.03) compared to other populations worldwide. Among MEZs, this allele showed a frequency of 0.15, intermediate between that in MAs and in Iberians (0.43). Moreover, Glu27 was the only SNP exhibiting a geographic gradient within the MEZ population (from 0.22 to 0.11), reflecting admixed mestizo ancestry across the country. Population differentiation analysis demonstrated that Glu27 had the highest FST value in MAs compared with Europeans (CEU) (0.71), and the lowest between MAs and Japanese (JPT) (0.01), even lower than that observed between MAs and MEZs (0.08). This analysis demonstrated the genetic diversity among Amerindian ethnicities, with the most extreme FST value (0.34) found between the Nahuatls from Morelos and the Seris. This is the first study of ADRB2 genetic variants among MA ethnicities. Our findings add to our understanding of the genetic contribution to variability in disease susceptibility in admixed populations.
| S-EPMC6886845 | biostudies-literature
Project description:The initiation of adolescent smoking is difficult to detect using carbon monoxide or cotinine assays. Previously, we and others have shown that the methylation of cg05575921 is an accurate predictor of adult smoking status. But the dose and time dependency of the demethylation response to smoking initiation in adolescents is not yet well understood. To this end, we conducted three consecutive annual in-person interviews and biological samplings of 448 high school students (wave 1 (W1)-wave 3 (W3)). At W1 (n = 448), 62 subjects reported using tobacco and 72 subjects reported using cannabis at least once in their life-time with 38 and 20 subjects having a positive cotinine and cannabinoid levels, respectively, at W1 intake. At W3 (n = 383), 67 subjects reported using tobacco and 60 subjects reported using cannabis at least once with 75 and 60 subjects having positive cotinine and cannabinoid levels, respectively, at W3. Subjects with undetectable cotinine levels at all three-time waves had stable levels of cg05575921 methylation throughout the study (88.7% at W1 and 88.8% at W3, n = 149), while subjects with positive cotinine levels at all 3 time points manifested a steady decrease in cg05575921 methylation (81.8% at W1 and 71.3% at the W3, n = 12). In those subjects with an affirmative smoking self-report at W3 (n = 17), the amount of demethylation at cg05575921 was correlated with time and intensity of smoking. We conclude that cg05575921 methylation is a sensitive, dose-dependent indicator of early stages of smoking, and may help to identify smokers in the early stages of smoking.
| S-EPMC7315557 | biostudies-literature
Project description:Several studies have identified nearly 40 different type 2 diabetes susceptibility loci, mainly in European populations, but few of them have been evaluated in the Mexican population. The aim of this study was to examine the extent to which 24 common genetic variants previously associated with type 2 diabetes are associated in Mexican Mestizos. Twenty-four single nucleotide polymorphisms (SNPs) in or near genes (KCNJ11, PPARG, TCF7L2, SLC30A8, HHEX, CDKN2A/2B, CDKAL1, IGF2BP2, ARHGEF11, JAZF1, CDC123/CAMK1D, FTO, TSPAN8/LGR5, KCNQ1, THADA, ADAMTS9, NOTCH2, NXPH1, RORA, UBQLNL, and RALGPS2) were genotyped in Mexican Mestizos. A case-control association study comprising 1,027 type 2 diabetic individuals and 990 control individuals was conducted. To account for population stratification, a panel of 104 ancestry-informative markers was analyzed. Association to type 2 diabetes was found for rs13266634 (SLC30A8), rs7923837 (HHEX), rs10811661 (CDKN2A/2B), rs4402960 (IGF2BP2), rs12779790 (CDC123/CAMK1D), and rs2237892 (KCNQ1). In addition, rs7754840 (CDKAL1) was associated in the nonobese type 2 diabetic subgroup, and for rs7903146 (TCF7L2), association was observed for early-onset type 2 diabetes. Lack of association for the rest of the variants may have resulted from insufficient power to detect smaller allele effects.
| S-EPMC3501881 | biostudies-literature