Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression

Many workers are daily exposed to occupational agents like gases/fumes, mineral dust or biological dust, which could induce adverse health effects. Epigenetic mechanisms, such as DNA methylation, have been suggested to play a role. We therefore aimed to identify differentially methylated regions (DMRs) upon occupational exposures in never-smokers and investigated if these DMRs associated with gene expression levels. To determine the effects of occupational exposures independent of smoking, 903 never-smokers of the LifeLines cohort study were included. We performed three genome-wide methylation analyses (Illumina 450 K), one per occupational exposure being gases/fumes, mineral dust and biological dust, using robust linear regression adjusted for appropriate confounders. DMRs were identified using comb-p in Python. Results were validated in the Rotterdam Study (233 never-smokers) and methylation-expression associations were assessed using Biobank-based Integrative Omics Study data (n = 2802). Of the total 21 significant DMRs, 14 DMRs were associated with gases/fumes and 7 with mineral dust. Three of these DMRs were associated with both exposures (RPLP1 and LINC02169 (2x)) and 11 DMRs were located within transcript start sites of gene expression regulating genes. We replicated two DMRs with gases/fumes (VTRNA2-1 and GNAS) and one with mineral dust (CCDC144NL). In addition, nine gases/fumes DMRs and six mineral dust DMRs significantly associated with gene expression levels. Our data suggest that occupational exposures may induce differential methylation of gene expression regulating genes and thereby may induce adverse health effects. Given the millions of workers that are exposed daily to occupational exposures, further studies on this epigenetic mechanism and health outcomes are warranted

The Relationship of DNA Methylation with Age, Gender and Genotype in Twins and Healthy Controls

Cytosine-5 methylation within CpG dinucleotides is a potentially important mechanism of epigenetic influence on human traits and disease. In addition to influences of age and gender, genetic control of DNA methylation levels has recently been described. We used whole blood genomic DNA in a twin set (23 MZ twin-pairs and 23 DZ twin-pairs, N = 92) as well as healthy controls (N = 96) to investigate heritability and relationship with age and gender of selected DNA methylation profiles using readily commercially available GoldenGate bead array technology. Despite the inability to detect meaningful methylation differences in the majority of CpG loci due to tissue type and locus selection issues, we found replicable significant associations of DNA methylation with age and gender. We identified associations of genetically heritable single nucleotide polymorphisms with large differences in DNA methylation levels near the polymorphism (cis effects) as well as associations with much smaller differences in DNA methylation levels elsewhere in the human genome (trans effects). Our results demonstrate the feasibility of array-based approaches in studies of DNA methylation and highlight the vast differences between individual loci. The identification of CpG loci of which DNA methylation levels are under genetic control or are related to age or gender will facilitate further studies into the role of DNA methylation and disease

Detection of high-risk human papillomavirus HPV by the novel AmpFire isothermal HPV assay among pregnant women in Pemba Island, Tanzania

Introduction: human papillomavirus (HPV) is the most common sexually transmitted virus in the world. Prevalence of infection differs, with highest rates reported in sub-Saharan African, including the country of Tanzania. In pregnancy, the hormonal changes and immune changes seem to facilitate HPV persistence, increasing the cancer risk and the risk of vertical transmission towards the placenta and the fetus. The burden of HPV infection is still high despite multiple screening and detection test available. The AmpFire® HPV assay is a novel nucleic acid isothermal amplification with real-time fluorescence detection assay that can test simultaneously 15 high-risk HPV. This nested cohort study aims to contribute evidence on the prevalence of HPV infection and persistence across two time points among pregnant women in Pemba island, Tanzania. Methods: vaginal swabs that were previously collected during pregnancy were stored in eNAT buffer (n1 =385 and n2 =187) and were tested with AmpFire® screening assay, for simultaneous detection of the HPV 16, 18 and other high-risk HPV genotypes 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66 and 68. Results: the AmpFire® HPV assay detected an 11% and 6% high-risk HPV prevalence at the two time points among pregnant women in Pemba island, consecutively. For the 133 women whose samples were tested at both time points, the persistence rate of high-risk HPV was 64%. Conclusion: novel isothermal HPV assay, such as the AmpFire®, might be feasible to use in low-income regions

Sexually Transmitted Infections and Behavioral Determinants of Sexual and Reproductive Health in the Allahabad District (India) Based on Data from the ChlamIndia Study

Background: Sexually transmitted infections (STIs), like Chlamydia trachomatis and Neisseria gonorrhoeae (CT and NG, respectively) are linked to an important sexual and reproductive health (SRH) burden worldwide. Behavior is an important predictor for SRH, as it dictates the risk for STIs. Assessing the behavior of a population helps to assess its risk profile. Methods: Study participants were recruited at a gynecology outpatient department (OPD) in the Allahabad district in Uttar Pradesh India, and a questionnaire was used to assess demographics, SRH, and obstetric history. Patients provided three samples (urine, vaginal swab, and whole blood). These samples were used to identify CT and NG using PCR/NAAT and CT IgG ELISA. Results: A total of 296 women were included for testing; mean age was 29 years. No positive cases of CT and NG were observed using PCR/NAAT. A 7% (22/296) positivity rate for CT was observed using IgG ELISA. No positive association was found between serology and symptoms (vaginal discharge, abdominal pain, dysuria, and dyspareunia) or adverse pregnancy outcomes (miscarriage and stillbirth). Positive relations with CT could be observed with consumption of alcohol, illiteracy, and tenesmus (p-value 0.02–0.03). Discussion: STI prevalence in this study was low, but a high burden of SRH morbidity was observed, with a high symptomatic load. High rates of miscarriage (31%) and stillbirth (8%) were also observed among study subjects. No associations could be found between these ailments and CT infection. These rates are high even for low- and middle-income country standards. Conclusion: This study puts forward high rates of SRH morbidity, and instances of adverse reproductive health outcomes are highlighted in this study, although no associations with CT infection could be found. This warrants more investigation into the causes leading to these complaints in the Indian scenario and potential biases to NAAT testing, such as consumption of over-the-counter antimicrobials

Genetic Analysis of Innate Immunity in Crohn's Disease and Ulcerative Colitis Identifies Two Susceptibility Loci Harboring CARD9 and IL18RAP

The two main phenotypes of inflammatory bowel disease (IBD)—Crohn's disease (CD) and ulcerative colitis (UC)—are chronic intestinal inflammatory disorders with a complex genetic background. Using a three-stage design, we performed a functional candidate-gene analysis of innate immune pathway in IBD. In phase I, we typed 354 SNPs from 85 innate immunity genes in 520 Dutch IBD patients (284 CD, 236 UC) and 808 controls. In phase II, ten autosomal SNPs showing association at p < 0.006 in phase I were replicated in a second cohort of 545 IBD patients (326 CD, 219 UC) and 360 controls. In phase III, four SNPs with p < 0.01 in the combined phase I and phase II analysis were genotyped in an additional 786 IBD samples (452 CD, 334 UC) and 768 independent controls. Joint analysis of 1851 IBD patients (1062 CD, 789 UC) and 1936 controls demonstrated strong association to the IL18RAP rs917997 SNP for both CD and UC (pIBD 1.9 × 10−8; OR 1.35). Association in CD is independently supported by the Crohn's disease dataset of the Wellcome Trust Case Control Consortium (imputed SNP rs917997, p = 9.19 × 10−4). In addition, an association of the CARD9 rs10870077 SNP to CD and UC was observed (pIBD = 3.25 × 10−5; OR 1.21). Both genes are located in extended haplotype blocks on 2q11-2q12 and 9q34.3, respectively. Our results indicate two IBD loci and further support the importance of the innate immune system in the predisposition to both CD and UC

Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression

Many workers are daily exposed to occupational agents like gases/fumes, mineral dust or biological dust, which could induce adverse health effects. Epigenetic mechanisms, such as DNA methylation, have been suggested to play a role. We therefore aimed to identify differentially methylated regions (DMRs) upon occupational exposures in never-smokers and investigated if these DMRs associated with gene expression levels. To determine the effects of occupational exposures independent of smoking, 903 never-smokers of the LifeLines cohort study were included. We performed three genome-wide methylation analyses (Illumina 450 K), one per occupational exposure being gases/fumes, mineral dust and biological dust, using robust linear regression adjusted for appropriate confounders. DMRs were identified using comb-p in Python. Results were validated in the Rotterdam Study (233 never-smokers) and methylation-expression associations were assessed using Biobank-based Integrative Omics Study data (n = 2802). Of the total 21 significant DMRs, 14 DMRs were associated with gases/fumes and 7 with mineral dust. Three of these DMRs were associated with both exposures (RPLP1 and LINC02169 (2x)) and 11 DMRs were located within transcript start sites of gene expression regulating genes. We replicated two DMRs with gases/fumes (VTRNA2-1 and GNAS) and one with mineral dust (CCDC144NL). In addition, nine gases/fumes DMRs and six mineral dust DMRs significantly associated with gene expression levels. Our data suggest that occupational exposures may induce differential methylation of gene expression regulating genes and thereby may induce adverse health effects. Given the millions of workers that are exposed daily to occupational exposures, further studies on this epigenetic mechanism and health outcomes are warranted.</p

Association of FcgR2a, but Not FcgR3a, with Inflammatory Bowel Diseases Across Three Caucasian Populations

Item does not contain fulltextBACKGROUND: The Fc receptors II and III (FcgR2a, and FcgR3a) play a crucial role in the regulation of the immune response. The FcgR2a*519GG and FcgR3a*559CC genotypes have been associated with several autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, nephritis, and possibly to type I diabetes, and celiac disease. In a large multicenter, two-stage study of 6570 people, we tested whether the FcgR2a and FcgR3a genes were also involved in inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC). METHODS: We genotyped the FcgR2a*A519G and FcgR3a*A559C functional variants in 4205 IBD patients in six well-phenotyped Caucasian IBD cohorts and 2365 ethnically matched controls recruited from the Netherlands, Spain, and New Zealand. RESULTS: In the initial Dutch study we found a significant association of FcgR2a genotypes with IBD (P-genotype = 0.02); while the FcgR2a*519GG was more common in controls (23%) than in IBD patients (18%; odds ratio [OR] = 0.75; 95% confidence interval [CI] 0.61-0.92; P = 0.004). This association was corroborated by a combined analysis across all the study populations (Mantel-Haenszel [MH] OR = 0.84; 0.74-0.95; P = 0.005) in the next stage. The Fcgr2a*GG genotype was associated with both UC (MH-OR = 0.84; 0.72-0.97; P = 0.01) and CD (MH-OR = 0.84; 0.73-0.97; P = 0.01), suggesting that this genotype confers a protective effect against IBD. There was no association of FcgR3a*A559C genotypes with IBD, CD, or UC in any of the three studied populations. CONCLUSIONS: The FcgR2a*519G functional variant was associated with IBD and reduced susceptibility to UC and to CD in Caucasians. There was no association between FcgR3a*5A559C and IBD, CD or UC.1 december 201