Systematic review of lung function and COPD with peripheral blood DNA methylation in population based studies

Background Epigenetic variations in peripheral blood have potential as biomarkers for disease. This systematic review assesses the association of lung function and chronic obstructive pulmonary disease (COPD) with DNA methylation profiles in peripheral blood from population-based studies. Methods Online databases Medline, Embase, and Web of Science were searched. Google Scholar was searched to identify grey literature. After removing duplicate articles, 1155 articles were independently screened by two investigators. Peer reviewed reports on population-based studies that examined peripheral blood DNA methylation in participants with measured lung function (FEV1, FEV1/FVC ratio) or known COPD status were selected for full-text review. Six articles were suitable for inclusion. Information regarding study characteristics, designs, methodologies and conclusions was extracted. A narrative synthesis was performed based on published results. Results Three of the six articles assessed the association of COPD with DNA methylation, and two of these also included associations with lung function. Overall, five reports examined the association of lung function with DNA methylation profiles. Five of the six articles reported ‘significant’ results. However, no consistent CpG sites were identified across studies for COPD status or lung function values. Conclusions DNA methylation patterns in peripheral blood from individuals with reduced lung function or COPD may be different to those in people with normal lung function. However, this systematic review did not find any consistent associations of lung function or COPD with differentially methylated CpG sites. Large studies with a longitudinal design to address reverse causality may prove a more fruitful area of research

Role of DNA methylation in the association of lung function with body mass index: a two-step epigenetic Mendelian randomisation study

Low lung function has been associated with increased body mass index (BMI). The aim of this study was to investigate whether the effect of BMI on lung function is mediated by DNA methylation.; We used individual data from 285,495 participants in four population-based cohorts: the European Community Respiratory Health Survey, the Northern Finland Birth Cohort 1966, the Swiss Study on Air Pollution and Lung Disease in Adults, and the UK Biobank. We carried out Mendelian randomisation (MR) analyses in two steps using a two-sample approach with SNPs as instrumental variables (IVs) in each step. In step 1 MR, we estimated the causal effect of BMI on peripheral blood DNA methylation (measured at genome-wide level) using 95 BMI-associated SNPs as IVs. In step 2 MR, we estimated the causal effect of DNA methylation on FEV; 1; , FVC, and FEV; 1; /FVC using two SNPs acting as methQTLs occurring close (in cis) to CpGs identified in the first step. These analyses were conducted after exclusion of weak IVs (F statistic < 10) and MR estimates were derived using the Wald ratio, with standard error from the delta method. Individuals whose data were used in step 1 were not included in step 2.; In step 1, we found that BMI might have a small causal effect on DNA methylation levels (less than 1% change in methylation per 1 kg/m2 increase in BMI) at two CpGs (cg09046979 and cg12580248). In step 2, we found no evidence of a causal effect of DNA methylation at cg09046979 on lung function. We could not estimate the causal effect of DNA methylation at cg12580248 on lung function as we could not find publicly available data on the association of this CpG with SNPs.; To our knowledge, this is the first paper to report the use of a two-step MR approach to assess the role of DNA methylation in mediating the effect of a non-genetic factor on lung function. Our findings do not support a mediating effect of DNA methylation in the association of lung function with BMI

Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes

Plasma levels of liver enzymes provide insights into hepatic function and related diseases. Here, the authors perform a genome-wide association study on three liver enzymes, identifying genetic variants associated with their plasma concentration as well as links to metabolic and cardiovascular diseases. Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease

Methyl-binding domain protein-based DNA isolation from human blood serum combines DNA analyses and serum-autoantibody testing

<p>Abstract</p> <p>Background</p> <p>Circulating cell free DNA in serum as well as serum-autoantibodies and the serum proteome have great potential to contribute to early cancer diagnostics via non invasive blood tests. However, most DNA preparation protocols destroy the protein fraction and therefore do not allow subsequent protein analyses. In this study a novel approach based on methyl binding domain protein (MBD) is described to overcome the technical difficulties of combining DNA and protein analysis out of one single serum sample.</p> <p>Methods</p> <p>Serum or plasma samples from 98 control individuals and 54 breast cancer patients were evaluated upon silica membrane- or MBD affinity-based DNA isolation via qPCR targeting potential DNA methylation markers as well as by protein-microarrays for tumor-autoantibody testing.</p> <p>Results</p> <p>In control individuals, an average DNA level of 22.8 ± 25.7 ng/ml was detected applying the silica membrane based protocol and 8.5 ± 7.5 ng/ml using the MBD-approach, both values strongly dependent on the serum sample preparation methods used. In contrast to malignant and benign tumor serum samples, cell free DNA concentrations were significantly elevated in sera of metastasizing breast cancer patients. Technical evaluation revealed that serum upon MBD-based DNA isolation is suitable for protein-array analyses when data are consistent to untreated serum samples.</p> <p>Conclusion</p> <p>MBD affinity purification allows DNA isolations under native conditions retaining the protein function, thus for example enabling combined analyses of DNA methylation and autoantigene-profiles from the same serum sample and thereby improving minimal invasive diagnostics.</p

Rare and low-frequency exonic variants and gene-by-smoking interactions in pulmonary function

Genome-wide association studies have identified numerous common genetic variants associated with spirometric measures of pulmonary function, including forced expiratory volume in one second (FEV1), forced vital capacity, and their ratio. However, variants with lower minor allele frequencies are less explored. We conducted a large-scale gene-smoking interaction meta-analysis on exonic rare and low-frequency variants involving 44,429 individuals of European ancestry in the discovery stage and sought replication in the UK BiLEVE study with 45,133 European ancestry samples and UK Biobank study with 59,478 samples. We leveraged data on cigarette smoking, the major environmental risk factor for reduced lung function, by testing gene-by-smoking interaction effects only and simultaneously testing the genetic main effects and interaction effects. The most statistically significant signal that replicated was a previously reported low-frequency signal in GPR126, distinct from common variant associations in this gene. Although only nominal replication was obtained for a top rare variant signal rs142935352 in one of the two studies, interaction and joint tests for current smoking and PDE3B were s

SERPINA1 methylation and lung function in tobacco-smoke exposed European children and adults:A meta-analysis of ALEC population-based cohorts

BackgroundThe pathophysiological role of SERPINA1 in respiratory health may be more strongly determined by the regulation of its expression than by common genetic variants. A family based study of predominantly smoking adults found methylation at two Cytosine-phosphate-Guanine sites (CpGs) in SERPINA1 gene to be associated with chronic obstructive pulmonary disease risk. The objective of this study was to confirm the association of lung function with SERPINA1 methylation in general population samples by testing a comprehensive set of CpGs in the SERPINA gene cluster. We considered lung function level and decline in adult smokers from three European population-based cohorts and lung function level and growth in tobacco-smoke exposed children from a birth cohort.MethodsDNA methylation using Illumina Infinium Human Methylation 450 k and EPIC beadchips and lung function were measured at two time points in 1076 SAPALDIA, ECRHS and NFBC adult cohort participants and 259 ALSPAC children. Associations of methylation at 119 CpG sites in the SERPINA gene cluster (PP4R4-SERPINA13P) with lung functions and circulating alpha-1-antitripsin (AAT) were assessed using multivariable cross-sectional and longitudinal regression models.ResultsMethylation at cg08257009 in the SERPINA gene cluster, located 32 kb downstream of SERPINA1, not annotated to a gene, was associated with FEV1/FVC at the Bonferroni corrected level in adults, but not in children. None of the methylation signals in the SERPINA1 gene showed associations with lung function after correcting for multiple testing.ConclusionsThe results do not support a role of SERPINA1 gene methylation as determinant of lung function across the life course in the tobacco smoke exposed general population exposed

Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P= 3.96 x 10(-14)). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.Peer reviewe