Publications by authors named "Alexandra Zhernakova"

141 Publications

Population-wide diversity and stability of serum antibody epitope repertoires against human microbiota.

Nat Med 2021 Jul 19. Epub 2021 Jul 19.

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.

Serum antibodies can recognize both pathogens and commensal gut microbiota. However, our current understanding of antibody repertoires is largely based on DNA sequencing of the corresponding B-cell receptor genes, and actual bacterial antigen targets remain incompletely characterized. Here we have profiled the serum antibody responses of 997 healthy individuals against 244,000 rationally selected peptide antigens derived from gut microbiota and pathogenic and probiotic bacteria. Leveraging phage immunoprecipitation sequencing (PhIP-Seq) based on phage-displayed synthetic oligo libraries, we detect a wide breadth of individual-specific as well as shared antibody responses against microbiota that associate with age and gender. We also demonstrate that these antibody epitope repertoires are more longitudinally stable than gut microbiome species abundances. Serum samples of more than 200 individuals collected five years apart could be accurately matched and could serve as an immunologic fingerprint. Overall, our results suggest that systemic antibody responses provide a non-redundant layer of information about microbiota beyond gut microbial species composition.
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http://dx.doi.org/10.1038/s41591-021-01409-3DOI Listing
July 2021

A Benchmark of Genetic Variant Calling Pipelines Using Metagenomic Short-Read Sequencing.

Front Genet 2021 10;12:648229. Epub 2021 May 10.

Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, Netherlands.

Microbes live in complex communities that are of major importance for environmental ecology, public health, and animal physiology and pathology. Short-read metagenomic shotgun sequencing is currently the state-of-the-art technique for exploring these communities. With the aid of metagenomics, our understanding of the microbiome is moving from composition toward functionality, even down to the genetic variant level. While the exploration of single-nucleotide variation in a genome is a standard procedure in genomics, and many sophisticated tools exist to perform this task, identification of genetic variation in metagenomes remains challenging. Major factors that hamper the widespread application of variant-calling analysis include low-depth sequencing of individual genomes (which is especially significant for the microorganisms present in low abundance), the existence of large genomic variation even within the same species, the absence of comprehensive reference genomes, and the noise introduced by next-generation sequencing errors. Some bioinformatics tools, such as metaSNV or InStrain, have been created to identify genetic variants in metagenomes, but the performance of these tools has not been systematically assessed or compared with the variant callers commonly used on single or pooled genomes. In this study, we benchmark seven bioinformatic tools for genetic variant calling in metagenomics data and assess their performance. To do so, we simulated metagenomic reads to mimic human microbial composition, sequencing errors, and genetic variability. We also simulated different conditions, including low and high depth of coverage and unique or multiple strains per species. Our analysis of the simulated data shows that probabilistic method-based tools such as HaplotypeCaller and Mutect2 from the GATK toolset show the best performance. By applying these tools to longitudinal gut microbiome data from the Human Microbiome Project, we show that the genetic similarity between longitudinal samples from the same individuals is significantly greater than the similarity between samples from different individuals. Our benchmark shows that probabilistic tools can be used to call metagenomes, and we recommend the use of GATK's tools as reliable variant callers for metagenomic samples.
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http://dx.doi.org/10.3389/fgene.2021.648229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141913PMC
May 2021

Stability of the human gut virome and effect of gluten-free diet.

Cell Rep 2021 May;35(7):109132

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9713GZ, the Netherlands. Electronic address:

The human gut microbiome consists of bacteria, archaea, eukaryotes, and viruses. The gut viruses are relatively underexplored. Here, we longitudinally analyzed the gut virome composition in 11 healthy adults: its stability, variation, and the effect of a gluten-free diet. Using viral enrichment and a de novo assembly-based approach, we demonstrate the quantitative dynamics of the gut virome, including dsDNA, ssDNA, dsRNA, and ssRNA viruses. We observe highly divergent individual viral communities, carrying on an average 2,143 viral genomes, 13.1% of which were present at all 3 time points. In contrast to previous reports, the Siphoviridae family dominates over Microviridae in studied individual viromes. We also show individual viromes to be stable at the family level but to vary substantially at the genera and species levels. Finally, we demonstrate that lower initial diversity of the human gut virome leads to a more pronounced effect of the dietary intervention on its composition.
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http://dx.doi.org/10.1016/j.celrep.2021.109132DOI Listing
May 2021

The long-term genetic stability and individual specificity of the human gut microbiome.

Cell 2021 Apr 9;184(9):2302-2315.e12. Epub 2021 Apr 9.

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9713GZ, the Netherlands; Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen 9713GZ, the Netherlands. Electronic address:

By following up the gut microbiome, 51 human phenotypes and plasma levels of 1,183 metabolites in 338 individuals after 4 years, we characterize microbial stability and variation in relation to host physiology. Using these individual-specific and temporally stable microbial profiles, including bacterial SNPs and structural variations, we develop a microbial fingerprinting method that shows up to 85% accuracy in classifying metagenomic samples taken 4 years apart. Application of our fingerprinting method to the independent HMP cohort results in 95% accuracy for samples taken 1 year apart. We further observe temporal changes in the abundance of multiple bacterial species, metabolic pathways, and structural variation, as well as strain replacement. We report 190 longitudinal microbial associations with host phenotypes and 519 associations with plasma metabolites. These associations are enriched for cardiometabolic traits, vitamin B, and uremic toxins. Finally, mediation analysis suggests that the gut microbiome may influence cardiometabolic health through its metabolites.
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http://dx.doi.org/10.1016/j.cell.2021.03.024DOI Listing
April 2021

Patient attitudes towards faecal sampling for gut microbiome studies and clinical care reveal positive engagement and room for improvement.

PLoS One 2021 8;16(4):e0249405. Epub 2021 Apr 8.

Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Faecal sample collection is crucial for gut microbiome research and its clinical applications. However, while patients and healthy volunteers are routinely asked to provide stool samples, their attitudes towards sampling remain largely unknown. Here, we investigate the attitudes of 780 Dutch patients, including participants in a large Inflammatory Bowel Disease (IBD) gut microbiome cohort and population controls, in order to identify barriers to sample collection and provide recommendations for gut microbiome researchers and clinicians. We sent questionnaires to 660 IBD patients and 112 patients with other disorders who had previously been approached to participate in gut microbiome studies. We also conducted 478 brief interviews with participants in our general population cohort who had collected stool samples. Statistical analysis of the data was performed using R. 97.4% of respondents reported that they had willingly participated in stool sample collection for gut microbiome research, and most respondents (82.9%) and interviewees (95.6%) indicated willingness to participate again, with their motivations for participating being mainly altruistic (57.0%). Responses indicated that storing stool samples in the home freezer for a prolonged time was the main barrier to participation (52.6%), but clear explanations of the sampling procedures and their purpose increased participant willingness to collect and freeze samples (P = 0.046, P = 0.003). To account for participant concerns, gut microbiome researchers establishing cohorts and clinicians trying new faecal tests should provide clear instructions, explain the rationale behind their protocol, consider providing a small freezer and inform patients about study outcomes. By assessing the attitudes, motives and barriers surrounding participation in faecal sample collection, we provide important information that will contribute to the success of gut microbiome research and its near-future clinical applications.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249405PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8031379PMC
April 2021

Long-term dietary patterns are associated with pro-inflammatory and anti-inflammatory features of the gut microbiome.

Gut 2021 Jul 2;70(7):1287-1298. Epub 2021 Apr 2.

Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands

Objective: The microbiome directly affects the balance of pro-inflammatory and anti-inflammatory responses in the gut. As microbes thrive on dietary substrates, the question arises whether we can nourish an anti-inflammatory gut ecosystem. We aim to unravel interactions between diet, gut microbiota and their functional ability to induce intestinal inflammation.

Design: We investigated the relation between 173 dietary factors and the microbiome of 1425 individuals spanning four cohorts: Crohn's disease, ulcerative colitis, irritable bowel syndrome and the general population. Shotgun metagenomic sequencing was performed to profile gut microbial composition and function. Dietary intake was assessed through food frequency questionnaires. We performed unsupervised clustering to identify dietary patterns and microbial clusters. Associations between diet and microbial features were explored per cohort, followed by a meta-analysis and heterogeneity estimation.

Results: We identified 38 associations between dietary patterns and microbial clusters. Moreover, 61 individual foods and nutrients were associated with 61 species and 249 metabolic pathways in the meta-analysis across healthy individuals and patients with IBS, Crohn's disease and UC (false discovery rate<0.05). Processed foods and animal-derived foods were consistently associated with higher abundances of Firmicutes, species of the genus and endotoxin synthesis pathways. The opposite was found for plant foods and fish, which were positively associated with short-chain fatty acid-producing commensals and pathways of nutrient metabolism.

Conclusion: We identified dietary patterns that consistently correlate with groups of bacteria with shared functional roles in both, health and disease. Moreover, specific foods and nutrients were associated with species known to infer mucosal protection and anti-inflammatory effects. We propose microbial mechanisms through which the diet affects inflammatory responses in the gut as a rationale for future intervention studies.
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http://dx.doi.org/10.1136/gutjnl-2020-322670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223641PMC
July 2021

Lifelines COVID-19 cohort: investigating COVID-19 infection and its health and societal impacts in a Dutch population-based cohort.

BMJ Open 2021 03 17;11(3):e044474. Epub 2021 Mar 17.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Purpose: The Lifelines COVID-19 cohort was set up to assess the psychological and societal impacts of the COVID-19 pandemic and investigate potential risk factors for COVID-19 within the Lifelines prospective population cohort.

Participants: Participants were recruited from the 140 000 eligible participants of Lifelines and the Lifelines NEXT birth cohort, who are all residents of the three northern provinces of the Netherlands. Participants filled out detailed questionnaires about their physical and mental health and experiences on a weekly basis starting in late March 2020, and the cohort consists of everyone who filled in at least one questionnaire in the first 8 weeks of the project. FINDINGS TO DATE: >71 000 unique participants responded to the questionnaires at least once during the first 8 weeks, with >22 000 participants responding to seven questionnaires. Compiled questionnaire results are continuously updated and shared with the public through the Corona Barometer website. Early results included a clear signal that younger people living alone were experiencing greater levels of loneliness due to lockdown, and subsequent results showed the easing of anxiety as lockdown was eased in June 2020.

Future Plans: Questionnaires were sent on a (bi)weekly basis starting in March 2020 and on a monthly basis starting July 2020, with plans for new questionnaire rounds to continue through 2020 and early 2021. Questionnaire frequency can be increased again for subsequent waves of infections. Cohort data will be used to address how the COVID-19 pandemic developed in the northern provinces of the Netherlands, which environmental and genetic risk factors predict disease susceptibility and severity and the psychological and societal impacts of the crisis. Cohort data are linked to the extensive health, lifestyle and sociodemographic data held for these participants by Lifelines, a 30-year project that started in 2006, and to data about participants held in national databases.
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http://dx.doi.org/10.1136/bmjopen-2020-044474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977080PMC
March 2021

The composition and metabolic potential of the human small intestinal microbiota within the context of inflammatory bowel disease.

J Crohns Colitis 2021 Jan 30. Epub 2021 Jan 30.

Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, the Netherlands.

Background And Aims: The human gastrointestinal tract harbours distinct microbial communities essential for health. Little is known about small intestinal communities, despite the small intestine playing a fundamental role in nutrient absorption and host-microbe immune homeostasis. We aimed to explore the small intestine microbial composition and metabolic potential, in the context of inflammatory bowel disease (IBD).

Methods: Metagenomes derived from faecal samples and extensive phenotypes were collected from 57 individuals with an ileostomy or ileoanal pouch, and compared with 1178 general population and 478 IBD faecal metagenomes. Microbiome features were identified using MetaPhAn2 and HUMAnN2, and association analyses were performed using multivariate linear regression.

Results: Small intestinal samples had a significantly lower bacterial diversity, compared with the general population and, to a lesser extent, IBD samples. Comparing bacterial composition, small intestinal samples clustered furthest from general population samples and closest to IBD samples with intestinal resections. Veillonella atypica, Streptococcus salivarius and Actinomyces graevenitzii were among the species significantly enriched in the small intestine. Predicted metabolic pathways in the small intestine are predominantly involved in simple carbohydrate and energy metabolism, but also suggest a higher proinflammatory potential.

Conclusion: We described the bacterial composition and metabolic potential of the small intestinal microbiota. The colonic microbiome of IBD patients, particularly with intestinal resections, showed resemblance to that of the small intestine. Moreover, several features characterising the small intestinal microbiome have been previously associated with IBD. These results highlight the importance of studying the small intestinal microbiota to gain new insight into disease pathogenesis.
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http://dx.doi.org/10.1093/ecco-jcc/jjab020DOI Listing
January 2021

Healthy Cotwins Share Gut Microbiome Signatures With Their Inflammatory Bowel Disease Twins and Unrelated Patients.

Gastroenterology 2021 May 19;160(6):1970-1985. Epub 2021 Jan 19.

Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. Electronic address:

Background & Aims: It is currently unclear whether reported changes in the gut microbiome are cause or consequence of inflammatory bowel disease (IBD). Therefore, we studied the gut microbiome of IBD-discordant and -concordant twin pairs, which offers the unique opportunity to assess individuals at increased risk of developing IBD, namely healthy cotwins from IBD-discordant twin pairs.

Methods: Fecal samples were obtained from 99 twins (belonging to 51 twin pairs), 495 healthy age-, sex-, and body mass index-matched controls, and 99 unrelated patients with IBD. Whole-genome metagenomic shotgun sequencing was performed. Taxonomic and functional (pathways) composition was compared among healthy cotwins, IBD-twins, unrelated patients with IBD, and healthy controls with multivariable (ie, adjusted for potential confounding) generalized linear models.

Results: No significant differences were observed in the relative abundance of species and pathways between healthy cotwins and their IBD-twins (false discovery rate <0.10). Compared with healthy controls, 13, 19, and 18 species, and 78, 105, and 153 pathways were found to be differentially abundant in healthy cotwins, IBD-twins, and unrelated patients with IBD, respectively (false discovery rate <0.10). Of these, 8 (42.1%) of 19 and 1 (5.6%) of 18 species, and 37 (35.2%) of 105 and 30 (19.6%) of 153 pathways overlapped between healthy cotwins and IBD-twins, and healthy cotwins and unrelated patients with IBD, respectively. Many of the shared species and pathways have previously been associated with IBD. The shared pathways include potentially inflammation-related pathways, for example, an increase in propionate degradation and L-arginine degradation pathways.

Conclusions: The gut microbiome of healthy cotwins from IBD-discordant twin pairs displays IBD-like signatures. These IBD-like microbiome signatures might precede the onset of IBD. However, longitudinal follow-up studies are needed to infer a causal relationship.
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http://dx.doi.org/10.1053/j.gastro.2021.01.030DOI Listing
May 2021

Large-scale association analyses identify host factors influencing human gut microbiome composition.

Nat Genet 2021 02 18;53(2):156-165. Epub 2021 Jan 18.

Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10 < P < 5 × 10) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
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http://dx.doi.org/10.1038/s41588-020-00763-1DOI Listing
February 2021

Genetic Association of a Gain-of-Function IFNGR1 Polymorphism and the Intergenic Region LNCAROD/DKK1 With Behçet's Disease.

Arthritis Rheumatol 2021 Jul 18;73(7):1244-1252. Epub 2021 May 18.

Universidad de Granada and ibs.GRANADA Instituto de Investigación Biosanitaria, Granada, Spain.

Objective: Behçet's disease is a complex systemic inflammatory vasculitis of incompletely understood etiology. This study was undertaken to investigate genetic associations with Behçet's disease in a diverse multiethnic population.

Methods: A total of 9,444 patients and controls from 7 different populations were included in this study. Genotyping was performed using an Infinium ImmunoArray-24 v.1.0 or v.2.0 BeadChip. Analysis of expression data from stimulated monocytes, and epigenetic and chromatin interaction analyses were performed.

Results: We identified 2 novel genetic susceptibility loci for Behçet's disease, including a risk locus in IFNGR1 (rs4896243) (odds ratio [OR] 1.25; P = 2.42 × 10 ) and within the intergenic region LNCAROD/DKK1 (rs1660760) (OR 0.78; P = 2.75 × 10 ). The risk variants in IFNGR1 significantly increased IFNGR1 messenger RNA expression in lipopolysaccharide-stimulated monocytes. In addition, our results replicated the association (P < 5 × 10 ) of 6 previously identified susceptibility loci in Behçet's disease: IL10, IL23R, IL12A-AS1, CCR3, ADO, and LACC1, reinforcing the notion that these loci are strong genetic factors in Behçet's disease shared across ancestries. We also identified >30 genetic susceptibility loci with a suggestive level of association (P < 5 × 10 ), which will require replication. Finally, functional annotation of genetic susceptibility loci in Behçet's disease revealed their possible regulatory roles and suggested potential causal genes and molecular mechanisms that could be further investigated.

Conclusion: We performed the largest genetic association study in Behçet's disease to date. Our findings reveal novel putative functional variants associated with the disease and replicate and extend the genetic associations in other loci across multiple ancestries.
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http://dx.doi.org/10.1002/art.41637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238846PMC
July 2021

An association between chronic widespread pain and the gut microbiome.

Rheumatology (Oxford) 2020 Dec 17. Epub 2020 Dec 17.

Department of Twin Research and Genetic Epidemiology, School of Life Course Sciences, King's College London, London, United Kingdom.

Objectives: Chronic widespread musculoskeletal pain (CWP) is a characteristic symptom of fibromyalgia, which has been shown to be associated with an altered gut microbiome. Microbiome studies to date have not examined the milder CWP phenotype specifically nor have they explored the role of raised BMI. The aim of this study was to investigate whether the microbiome is abnormal in CWP.

Methods: CWP was assessed using a standardized screening questionnaire in female volunteers from the TwinsUK cohort including 113 CWP cases and 1623 controls. The stool microbiome was characterised using 16S rRNA amplicon sequencing and amplicon sequence variants (ASVs), and associations with CWP examined using linear mixed-effects models adjusting for BMI, age, diet, family relatedness and technical factors.

Results: Alpha diversity was significantly lower in CWP cases than controls (Mann-Whitney test, p-values 2.3e-04 and 1.2e-02, respectively). The species Coprococcus comes was significantly depleted in CWP cases (p.adj = 3.04e-03). A genome-wide association study (GWAS) performed for C. comes in TwinsUK followed by meta-analysis with three Dutch cohorts (total n = 3521) resulted in nine suggestive regions, with the most convincing on chromosome 4 near the TRAM1L1 gene (rs76957229, p= 7.4e-8). A Mendelian randomisation study based on the results of the GWAS did not support a causal role for C. comes on the development of CWP.

Conclusions: We have demonstrated reduced diversity in the microbiome in CWP, indicating an involvement of the gut microbiota in CWP; prospectively the microbiome may offer therapeutic opportunities for this condition.
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http://dx.doi.org/10.1093/rheumatology/keaa847DOI Listing
December 2020

Metabolic Age Based on the BBMRI-NL H-NMR Metabolomics Repository as Biomarker of Age-related Disease.

Circ Genom Precis Med 2020 10 14;13(5):541-547. Epub 2020 Aug 14.

Department of Internal Medicine, Maastricht University Medical Center, the Netherlands (C.D.A.S., C.J.H.v.d.K., M.M.J.v.G.).

Background: The blood metabolome incorporates cues from the environment and the host's genetic background, potentially offering a holistic view of an individual's health status.

Methods: We have compiled a vast resource of proton nuclear magnetic resonance metabolomics and phenotypic data encompassing over 25 000 samples derived from 26 community and hospital-based cohorts.

Results: Using this resource, we constructed a metabolomics-based age predictor (metaboAge) to calculate an individual's biological age. Exploration in independent cohorts demonstrates that being judged older by one's metabolome, as compared with one's chronological age, confers an increased risk on future cardiovascular disease, mortality, and functionality in older individuals. A web-based tool for calculating metaboAge (metaboage.researchlumc.nl) allows easy incorporation in other epidemiological studies. Access to data can be requested at bbmri.nl/samples-images-data.

Conclusions: In summary, we present a vast resource of metabolomics data and illustrate its merit by constructing a metabolomics-based score for biological age that captures aspects of current and future cardiometabolic health.
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http://dx.doi.org/10.1161/CIRCGEN.119.002610DOI Listing
October 2020

Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.

Nat Metab 2020 10 16;2(10):1135-1148. Epub 2020 Oct 16.

SCALLOP consortium.

Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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http://dx.doi.org/10.1038/s42255-020-00287-2DOI Listing
October 2020

Genetic and Microbial Associations to Plasma and Fecal Bile Acids in Obesity Relate to Plasma Lipids and Liver Fat Content.

Cell Rep 2020 10;33(1):108212

Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen 9713AV, the Netherlands; Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen 9713AV, the Netherlands. Electronic address:

Bile acids (BAs) are implicated in the etiology of obesity-related conditions such as non-alcoholic fatty liver disease. Differently structured BA species display variable signaling activities via farnesoid X receptor (FXR) and Takeda G protein-coupled BA receptor 1 (TGR5). This study profiles plasma and fecal BAs and plasma 7α-hydroxy-4-cholesten-3-one (C4) in 297 persons with obesity, identifies underlying genetic and microbial determinants, and establishes BA correlations with liver fat and plasma lipid parameters. We identify 27 genetic associations (p < 5 × 10) and 439 microbial correlations (FDR < 0.05) for 50 BA entities. Additionally, we report 111 correlations between BA and 88 lipid parameters (FDR < 0.05), mainly for C4 reflecting hepatic BA synthesis. Inter-individual variability in the plasma BA profile does not reflect hepatic BA synthetic pathways, but rather transport and metabolism within the enterohepatic circulation. Our study reveals genetic and microbial determinants of BAs in obesity and their relationship to disease-relevant lipid parameters that are important for the design of personalized therapies targeting BA-signaling pathways.
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http://dx.doi.org/10.1016/j.celrep.2020.108212DOI Listing
October 2020

The Effects of Urbanization on the Infant Gut Microbiota and Health Outcomes.

Front Pediatr 2020 29;8:408. Epub 2020 Jul 29.

Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.

Humans and their gut microbiota have co-evolved over thousands of years, resulting in the establishment of a complex host-microbiota ecosystem. Early life environmental factors, such as delivery mode, nutrition, and medication use, have been shown to substantially affect both host-microbiota interactions and health outcomes. However, the effects of urbanization (characterized by the spectrum of rural and urban populations) on these early life events have been overlooked. A deeper understanding of the relationship between urbanization and microbiota development will allow for the identification of novel biological and social approaches that can be implemented to prevent and treat disease and promote maternal and infant/child health. The aim of this narrative review is to summarize how factors associated with urbanization differentially impact delivery mode, nutrition, and medication use, and how these changes subsequently affect the gut microbiota and health outcomes of infants. This narrative review also describes the important evidence gaps associated with these relationships and recommends actions that can be taken to improve the health of mothers and infants worldwide.
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http://dx.doi.org/10.3389/fped.2020.00408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438894PMC
July 2020

Gut microbial co-abundance networks show specificity in inflammatory bowel disease and obesity.

Nat Commun 2020 08 11;11(1):4018. Epub 2020 Aug 11.

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

The gut microbiome is an ecosystem that involves complex interactions. Currently, our knowledge about the role of the gut microbiome in health and disease relies mainly on differential microbial abundance, and little is known about the role of microbial interactions in the context of human disease. Here, we construct and compare microbial co-abundance networks using 2,379 metagenomes from four human cohorts: an inflammatory bowel disease (IBD) cohort, an obese cohort and two population-based cohorts. We find that the strengths of 38.6% of species co-abundances and 64.3% of pathway co-abundances vary significantly between cohorts, with 113 species and 1,050 pathway co-abundances showing IBD-specific effects and 281 pathway co-abundances showing obesity-specific effects. We can also replicate these IBD microbial co-abundances in longitudinal data from the IBD cohort of the integrative human microbiome (iHMP-IBD) project. Our study identifies several key species and pathways in IBD and obesity and provides evidence that altered microbial abundances in disease can influence their co-abundance relationship, which expands our current knowledge regarding microbial dysbiosis in disease.
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http://dx.doi.org/10.1038/s41467-020-17840-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419557PMC
August 2020

A cross-omics integrative study of metabolic signatures of chronic obstructive pulmonary disease.

BMC Pulm Med 2020 Jul 16;20(1):193. Epub 2020 Jul 16.

Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.

Background: Chronic obstructive pulmonary disease (COPD) is a common lung disorder characterized by persistent and progressive airflow limitation as well as systemic changes. Metabolic changes in blood may help detect COPD in an earlier stage and predict prognosis.

Methods: We conducted a comprehensive study of circulating metabolites, measured by proton Nuclear Magnetic Resonance Spectroscopy, in relation with COPD and lung function. The discovery sample consisted of 5557 individuals from two large population-based studies in the Netherlands, the Rotterdam Study and the Erasmus Rucphen Family study. Significant findings were replicated in 12,205 individuals from the Lifelines-DEEP study, FINRISK and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) studies. For replicated metabolites further investigation of causality was performed, utilizing genetics in the Mendelian randomization approach.

Results: There were 602 cases of COPD and 4955 controls used in the discovery meta-analysis. Our logistic regression results showed that higher levels of plasma Glycoprotein acetyls (GlycA) are significantly associated with COPD (OR = 1.16, P = 5.6 × 10 in the discovery and OR = 1.30, P = 1.8 × 10 in the replication sample). A bi-directional two-sample Mendelian randomization analysis suggested that circulating blood GlycA is not causally related to COPD, but that COPD causally increases GlycA levels. Using the prospective data of the same sample of Rotterdam Study in Cox-regression, we show that the circulating GlycA level is a predictive biomarker of COPD incidence (HR = 1.99, 95%CI 1.52-2.60, comparing those in the highest and lowest quartile of GlycA) but is not significantly associated with mortality in COPD patients (HR = 1.07, 95%CI 0.94-1.20).

Conclusions: Our study shows that circulating blood GlycA is a biomarker of early COPD pathology.
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http://dx.doi.org/10.1186/s12890-020-01222-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364599PMC
July 2020

Whole exome sequencing analyses reveal gene-microbiota interactions in the context of IBD.

Gut 2021 Feb 10;70(2):285-296. Epub 2020 Jul 10.

Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands

Objective: Both the gut microbiome and host genetics are known to play significant roles in the pathogenesis of IBD. However, the interaction between these two factors and its implications in the aetiology of IBD remain underexplored. Here, we report on the influence of host genetics on the gut microbiome in IBD.

Design: To evaluate the impact of host genetics on the gut microbiota of patients with IBD, we combined whole exome sequencing of the host genome and whole genome shotgun sequencing of 1464 faecal samples from 525 patients with IBD and 939 population-based controls. We followed a four-step analysis: (1) exome-wide microbial quantitative trait loci (mbQTL) analyses, (2) a targeted approach focusing on IBD-associated genomic regions and protein truncating variants (PTVs, minor allele frequency (MAF) >5%), (3) gene-based burden tests on PTVs with MAF <5% and exome copy number variations (CNVs) with site frequency <1%, (4) joint analysis of both cohorts to identify the interactions between disease and host genetics.

Results: We identified 12 mbQTLs, including variants in the IBD-associated genes , , and . For example, the decrease of the pathway acetyl-coenzyme A biosynthesis, which is involved in short chain fatty acids production, was associated with variants in the gene (false discovery rate <0.05). Changes in functional pathways involved in the metabolic potential were also observed in participants carrying rare PTVs or CNVs in , and genes. These genes are known for their function in the immune system. Moreover, interaction analyses confirmed previously known IBD disease-specific mbQTLs in .

Conclusion: This study highlights that both common and rare genetic variants affecting the immune system are key factors in shaping the gut microbiota in the context of IBD and pinpoints towards potential mechanisms for disease treatment.
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http://dx.doi.org/10.1136/gutjnl-2019-319706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815889PMC
February 2021

Lack of Association Between Genetic Variants at and Genes Involved in SARS-CoV-2 Infection and Human Quantitative Phenotypes.

Front Genet 2020 8;11:613. Epub 2020 Jun 8.

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

Coronavirus disease 2019 (COVID-19) shows a wide variation in expression and severity of symptoms, from very mild or no symptoms, to flu-like symptoms, and in more severe cases, to pneumonia, acute respiratory distress syndrome, and even death. Large differences in outcome have also been observed between males and females. The causes for this variability are likely to be multifactorial, and to include genetics. The SARS-CoV-2 virus responsible for the infection depends on two human genes: the human receptor angiotensin converting enzyme 2 () for cell invasion, and the serine protease for S protein priming. Genetic variation in these two genes may thus modulate an individual's genetic predisposition to infection and virus clearance. While genetic data on COVID-19 patients is being gathered, we carried out a phenome-wide association scan (PheWAS) to investigate the role of these genes in other human phenotypes in the general population. We examined 178 quantitative phenotypes including cytokines and cardio-metabolic biomarkers, as well as usage of 58 medications in 36,339 volunteers from the Lifelines population cohort, in relation to 1,273 genetic variants located in or near and . While none reached our threshold for significance, we observed several interesting suggestive associations. For example, single nucleotide polymorphisms (SNPs) near the genes were associated with thrombocytes count ( = 1.8 × 10). SNPs within the gene were associated with (1) the use of angiotensin II receptor blockers (ARBs) combination therapies ( = 5.7 × 10), an association that is significantly stronger in females ( = 0.01), and (2) with the use of non-steroid anti-inflammatory and antirheumatic products ( = 5.5 × 10). While these associations need to be confirmed in larger sample sizes, they suggest that these variants could play a role in diseases such as thrombocytopenia, hypertension, and chronic inflammation that are often observed in the more severe COVID-19 cases. Further investigation of these genetic variants in the context of COVID-19 is thus promising for better understanding of disease variability. Full results are available at https://covid19research.nl.
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http://dx.doi.org/10.3389/fgene.2020.00613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295011PMC
June 2020

Identification, Heritability, and Relation With Gene Expression of Novel DNA Methylation Loci for Blood Pressure.

Hypertension 2020 07 10;76(1):195-205. Epub 2020 Jun 10.

Department of Endocrinology (B.H.R.W., J.V.v.V.-O.), University Medical Center Groningen, University of Groningen, The Netherlands.

We conducted an epigenome-wide association study meta-analysis on blood pressure (BP) in 4820 individuals of European and African ancestry aged 14 to 69. Genome-wide DNA methylation data from peripheral leukocytes were obtained using the Infinium Human Methylation 450k BeadChip. The epigenome-wide association study meta-analysis identified 39 BP-related CpG sites with <1×10. In silico replication in the CHARGE consortium of 17 010 individuals validated 16 of these CpG sites. Out of the 16 CpG sites, 13 showed novel association with BP. Conversely, out of the 126 CpG sites identified as being associated (<1×10) with BP in the CHARGE consortium, 21 were replicated in the current study. Methylation levels of all the 34 CpG sites that were cross-validated by the current study and the CHARGE consortium were heritable and 6 showed association with gene expression. Furthermore, 9 CpG sites also showed association with BP with <0.05 and consistent direction of the effect in the meta-analysis of the Finnish Twin Cohort (199 twin pairs and 4 singletons; 61% monozygous) and the Netherlands Twin Register (266 twin pairs and 62 singletons; 84% monozygous). Bivariate quantitative genetic modeling of the twin data showed that a majority of the phenotypic correlations between methylation levels of these CpG sites and BP could be explained by shared unique environmental rather than genetic factors, with 100% of the correlations of systolic BP with cg19693031 () and cg00716257 () determined by environmental effects acting on both systolic BP and methylation levels.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.14973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295009PMC
July 2020

A Two-Sample Mendelian Randomization Analysis Investigates Associations Between Gut Microbiota and Celiac Disease.

Nutrients 2020 May 14;12(5). Epub 2020 May 14.

Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU) and Biocruces-Bizkaia Health Research Institute, 48940 Leioa, Spain.

Celiac disease (CeD) is a complex immune-mediated inflammatory condition triggered by the ingestion of gluten in genetically predisposed individuals. Literature suggests that alterations in gut microbiota composition and function precede the onset of CeD. Considering that microbiota is partly determined by host genetics, we speculated that the genetic makeup of CeD patients could elicit disease development through alterations in the intestinal microbiota. To evaluate potential causal relationships between gut microbiota and CeD, we performed a two-sample Mendelian randomization analysis (2SMR). Exposure data were obtained from the raw results of a previous genome-wide association study (GWAS) of gut microbiota and outcome data from summary statistics of CeD GWAS and Immunochip studies. We identified a number of putative associations between gut microbiota single nucleotide polymorphisms (SNPs) associated with CeD. Regarding bacterial composition, most of the associated SNPs were related to Firmicutes phylum, whose relative abundance has been previously reported to be altered in CeD patients. In terms of functional units, we linked a number of SNPs to several bacterial metabolic pathways that seemed to be related to CeD. Overall, this study represented the first 2SMR approach to elucidate the relationship between microbiome and CeD.
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http://dx.doi.org/10.3390/nu12051420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284592PMC
May 2020

Interaction between drugs and the gut microbiome.

Gut 2020 08 14;69(8):1510-1519. Epub 2020 May 14.

Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.

The human gut microbiome is a complex ecosystem that can mediate the interaction of the human host with their environment. The interaction between gut microbes and commonly used non-antibiotic drugs is complex and bidirectional: gut microbiome composition can be influenced by drugs, but, vice versa, the gut microbiome can also influence an individual's response to a drug by enzymatically transforming the drug's structure and altering its bioavailability, bioactivity or toxicity (pharmacomicrobiomics). The gut microbiome can also indirectly impact an individual's response to immunotherapy in cancer treatment. In this review we discuss the bidirectional interactions between microbes and drugs, describe the changes in gut microbiota induced by commonly used non-antibiotic drugs, and their potential clinical consequences and summarise how the microbiome impacts drug effectiveness and its role in immunotherapy. Understanding how the microbiome metabolises drugs and reduces treatment efficacy will unlock the possibility of modulating the gut microbiome to improve treatment.
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http://dx.doi.org/10.1136/gutjnl-2019-320204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398478PMC
August 2020

Lifelines NEXT: a prospective birth cohort adding the next generation to the three-generation Lifelines cohort study.

Eur J Epidemiol 2020 Feb 25;35(2):157-168. Epub 2020 Feb 25.

Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.

Epidemiological research has shown there to be a strong relationship between preconceptional, prenatal, birth and early-life factors and lifelong health. The Lifelines NEXT is a birth cohort designed to study the effects of intrinsic and extrinsic determinants on health and disease in a four-generation design. It is embedded within the Lifelines cohort study, a prospective three-generation population-based cohort study recording the health and health-related aspects of 167,729 individuals living in Northern Netherlands. In Lifelines NEXT we aim to include 1500 pregnant Lifelines participants and intensively follow them, their partners and their children until at least 1 year after birth. Longer-term follow-up of physical and psychological health will then be embedded following Lifelines procedures. During the Lifelines NEXT study period biomaterials-including maternal and neonatal (cord) blood, placental tissue, feces, breast milk, nasal swabs and urine-will be collected from the mother and child at 10 time points. We will also collect data on medical, social, lifestyle and environmental factors via questionnaires at 14 different time points and continuous data via connected devices. The extensive collection of different (bio)materials from mother and child during pregnancy and afterwards will provide the means to relate environmental factors including maternal and neonatal microbiome composition) to (epi)genetics, health and developmental outcomes. The nesting of the study within Lifelines enables us to include preconceptional transgenerational data and can be used to identify other extended families within the cohort.
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http://dx.doi.org/10.1007/s10654-020-00614-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125065PMC
February 2020

Impact of commonly used drugs on the composition and metabolic function of the gut microbiota.

Nat Commun 2020 01 17;11(1):362. Epub 2020 Jan 17.

Dept. of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.

The human gut microbiota has now been associated with drug responses and efficacy, while chemical compounds present in these drugs can also impact the gut bacteria. However, drug-microbe interactions are still understudied in the clinical context, where polypharmacy and comorbidities co-occur. Here, we report relations between commonly used drugs and the gut microbiome. We performed metagenomics sequencing of faecal samples from a population cohort and two gastrointestinal disease cohorts. Differences between users and non-users were analysed per cohort, followed by a meta-analysis. While 19 of 41 drugs are found to be associated with microbial features, when controlling for the use of multiple medications, proton-pump inhibitors, metformin, antibiotics and laxatives show the strongest associations with the microbiome. We here provide evidence for extensive changes in taxonomy, metabolic potential and resistome in relation to commonly used drugs. This paves the way for future studies and has implications for current microbiome studies by demonstrating the need to correct for multiple drug use.
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http://dx.doi.org/10.1038/s41467-019-14177-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969170PMC
January 2020

Integration of epidemiologic, pharmacologic, genetic and gut microbiome data in a drug-metabolite atlas.

Nat Med 2020 01 13;26(1):110-117. Epub 2020 Jan 13.

Amsterdam Public Health Research Institute, Amsterdam, the Netherlands.

Progress in high-throughput metabolic profiling provides unprecedented opportunities to obtain insights into the effects of drugs on human metabolism. The Biobanking BioMolecular Research Infrastructure of the Netherlands has constructed an atlas of drug-metabolite associations for 87 commonly prescribed drugs and 150 clinically relevant plasma-based metabolites assessed by proton nuclear magnetic resonance. The atlas includes a meta-analysis of ten cohorts (18,873 persons) and uncovers 1,071 drug-metabolite associations after evaluation of confounders including co-treatment. We show that the effect estimates of statins on metabolites from the cross-sectional study are comparable to those from intervention and genetic observational studies. Further data integration links proton pump inhibitors to circulating metabolites, liver function, hepatic steatosis and the gut microbiome. Our atlas provides a tool for targeted experimental pharmaceutical research and clinical trials to improve drug efficacy, safety and repurposing. We provide a web-based resource for visualization of the atlas (http://bbmri.researchlumc.nl/atlas/).
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http://dx.doi.org/10.1038/s41591-019-0722-xDOI Listing
January 2020

Systematic review with meta-analysis: the risks of proton pump inhibitors during pregnancy.

Aliment Pharmacol Ther 2020 02 7;51(4):410-420. Epub 2020 Jan 7.

Centre for Translational Microbiome Research, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.

Background: There have been safety concerns considering long-term proton pump inhibitor (PPI) use, also during pregnancy.

Aims: To assess the risk of adverse neonatal outcomes associated with maternal intake of PPIs by means of systematic review and meta-analysis.

Methods: The systematic search included PubMed, Web of Science, Cochrane Database and Embase (inception until June 2019). All studies reporting ≥1 adverse pregnancy outcome comparing PPI users to non-users. Histamine-2 receptor antagonists (H2RA) were also compared to both non-users and PPI users. Outcomes included congenital malformations, abortion, stillbirth, neonatal death, preterm birth, small for gestational age and low birth weight. Pooled odds ratios (OR) and 95% confidence intervals (CI) were obtained by random-effects modelling. PROSPERO study-protocol: CRD42018103320.

Results: In total, 26 observational studies (20 cohort, 6 case-control studies) were identified, of which 19 assessed PPIs and 12 H2RA. PPI use was associated with an increased risk of congenital malformations (OR 1.28, 95% CI 1.09-1.52), especially in case-control studies (OR 2.04, 1.46-2.86). No associations were found between H2RA and congenital malformations. No significant associations were found between PPI use and abortions, stillbirth, neonatal death, preterm birth and low-birth weight, although H2RA use may be associated with an increased risk of preterm birth (OR 1.25, 95% CI 1.02-1.56). Although statistical heterogeneity and the risk of bias were overall low, clinical heterogeneity, information and selection bias may be present in the individual studies.

Conclusions: This meta-analysis suggests an association between maternal PPI use and congenital malformations in humans, yet power was insufficient to assess specific malformations and drugs.
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http://dx.doi.org/10.1111/apt.15610DOI Listing
February 2020

Relationship between gut microbiota and circulating metabolites in population-based cohorts.

Nat Commun 2019 12 20;10(1):5813. Epub 2019 Dec 20.

Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

Gut microbiota has been implicated in major diseases affecting the human population and has also been linked to triglycerides and high-density lipoprotein levels in the circulation. Recent development in metabolomics allows classifying the lipoprotein particles into more details. Here, we examine the impact of gut microbiota on circulating metabolites measured by Nuclear Magnetic Resonance technology in 2309 individuals from the Rotterdam Study and the LifeLines-DEEP cohort. We assess the relationship between gut microbiota and metabolites by linear regression analysis while adjusting for age, sex, body-mass index, technical covariates, medication use, and multiple testing. We report an association of 32 microbial families and genera with very-low-density and high-density subfractions, serum lipid measures, glycolysis-related metabolites, ketone bodies, amino acids, and acute-phase reaction markers. These observations provide insights into the role of microbiota in host metabolism and support the potential of gut microbiota as a target for therapeutic and preventive interventions.
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http://dx.doi.org/10.1038/s41467-019-13721-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925111PMC
December 2019

DNA methylation is associated with lung function in never smokers.

Respir Res 2019 Dec 2;20(1):268. Epub 2019 Dec 2.

University of Groningen, University Medical Center Groningen, Department of Epidemiology, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.

Background: Active smoking is the main risk factor for COPD. Here, epigenetic mechanisms may play a role, since cigarette smoking is associated with differential DNA methylation in whole blood. So far, it is unclear whether epigenetics also play a role in subjects with COPD who never smoked. Therefore, we aimed to identify differential DNA methylation associated with lung function in never smokers.

Methods: We determined epigenome-wide DNA methylation levels of 396,243 CpG-sites (Illumina 450 K) in blood of never smokers in four independent cohorts, LifeLines COPD&C (N = 903), LifeLines DEEP (N = 166), Rotterdam Study (RS)-III (N = 150) and RS-BIOS (N = 206). We meta-analyzed the cohort-specific methylation results to identify differentially methylated CpG-sites with FEV/FVC. Expression Quantitative Trait Methylation (eQTM) analysis was performed in the Biobank-based Integrative Omics Studies (BIOS).

Results: A total of 36 CpG-sites were associated with FEV/FVC in never smokers at p-value< 0.0001, but the meta-analysis did not reveal any epigenome-wide significant CpG-sites. Of interest, 35 of these 36 CpG-sites have not been associated with lung function before in studies including subjects irrespective of smoking history. Among the top hits were cg10012512, cg02885771, annotated to the gene LTV1 Ribosome Biogenesis factor (LTV1), and cg25105536, annotated to Kelch Like Family Member 32 (KLHL32). Moreover, a total of 11 eQTMS were identified.

Conclusions: With the identification of 35 CpG-sites that are unique for never smokers, our study shows that DNA methylation is also associated with FEV/FVC in subjects that never smoked and therefore not merely related to smoking.
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http://dx.doi.org/10.1186/s12931-019-1222-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889726PMC
December 2019