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Hedman, Åsa K
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Publications (10 of 30) Show all publications
Wang, Y., Karlsson, R., Lampa, E., Zhang, Q., Hedman, Å. K., Almgren, M., . . . Hagg, S. (2018). Epigenetic influences on aging: a longitudinal genome-wide methylation study in old Swedish twins. Epigenetics, 13(9), 975-987
Open this publication in new window or tab >>Epigenetic influences on aging: a longitudinal genome-wide methylation study in old Swedish twins
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2018 (English)In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 13, no 9, p. 975-987Article in journal (Refereed) Published
Abstract [en]

Age-related changes in DNA methylation were observed in cross-sectional studies, but longitudinal evidence is still limited. Here, we aimed to characterize longitudinal age-related methylation patterns using 1011 blood samples collected from 385 Swedish twins (age at entry: mean 69 and standard deviation 9.7, 73 monozygotic and 96 dizygotic pairs) up to five times (mean 2.6) over 20 years (mean 8.7). We identified 1316 age-associated methylation sites (P<1.3x10(-7)) using a longitudinal epigenome-wide association study design. We measured how estimated cellular compositions changed with age and how much they confounded the age effect. We validated the results in two independent longitudinal cohorts, where 118 CpGs were replicated in Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS, 390 samples) (P<3.9x10(-5)), 594 in Lothian Birth Cohort (LBC, 3018 samples) (P<5.1x10(-5)) and 63 in both. Functional annotation of age-associated CpGs showed enrichment in CCCTC-binding factor (CTCF) and other transcription factor binding sites. We further investigated genetic influences on methylation and found no interaction between age and genetic effects in the 1316 age-associated CpGs. Moreover, in the same CpGs, methylation differences within twin pairs increased with 6.4% over 10 years, where monozygotic twins had smaller intra-pair differences than dizygotic twins. In conclusion, we show that age-related methylation changes persist in a longitudinal perspective, and are fairly stable across cohorts. The changes are under genetic influence, although this effect is independent of age. Moreover, methylation variability increase over time, especially in age-associated CpGs, indicating the increase of environmental contributions on DNA methylation with age.

Keywords
DNA methylation, aging, longitudinal study, meQTL, twin-pair analysis
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-371062 (URN)10.1080/15592294.2018.1526028 (DOI)000450445600006 ()30264654 (PubMedID)
Funder
Forte, Swedish Research Council for Health, Working Life and Welfare, 97: 0147Forte, Swedish Research Council for Health, Working Life and Welfare, 2009-0795Forte, Swedish Research Council for Health, Working Life and Welfare, 2013-2292Swedish Research Council, 825-2007-7460Swedish Research Council, 825-2009-6141Swedish Research Council, 521-2013-8689NIH (National Institute of Health), AG04563NIH (National Institute of Health), AG10175NIH (National Institute of Health), AG028555EU, Horizon 2020, 634821The Karolinska Institutet's Research Foundation
Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2018-12-19Bibliographically approved
Mendelson, M. M., Marioni, R. E., Joehanes, R., Liu, C., Hedman, Å. K., Aslibekyan, S., . . . Deary, L. J. (2017). Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach. PLoS Medicine, 14(1), Article ID e1002215.
Open this publication in new window or tab >>Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach
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2017 (English)In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 14, no 1, article id e1002215Article in journal (Refereed) Published
Abstract [en]

Background The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain. Methods and Findings We conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs that replicated across cohorts; BMI-related differential methylation was associated with concurrent changes in the expression of genes in lipid metabolism pathways. Genetic instrumental variable analysis of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to sterol regulatory element binding transcription factor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci was found to be secondary to differences in BMI. However, the cross-sectional nature of the data limits definitive causal determination. Conclusions We present robust associations of BMI with differential DNA methylation at numerous loci in blood cells. BMI-related DNA methylation and gene expression provide mechanistic insights into the relationship between DNA methylation, obesity, and adiposity-related diseases.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-319336 (URN)10.1371/journal.pmed.10022151 (DOI)000395719900011 ()
Available from: 2017-04-03 Created: 2017-04-03 Last updated: 2017-11-29Bibliographically approved
Hedman, Å. K., Mendelson, M. M., Marioni, R. E., Gustafsson, S., Joehanes, R., Irvin, M. R., . . . Ingelsson, E. (2017). Epigenetic Patterns in Blood Associated With Lipid Traits Predict Incident Coronary Heart Disease Events and Are Enriched for Results From Genome-Wide Association Studies. Circulation: Cardiovascular Genetics, 10(1), Article ID UNSP e001487.
Open this publication in new window or tab >>Epigenetic Patterns in Blood Associated With Lipid Traits Predict Incident Coronary Heart Disease Events and Are Enriched for Results From Genome-Wide Association Studies
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2017 (English)In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 10, no 1, article id UNSP e001487Article in journal (Refereed) Published
Abstract [en]

Background- Genome-wide association studies have identified loci influencing circulating lipid concentrations in humans; further information on novel contributing genes, pathways, and biology may be gained through studies of epigenetic modifications. Methods and Results- To identify epigenetic changes associated with lipid concentrations, we assayed genome-wide DNA methylation at cytosine-guanine dinucleotides (CpGs) in whole blood from 2306 individuals from 2 population-based cohorts, with replication of findings in 2025 additional individuals. We identified 193 CpGs associated with lipid levels in the discovery stage (P < 1.08E-07) and replicated 33 (at Bonferroni-corrected P < 0.05), including 25 novel CpGs not previously associated with lipids. Genes at lipid-associated CpGs were enriched in lipid and amino acid metabolism processes. A differentially methylated locus associated with triglyceridesand high-density lipoprotein cholesterol (HDL- C; cg27243685; P= 8.1E-26 and 9.3E-19) was associated with cis-expression of a reverse cholesterol transporter (ABCG1; P= 7.2E-28) and incident cardiovascular disease events (hazard ratio per SD increment, 1.38; 95% confidence interval, 1.15-1.66; P= 0.0007). We found significant cis-methylation quantitative trait loci at 64% of the 193 CpGs with an enrichment of signals from genome-wide association studies of lipid levels (P-TC = 0.004, PHDL-C = 0.008 and P-triglycerides = 0.00003) and coronary heart disease ( P= 0.0007). For example, genome-wide significant variants associated with low-density lipoprotein cholesterol and coronary heart disease at APOB were cis-methylation quantitative trait loci for a low-density lipoprotein cholesterol-related differentially methylated locus. Conclusions-We report novel associations of DNA methylation with lipid levels, describe epigenetic mechanisms related to previous genome-wide association studies discoveries, and provide evidence implicating epigenetic regulation of reverse cholesterol transport in blood in relation to occurrence of cardiovascular disease events.

Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2017
Keywords
cardiovascular diseases, DNA Methylation, epigenomics, gene expression, lipids
National Category
Cardiac and Cardiovascular Systems Medical Genetics
Identifiers
urn:nbn:se:uu:diva-320506 (URN)10.1161/CIRCGENETICS.116.001487 (DOI)000396862100004 ()
Funder
NIH (National Institute of Health), N01-HC-25195 HHSN2682015000011 P30 DK46200 1R01DK106236-01A1 1R01HL135313-01 R01 HL104135-01Swedish Research Council, 2012-1397Swedish Heart Lung Foundation, 20120197Knut and Alice Wallenberg FoundationWellcome trustEU, FP7, Seventh Framework Programme
Available from: 2017-04-20 Created: 2017-04-20 Last updated: 2018-01-13Bibliographically approved
Ek, W. E., Tobi, E. W., Ahsan, M., Lampa, E., Ponzi, E., Kyrtopoulos, S. A., . . . Johansson, Å. (2017). Tea and coffee consumption in relation to DNA methylation in four European cohorts. Human Molecular Genetics, 26(16), pp. 3221-3231
Open this publication in new window or tab >>Tea and coffee consumption in relation to DNA methylation in four European cohorts
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2017 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 26, no 16, p. 3221-3231Article in journal, News item (Refereed) Published
Abstract [en]

Lifestyle factors, such as food choices and exposure to chemicals, can alter DNA methylation and lead to changes in gene activity. Two such exposures with pharmacologically active components are coffee and tea consumption. Both coffee and tea have been suggested to play an important role in modulating disease-risk in humans by suppressing tumour progression, decreasing inflammation and influencing estrogen metabolism. These mechanisms may be mediated by changes in DNA methylation. To investigate if DNA methylation in blood is associated with coffee and tea consumption, we performed a genome-wide DNA methylation study for coffee and tea consumption in four European cohorts (N = 3,096). DNA methylation was measured from whole blood at 421,695 CpG sites distributed throughout the genome and analysed in men and women both separately and together in each cohort. Meta-analyses of the results and additional regional-level analyses were performed. After adjusting for multiple testing, the meta-analysis revealed that two individual CpG-sites, mapping to DNAJC16 and TTC17, were differentially methylated in relation to tea consumption in women. No individual sites were associated with men or with the sex-combined analysis for tea or coffee. The regional analysis revealed that 28 regions were differentially methylated in relation to tea consumption in women. These regions contained genes known to interact with estradiol metabolism and cancer. No significant regions were found in the sex-combined and male-only analysis for either tea or coffee consumption.

Place, publisher, year, edition, pages
Oxford University Press, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-332048 (URN)10.1093/hmg/ddx194 (DOI)000406794000017 ()28535255 (PubMedID)
Available from: 2017-10-23 Created: 2017-10-23 Last updated: 2019-11-20Bibliographically approved
Hedman, Å. K., Zilmer, M., Sundström, J., Lind, L. & Ingelsson, E. (2016). DNA methylation patterns associated with oxidative stress in an ageing population. BMC Medical Genomics, 9, Article ID 72.
Open this publication in new window or tab >>DNA methylation patterns associated with oxidative stress in an ageing population
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2016 (English)In: BMC Medical Genomics, ISSN 1755-8794, E-ISSN 1755-8794, Vol. 9, article id 72Article in journal (Refereed) Published
Abstract [en]

Background: Oxidative stress has been related to type 2 diabetes (T2D) and cardiovascular disease (CVD), the leading global cause of death. Contributions of environmental factors such as oxidative stress on complex traits and disease may be partly mediated through changes in epigenetic marks (e.g. DNA methylation). Studies relating differential methylation with intermediate phenotypes and disease endpoints may be useful in identifying additional candidate genes and mechanisms involved in disease. Methods: To investigate the role of epigenetic variation in oxidative stress marker levels and subsequent development of CVD and T2D, we performed analyses of genome-wide DNA methylation in blood, ten markers of oxidative stress (total glutathione [TGSH], reduced glutathione [GSH], oxidised glutathione [GSSG], GSSG to GSH ratio, homocysteine [HCY], oxidised low-density lipoprotein (oxLDL), antibodies against oxLDL [OLAB], conjugated dienes [CD], baseline conjugated dienes [BCD]-LDL and total antioxidant capacity [TAOC]) and incident disease in up to 966 age-matched individuals. Results: In total, we found 66 cytosine-guanine (CpG) sites associated with one or more oxidative stress markers (false discovery rate [FDR] <0.05). These sites were enriched in regulatory regions of the genome. Genes annotated to CpG sites showed enrichment in annotation clusters relating to phospho-metabolism and proteins with pleckstrin domains. We investigated the contribution of oxidative stress-associated CpGs to development of cardiometabolic disease. Methylation variation at CpGs in the 3'-UTR of HIST1H4D (cg08170869; histone cluster 1, H4d) and in the body of DVL1 (cg03465880; dishevelled-1) were associated with incident T2D events during 10 years of follow-up (all permutation p-values < 0.01), indicating a role of epigenetic regulation in oxidative stress processes leading to development or progression of diabetes. Methylation QTL (meQTL) analysis showed significant associations with genetic sequence variants in cis at 28 (42%) of oxidative stress phenotype-associated sites (FDR < 0.05). Integrating cis-meQTLs with genotype-phenotype associations indicated that genetic effects on oxidative stress phenotype at one locus (cg07547695; BCL2L11) may be mediated through DNA methylation. Conclusions: In conclusion, we report novel associations of DNA methylation with oxidative stress, some of which also show evidence of a relation with T2D incidence.

Keywords
DNA methylation, Epigenetics, Oxidative stress, Type 2 diabetes, Cardiovascular disease
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-311185 (URN)10.1186/s12920-016-0235-0 (DOI)000388539300001 ()27884142 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research Council, 2012-1397Swedish Heart Lung Foundation, 20120197EU, European Research Council, 2014-2020.4.01.15-0012
Available from: 2016-12-22 Created: 2016-12-22 Last updated: 2018-01-13Bibliographically approved
Ek, W. E., Hedman, Å. K., Enroth, S., Morris, A. P., Lindgren, C. M., Mahajan, A., . . . Johansson, Å. (2016). Genome-wide DNA methylation study identifies genes associated with the cardiovascular biomarker GDF-15. Human Molecular Genetics, 25(4), 817-827
Open this publication in new window or tab >>Genome-wide DNA methylation study identifies genes associated with the cardiovascular biomarker GDF-15
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2016 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 25, no 4, p. 817-827Article in journal (Refereed) Published
Abstract [en]

Growth-differentiation factor 15 (GDF-15) is expressed in low to moderate levels in most healthy tissues and increases in response to inflammation. GDF-15 is associated with cardiovascular dysfunction and over-expressed in the myocardium of patients with myocardial infarction (MI). However, little is known about the function of GDF-15 in cardiovascular disease, and the underlying regulatory network of GDF-15 is not known. To investigate a possible association between GDF-15 levels and DNA methylation, we performed a genome-wide DNA methylation study of white blood cells in a population-based study (N = 717). Significant loci where replicated in an independent cohort (N = 963). We also performed a gene ontology (GO) enrichment analysis. We identified and replicated 16 CpG-sites (false discovery rate [FDR] < 0.05), at 11 independent loci including MIR21. MIR21 encodes a microRNA (miR-21) that has previously been shown to be associated with the development of heart disease. Interestingly, GDF15 mRNA contains a binding site for miR-21. Four sites were also differentially methylated in blood from participants previously diagnosed with MI and 14 enriched GO terms (FDR < 0.05, enrichment > 2) were identified, including 'cardiac muscle cell differentiation'. This study shows that GDF-15 levels are associated with differences in DNA methylation in blood cells, and a subset of the loci are also differentially methylated in participants with MI. However, there might be interactions between GDF-15 levels and methylation in other tissues not addressed in this study. These results provide novel links between GDF-15 and cardiovascular disease.

National Category
Clinical Medicine Medical Genetics Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-275282 (URN)10.1093/hmg/ddv511 (DOI)000372151000017 ()26681806 (PubMedID)
Funder
Göran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of TechnologySwedish Foundation for Strategic Research EU, European Research Council, 01947 (LSHG-CT-2006-01947)Swedish Society for Medical Research (SSMF)Åke Wiberg FoundationWellcome trust, WT098017
Available from: 2016-02-04 Created: 2016-02-02 Last updated: 2018-07-06Bibliographically approved
Kilpeläinen, T. O., Carli, J. F., Skowronski, A. A., Sun, Q., Kriebel, J., Feitosa, M. F., . . . Loos, R. J. (2016). Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels. Nature Communications, 7, Article ID 10494.
Open this publication in new window or tab >>Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
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2016 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 10494Article in journal (Refereed) Published
Abstract [en]

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

National Category
Medical and Health Sciences Medical Genetics
Identifiers
urn:nbn:se:uu:diva-275673 (URN)10.1038/ncomms10494 (DOI)000371012200001 ()26833098 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, FP7-201668 FP7-223004 FP7-259679 FP7-305739 FP7-IDEAS-ERC-323195GlaxoSmithKline (GSK)Göran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of TechnologyKnut and Alice Wallenberg FoundationNIH (National Institute of Health), DK52431 HG004399 HG004446 CA087969 CA055075 DK058845 CA65725 CA49449 CA67262 CA50385 UO1CA098233Novo NordiskSwedish Diabetes AssociationSwedish Foundation for Strategic Research Swedish Heart Lung Foundation, 20140422Swedish Research Council, 2012-1397Ragnar Söderbergs stiftelseTorsten Söderbergs stiftelseWellcome trust, WT064890 WT089062 WT090532 WT098017 WT098051 WT091551 081917/Z/07/Z 086596/Z/08/Z
Available from: 2016-02-04 Created: 2016-02-04 Last updated: 2018-01-10Bibliographically approved
Lu, Y., Day, F. R., Gustafsson, S., Buchkovich, M. L., Na, J., Bataille, V., . . . Loos, R. J. (2016). New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk. Nature Communications, 7, Article ID 10495.
Open this publication in new window or tab >>New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
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2016 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 10495Article in journal (Refereed) Published
Abstract [en]

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.

National Category
Medical and Health Sciences Medical Genetics
Identifiers
urn:nbn:se:uu:diva-275672 (URN)10.1038/ncomms10495 (DOI)000371012200002 ()26833246 (PubMedID)
Funder
AstraZenecaGerman Research Foundation (DFG)German Research Foundation (DFG), SFB992EU, FP7, Seventh Framework ProgrammeEU, European Research Council, ERC-StG-281641Knut and Alice Wallenberg FoundationGlaxoSmithKline (GSK)Novo NordiskThe Royal Swedish Academy of SciencesSwedish Diabetes AssociationSwedish Foundation for Strategic Research Swedish Heart Lung FoundationWellcome trust
Available from: 2016-02-04 Created: 2016-02-04 Last updated: 2018-02-22Bibliographically approved
Allum, F., Shao, X., Guénard, F., Simon, M.-M., Busche, S., Caron, M., . . . Grundberg, E. (2015). Characterization of functional methylomes by next-generation capture sequencing identifies novel disease-associated variants. Nature Communications, 6, Article ID 7211.
Open this publication in new window or tab >>Characterization of functional methylomes by next-generation capture sequencing identifies novel disease-associated variants
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2015 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id 7211Article in journal (Refereed) Published
Abstract [en]

Most genome-wide methylation studies (EWAS) of multifactorial disease traits use targeted arrays or enrichment methodologies preferentially covering CpG-dense regions, to characterize sufficiently large samples. To overcome this limitation, we present here a new customizable, cost-effective approach, methylC-capture sequencing (MCC-Seq), for sequencing functional methylomes, while simultaneously providing genetic variation information. To illustrate MCC-Seq, we use whole-genome bisulfite sequencing on adipose tissue (AT) samples and public databases to design AT-specific panels. We establish its efficiency for high-density interrogation of methylome variability by systematic comparisons with other approaches and demonstrate its applicability by identifying novel methylation variation within enhancers strongly correlated to plasma triglyceride and HDL-cholesterol, including at CD36. Our more comprehensive AT panel assesses tissue methylation and genotypes in parallel at ∼4 and ∼3 M sites, respectively. Our study demonstrates that MCC-Seq provides comparable accuracy to alternative approaches but enables more efficient cataloguing of functional and disease-relevant epigenetic and genetic variants for large-scale EWAS.

National Category
Rheumatology and Autoimmunity
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-253885 (URN)10.1038/ncomms8211 (DOI)000355537600002 ()26021296 (PubMedID)
Available from: 2015-06-03 Created: 2015-06-03 Last updated: 2017-12-04Bibliographically approved
Pfeiffer, L., Wahl, S., Pilling, L. C., Reischl, E., Sandling, J. K., Kunze, S., . . . Waldenberger, M. (2015). DNA methylation of lipid-related genes affects blood lipid levels. Circ Cardiovasc Genet, 8(2), 334-42
Open this publication in new window or tab >>DNA methylation of lipid-related genes affects blood lipid levels
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2015 (English)In: Circ Cardiovasc Genet, Vol. 8, no 2, p. 334-42Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Epigenetic mechanisms might be involved in the regulation of interindividual lipid level variability and thus may contribute to the cardiovascular risk profile. The aim of this study was to investigate the association between genome-wide DNA methylation and blood lipid levels high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and total cholesterol. Observed DNA methylation changes were also further analyzed to examine their relationship with previous hospitalized myocardial infarction. METHODS AND RESULTS: Genome-wide DNA methylation patterns were determined in whole blood samples of 1776 subjects of the Cooperative Health Research in the Region of Augsburg F4 cohort using the Infinium HumanMethylation450 BeadChip (Illumina). Ten novel lipid-related CpG sites annotated to various genes including ABCG1, MIR33B/SREBF1, and TNIP1 were identified. CpG cg06500161, located in ABCG1, was associated in opposite directions with both high-density lipoprotein cholesterol (beta coefficient=-0.049; P=8.26E-17) and triglyceride levels (beta=0.070; P=1.21E-27). Eight associations were confirmed by replication in the Cooperative Health Research in the Region of Augsburg F3 study (n=499) and in the Invecchiare in Chianti, Aging in the Chianti Area study (n=472). Associations between triglyceride levels and SREBF1 and ABCG1 were also found in adipose tissue of the Multiple Tissue Human Expression Resource cohort (n=634). Expression analysis revealed an association between ABCG1 methylation and lipid levels that might be partly mediated by ABCG1 expression. DNA methylation of ABCG1 might also play a role in previous hospitalized myocardial infarction (odds ratio, 1.15; 95% confidence interval=1.06-1.25). CONCLUSIONS: Epigenetic modifications of the newly identified loci might regulate disturbed blood lipid levels and thus contribute to the development of complex lipid-related diseases.

Keywords
*ATP-Binding Cassette Transporters/biosynthesis/genetics, Adult, Aged, Aged, 80 and over, Cohort Studies, DNA Methylation/*genetics, *Epigenesis, Genetic, Female, Genetic Loci, Germany, Humans, Lipids/*blood, Male, Middle Aged, *Myocardial Infarction/blood/genetics, *Sterol Regulatory Element Binding Protein 1/biosynthesis/genetics
National Category
Medical and Health Sciences Biological Sciences
Identifiers
urn:nbn:se:uu:diva-275635 (URN)1942-3268 (Electronic) 1942-3268 (Linking) (ISBN)
Note

Pfeiffer, Liliane Wahl, Simone Pilling, Luke C Reischl, Eva Sandling, Johanna K Kunze, Sonja Holdt, Lesca M Kretschmer, Anja Schramm, Katharina Adamski, Jerzy Klopp, Norman Illig, Thomas Hedman, Asa K Roden, Michael Hernandez, Dena G Singleton, Andrew B Thasler, Wolfgang E Grallert, Harald Gieger, Christian Herder, Christian Teupser, Daniel Meisinger, Christa Spector, Timothy D Kronenberg, Florian Prokisch, Holger Melzer, David Peters, Annette Deloukas, Panos Ferrucci, Luigi Waldenberger, Melanie 081917/Z/07/Z/Wellcome Trust/United Kingdom Clinical Trial Multicenter Study Research Support, Non-U.S. Gov't United States Circulation. Cardiovascular genetics Circ Cardiovasc Genet. 2015 Apr;8(2):334-42. doi: 10.1161/CIRCGENETICS.114.000804. Epub 2015 Jan 12.

Available from: 2016-02-04 Created: 2016-02-04 Last updated: 2016-02-04
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