05220nas a2201201 4500008004100000022001400041245010300055210006900158260001600227300000800243490000700251520181700258100002002075700001802095700002302113700002602136700002302162700002002185700002002205700002202225700001902247700001702266700002302283700001602306700002202322700001702344700001802361700001802379700002802397700001902425700001902444700002002463700002202483700002202505700001702527700002302544700001302567700002302580700001902603700002302622700002202645700002102667700002102688700001802709700001602727700001402743700002402757700002902781700002102810700002502831700001802856700002002874700002002894700002102914700001902935700001902954700002202973700002102995700001403016700001603030700002003046700001903066700001903085700002003104700001903124700002503143700002203168700002403190700001903214700002303233700002403256700002403280700002103304700002503325700002503350700002503375700002003400700002603420700002203446700002203468700002303490700002803513700002603541700002103567700002203588700001703610700002303627700001803650700002203668700001903690700002003709700001603729700002903745700002103774700002103795700002103816700002603837700002403863700001903887710002703906710004903933856003603982 2016 eng d a1474-760X00aDNA methylation signatures of chronic low-grade inflammation are associated with complex diseases.0 aDNA methylation signatures of chronic lowgrade inflammation are c2016 Dec 12 a2550 v173 a
BACKGROUND: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.
RESULTS: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10(-7)) in the discovery panel of European ancestry and replicated (P < 2.29 × 10(-4)) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10(-5)), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10(-3)), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10(-5)). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.
CONCLUSION: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.
1 aLigthart, Symen1 aMarzi, Carola1 aAslibekyan, Stella1 aMendelson, Michael, M1 aConneely, Karen, N1 aTanaka, Toshiko1 aColicino, Elena1 aWaite, Lindsay, L1 aJoehanes, Roby1 aGuan, Weihua1 aBrody, Jennifer, A1 aElks, Cathy1 aMarioni, Riccardo1 aJhun, Min, A1 aAgha, Golareh1 aBressler, Jan1 aWard-Caviness, Cavin, K1 aChen, Brian, H1 aHuan, Tianxiao1 aBakulski, Kelly1 aSalfati, Elias, L1 aFiorito, Giovanni1 aWahl, Simone1 aSchramm, Katharina1 aSha, Jin1 aHernandez, Dena, G1 aJust, Allan, C1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aPilling, Luke, C1 aPankow, James, S1 aTsao, Phil, S1 aLiu, Chunyu1 aZhao, Wei1 aGuarrera, Simonetta1 aMichopoulos, Vasiliki, J1 aSmith, Alicia, K1 aPeters, Marjolein, J1 aMelzer, David1 aVokonas, Pantel1 aFornage, Myriam1 aProkisch, Holger1 aBis, Joshua, C1 aChu, Audrey, Y1 aHerder, Christian1 aGrallert, Harald1 aYao, Chen1 aShah, Sonia1 aMcRae, Allan, F1 aLin, Honghuang1 aHorvath, Steve1 aFallin, Daniele1 aHofman, Albert1 aWareham, Nicholas, J1 aWiggins, Kerri, L1 aFeinberg, Andrew, P1 aStarr, John, M1 aVisscher, Peter, M1 aMurabito, Joanne, M1 aKardia, Sharon, L R1 aAbsher, Devin, M1 aBinder, Elisabeth, B1 aSingleton, Andrew, B1 aBandinelli, Stefania1 aPeters, Annette1 aWaldenberger, Melanie1 aMatullo, Giuseppe1 aSchwartz, Joel, D1 aDemerath, Ellen, W1 aUitterlinden, André, G1 avan Meurs, Joyce, B J1 aFranco, Oscar, H1 aChen, Yii-Der Ida1 aLevy, Daniel1 aTurner, Stephen, T1 aDeary, Ian, J1 aRessler, Kerry, J1 aDupuis, Josée1 aFerrucci, Luigi1 aOng, Ken, K1 aAssimes, Themistocles, L1 aBoerwinkle, Eric1 aKoenig, Wolfgang1 aArnett, Donna, K1 aBaccarelli, Andrea, A1 aBenjamin, Emelia, J1 aDehghan, Abbas1 aWHI-EMPC Investigators1 aCHARGE epigenetics of Coronary Heart Disease uhttps://chs-nhlbi.org/node/734905010nas a2201129 4500008004100000022001400041245004800055210004700103260001300150300001200163490000600175520193900181100001902120700001902139700002502158700002102183700002502204700002402229700001702253700001202270700001902282700002302301700002902324700002302353700002302376700002102399700001802420700002102438700001702459700001902476700002002495700001702515700001302532700002102545700002002566700001402586700002302600700001802623700002002641700001902661700001602680700002602696700001402722700002102736700002002757700002202777700002302799700001902822700001902841700002002860700002502880700002502905700002502930700001502955700002002970700001802990700002403008700002803032700001903060700001903079700002003098700001603118700002303134700002303157700002503180700002503205700002303230700001803253700002103271700002103292700002503313700002003338700002003358700002003378700002403398700001803422700001903440700002403459700001903483700002203502700002303524700002203547700002403569700001803593700002603611700002603637700002103663700002103684700001603705700001703721700002603738700001803764700002003782700001703802700002503819856003603844 2016 eng d a1942-326800aEpigenetic Signatures of Cigarette Smoking.0 aEpigenetic Signatures of Cigarette Smoking c2016 Oct a436-4470 v93 aBACKGROUND: DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders.
METHODS AND RESULTS: To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15 907 blood-derived DNA samples from participants in 16 cohorts (including 2433 current, 6518 former, and 6956 never smokers). Comparing current versus never smokers, 2623 cytosine-phosphate-guanine sites (CpGs), annotated to 1405 genes, were statistically significantly differentially methylated at Bonferroni threshold of P<1×10(-7) (18 760 CpGs at false discovery rate <0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases, and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant P<1×10(-7) (2623 CpGs at false discovery rate <0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs.
CONCLUSIONS: Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biological effects of smoking and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.
1 aJoehanes, Roby1 aJust, Allan, C1 aMarioni, Riccardo, E1 aPilling, Luke, C1 aReynolds, Lindsay, M1 aMandaviya, Pooja, R1 aGuan, Weihua1 aXu, Tao1 aElks, Cathy, E1 aAslibekyan, Stella1 aMoreno-Macias, Hortensia1 aSmith, Jennifer, A1 aBrody, Jennifer, A1 aDhingra, Radhika1 aYousefi, Paul1 aPankow, James, S1 aKunze, Sonja1 aShah, Sonia, H1 aMcRae, Allan, F1 aLohman, Kurt1 aSha, Jin1 aAbsher, Devin, M1 aFerrucci, Luigi1 aZhao, Wei1 aDemerath, Ellen, W1 aBressler, Jan1 aGrove, Megan, L1 aHuan, Tianxiao1 aLiu, Chunyu1 aMendelson, Michael, M1 aYao, Chen1 aKiel, Douglas, P1 aPeters, Annette1 aWang-Sattler, Rui1 aVisscher, Peter, M1 aWray, Naomi, R1 aStarr, John, M1 aDing, Jingzhong1 aRodriguez, Carlos, J1 aWareham, Nicholas, J1 aIrvin, Marguerite, R1 aZhi, Degui1 aBarrdahl, Myrto1 aVineis, Paolo1 aAmbatipudi, Srikant1 aUitterlinden, André, G1 aHofman, Albert1 aSchwartz, Joel1 aColicino, Elena1 aHou, Lifang1 aVokonas, Pantel, S1 aHernandez, Dena, G1 aSingleton, Andrew, B1 aBandinelli, Stefania1 aTurner, Stephen, T1 aWare, Erin, B1 aSmith, Alicia, K1 aKlengel, Torsten1 aBinder, Elisabeth, B1 aPsaty, Bruce, M1 aTaylor, Kent, D1 aGharib, Sina, A1 aSwenson, Brenton, R1 aLiang, Liming1 aDeMeo, Dawn, L1 aO'Connor, George, T1 aHerceg, Zdenko1 aRessler, Kerry, J1 aConneely, Karen, N1 aSotoodehnia, Nona1 aKardia, Sharon, L R1 aMelzer, David1 aBaccarelli, Andrea, A1 avan Meurs, Joyce, B J1 aRomieu, Isabelle1 aArnett, Donna, K1 aOng, Ken, K1 aLiu, Yongmei1 aWaldenberger, Melanie1 aDeary, Ian, J1 aFornage, Myriam1 aLevy, Daniel1 aLondon, Stephanie, J uhttps://chs-nhlbi.org/node/726104937nas a2201345 4500008004100000022001400041245012400055210006900179260001300248300001200261490000700273520113500280100001601415700001901431700002301450700002301473700002301496700001901519700001801538700002401556700001801580700001801598700001701616700001901633700002001652700002201672700002301694700001901717700001901736700001801755700001901773700001601792700001401808700002601822700001501848700002601863700001601889700001301905700001301918700001901931700002201950700002001972700002101992700002002013700001402033700001902047700001802066700002402084700002202108700001902130700002402149700002002173700001202193700002702205700002202232700002002254700002402274700002802298700002402326700002102350700002402371700002102395700002202416700002802438700002102466700002702487700003002514700002002544700001502564700002402579700002002603700001702623700002302640700001902663700001902682700002202701700002202723700001802745700002202763700001902785700001902804700001402823700001802837700001402855700002102869700002302890700002802913700001702941700001902958700001902977700001702996700002003013700002103033700002403054700002503078700002303103700002303126700002103149700002603170700002203196700002003218700002003238700002003258700002003278700002903298700001703327700002303344710002603367710002303393710002603416710002503442710006603467710002203533856003603555 2016 eng d a1546-171800aMeta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci.0 aMetaanalysis identifies common and rare variants influencing blo c2016 Oct a1162-700 v483 aMeta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.
1 aLiu, Chunyu1 aKraja, Aldi, T1 aSmith, Jennifer, A1 aBrody, Jennifer, A1 aFranceschini, Nora1 aBis, Joshua, C1 aRice, Kenneth1 aMorrison, Alanna, C1 aLu, Yingchang1 aWeiss, Stefan1 aGuo, Xiuqing1 aPalmas, Walter1 aMartin, Lisa, W1 aChen, Yii-Der Ida1 aSurendran, Praveen1 aDrenos, Fotios1 aCook, James, P1 aAuer, Paul, L1 aChu, Audrey, Y1 aGiri, Ayush1 aZhao, Wei1 aJakobsdottir, Johanna1 aLin, Li-An1 aStafford, Jeanette, M1 aAmin, Najaf1 aMei, Hao1 aYao, Jie1 aVoorman, Arend1 aLarson, Martin, G1 aGrove, Megan, L1 aSmith, Albert, V1 aHwang, Shih-Jen1 aChen, Han1 aHuan, Tianxiao1 aKosova, Gulum1 aStitziel, Nathan, O1 aKathiresan, Sekar1 aSamani, Nilesh1 aSchunkert, Heribert1 aDeloukas, Panos1 aLi, Man1 aFuchsberger, Christian1 aPattaro, Cristian1 aGorski, Mathias1 aKooperberg, Charles1 aPapanicolaou, George, J1 aRossouw, Jacques, E1 aFaul, Jessica, D1 aKardia, Sharon, L R1 aBouchard, Claude1 aRaffel, Leslie, J1 aUitterlinden, André, G1 aFranco, Oscar, H1 aVasan, Ramachandran, S1 aO'Donnell, Christopher, J1 aTaylor, Kent, D1 aLiu, Kiang1 aBottinger, Erwin, P1 aGottesman, Omri1 aDaw, Warwick1 aGiulianini, Franco1 aGanesh, Santhi1 aSalfati, Elias1 aHarris, Tamara, B1 aLauner, Lenore, J1 aDörr, Marcus1 aFelix, Stephan, B1 aRettig, Rainer1 aVölzke, Henry1 aKim, Eric1 aLee, Wen-Jane1 aLee, I-Te1 aSheu, Wayne, H-H1 aTsosie, Krystal, S1 aEdwards, Digna, R Velez1 aLiu, Yongmei1 aCorrea, Adolfo1 aWeir, David, R1 aVölker, Uwe1 aRidker, Paul, M1 aBoerwinkle, Eric1 aGudnason, Vilmundur1 aReiner, Alexander, P1 aDuijn, Cornelia, M1 aBorecki, Ingrid, B1 aEdwards, Todd, L1 aChakravarti, Aravinda1 aRotter, Jerome, I1 aPsaty, Bruce, M1 aLoos, Ruth, J F1 aFornage, Myriam1 aEhret, Georg, B1 aNewton-Cheh, Christopher1 aLevy, Daniel1 aChasman, Daniel, I1 aCHD Exome+ Consortium1 aExomeBP Consortium1 aGoT2DGenes Consortium1 aT2D-GENES Consortium1 aMyocardial Infarction Genetics and CARDIoGRAM Exome Consortia1 aCKDGen Consortium uhttps://chs-nhlbi.org/node/726404860nas a2201081 4500008004100000022001400041245007600055210006900131260001600200300001200216490000800228520186200236653000902098653001902107653001602126653002802142653002002170653002402190653002202214653003402236653001102270653003702281653001602318653002602334653002802360653001702388100002402405700001902429700002002448700002002468700001702488700002302505700002502528700002202553700001902575700002002594700002202614700001702636700001902653700002202672700002102694700001702715700002202732700001802754700002402772700001602796700002602812700002802838700002402866700002102890700002002911700001202931700002202943700001902965700002002984700002203004700002403026700001403050700002303064700001803087700002303105700001903128700002003147700001603167700001903183700002203202700002303224700002003247700002003267700002003287700002303307700002203330700001903352700001703371700001803388700001903406700002603425700001703451700002003468700002903488700002203517700002303539700002103562700001803583700002603601700002103627700001803648700001903666700001703685700002003702710002003722856003603742 2017 eng d a1537-660500aDNA Methylation Analysis Identifies Loci for Blood Pressure Regulation.0 aDNA Methylation Analysis Identifies Loci for Blood Pressure Regu c2017 Dec 07 a888-9020 v1013 aGenome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p < 1.6 × 10-3). The replicated methylation sites are heritable (h2 > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.
10aAged10aBlood Pressure10aCpG Islands10aCross-Sectional Studies10aDNA Methylation10aEpigenesis, Genetic10aGenetic Variation10aGenome-Wide Association Study10aHumans10aMendelian Randomization Analysis10aMiddle Aged10aNerve Tissue Proteins10aQuantitative Trait Loci10aTetraspanins1 aRichard, Melissa, A1 aHuan, Tianxiao1 aLigthart, Symen1 aGondalia, Rahul1 aJhun, Min, A1 aBrody, Jennifer, A1 aIrvin, Marguerite, R1 aMarioni, Riccardo1 aShen, Jincheng1 aTsai, Pei-Chien1 aMontasser, May, E1 aJia, Yucheng1 aSyme, Catriona1 aSalfati, Elias, L1 aBoerwinkle, Eric1 aGuan, Weihua1 aMosley, Thomas, H1 aBressler, Jan1 aMorrison, Alanna, C1 aLiu, Chunyu1 aMendelson, Michael, M1 aUitterlinden, André, G1 avan Meurs, Joyce, B1 aFranco, Oscar, H1 aZhang, Guosheng1 aLi, Yun1 aStewart, James, D1 aBis, Joshua, C1 aPsaty, Bruce, M1 aChen, Yii-Der Ida1 aKardia, Sharon, L R1 aZhao, Wei1 aTurner, Stephen, T1 aAbsher, Devin1 aAslibekyan, Stella1 aStarr, John, M1 aMcRae, Allan, F1 aHou, Lifang1 aJust, Allan, C1 aSchwartz, Joel, D1 aVokonas, Pantel, S1 aMenni, Cristina1 aSpector, Tim, D1 aShuldiner, Alan1 aDamcott, Coleen, M1 aRotter, Jerome, I1 aPalmas, Walter1 aLiu, Yongmei1 aPaus, Tomáš1 aHorvath, Steve1 aO'Connell, Jeffrey, R1 aGuo, Xiuqing1 aPausova, Zdenka1 aAssimes, Themistocles, L1 aSotoodehnia, Nona1 aSmith, Jennifer, A1 aArnett, Donna, K1 aDeary, Ian, J1 aBaccarelli, Andrea, A1 aBell, Jordana, T1 aWhitsel, Eric1 aDehghan, Abbas1 aLevy, Daniel1 aFornage, Myriam1 aBIOS Consortium uhttps://chs-nhlbi.org/node/758304963nas a2201357 4500008004100000022001400041245010700055210006900162260001600231300000900247490000600256520112300262100001901385700001701404700002001421700002301441700002401464700001901488700002601507700002601533700002001559700002101579700001301600700002801613700001601641700002701657700001501684700001701699700002401716700001801740700002101758700002901779700002501808700001901833700001901852700002001871700001901891700001901910700002401929700001601953700002101969700001801990700001802008700002202026700002202048700001702070700002302087700002502110700002402135700001702159700002702176700002102203700002002224700002202244700001702266700002302283700002902306700002202335700002702357700001902384700002102403700002202424700002202446700002402468700002402492700002202516700002802538700002102566700002302587700002202610700002202632700003402654700001802688700001702706700001202723700002302735700002302758700002202781700001702803700001702820700002502837700002402862700002002886700002102906700002002927700002502947700002402972700001602996700002403012700001903036700002003055700002003075700002203095700002103117700001903138700002103157700002503178700001703203700001803220700001903238700001803257700001903275700002403294700002103318700002903339700002703368700002803395700001903423700002003442700002203462700002003484700001903504700002103523700002503544856003603569 2018 eng d a2041-172300aMultiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function.0 aMultiethnic metaanalysis identifies ancestryspecific and crossan c2018 Jul 30 a29760 v93 aNearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.
1 aWyss, Annah, B1 aSofer, Tamar1 aLee, Mi, Kyeong1 aTerzikhan, Natalie1 aNguyen, Jennifer, N1 aLahousse, Lies1 aLatourelle, Jeanne, C1 aSmith, Albert, Vernon1 aBartz, Traci, M1 aFeitosa, Mary, F1 aGao, Wei1 aAhluwalia, Tarunveer, S1 aTang, Wenbo1 aOldmeadow, Christopher1 aDuan, Qing1 ade Jong, Kim1 aWojczynski, Mary, K1 aWang, Xin-Qun1 aNoordam, Raymond1 aHartwig, Fernando, Pires1 aJackson, Victoria, E1 aWang, Tianyuan1 aObeidat, Ma'en1 aHobbs, Brian, D1 aHuan, Tianxiao1 aGui, Hongsheng1 aParker, Margaret, M1 aHu, Donglei1 aMogil, Lauren, S1 aKichaev, Gleb1 aJin, Jianping1 aGraff, Mariaelisa1 aHarris, Tamara, B1 aKalhan, Ravi1 aHeckbert, Susan, R1 aPaternoster, Lavinia1 aBurkart, Kristin, M1 aLiu, Yongmei1 aHolliday, Elizabeth, G1 aWilson, James, G1 aVonk, Judith, M1 aSanders, Jason, L1 aBarr, Graham1 ade Mutsert, Renée1 aMenezes, Ana, Maria Bapt1 aAdams, Hieab, H H1 avan den Berge, Maarten1 aJoehanes, Roby1 aLevin, Albert, M1 aLiberto, Jennifer1 aLauner, Lenore, J1 aMorrison, Alanna, C1 aSitlani, Colleen, M1 aCeledón, Juan, C1 aKritchevsky, Stephen, B1 aScott, Rodney, J1 aChristensen, Kaare1 aRotter, Jerome, I1 aBonten, Tobias, N1 aWehrmeister, Fernando, César1 aBossé, Yohan1 aXiao, Shujie1 aOh, Sam1 aFranceschini, Nora1 aBrody, Jennifer, A1 aKaplan, Robert, C1 aLohman, Kurt1 aMcEvoy, Mark1 aProvince, Michael, A1 aRosendaal, Frits, R1 aTaylor, Kent, D1 aNickle, David, C1 aWilliams, Keoki1 aBurchard, Esteban, G1 aWheeler, Heather, E1 aSin, Don, D1 aGudnason, Vilmundur1 aNorth, Kari, E1 aFornage, Myriam1 aPsaty, Bruce, M1 aMyers, Richard, H1 aO'Connor, George1 aHansen, Torben1 aLaurie, Cathy, C1 aCassano, Patricia, A1 aSung, Joohon1 aKim, Woo, Jin1 aAttia, John, R1 aLange, Leslie1 aBoezen, Marike1 aThyagarajan, Bharat1 aRich, Stephen, S1 aMook-Kanamori, Dennis, O1 aHorta, Bernardo, Lessa1 aUitterlinden, André, G1 aIm, Hae, Kyung1 aCho, Michael, H1 aBrusselle, Guy, G1 aGharib, Sina, A1 aDupuis, Josée1 aManichaikul, Ani1 aLondon, Stephanie, J uhttps://chs-nhlbi.org/node/781904760nas a2201057 4500008004100000022001400041245011000055210006900165260001500234300001200249490000800261520187700269653001002146653000902156653001902165653002102184653001602205653002002221653001102241653001102252653003402263653001102297653001402308653001502322653000902337653001602346653002602362653002202388653001402410653002402424653000902448653001802457100001802475700002602493700002802519700001902547700001902566700002002585700001902605700002302624700002202647700001802669700001902687700002002706700002402726700002002750700001902770700001702789700002202806700002102828700002002849700002302869700002102892700002502913700002402938700002002962700002202982700002003004700001203024700002003036700002203056700002003078700002203098700002203120700002203142700002003164700002003184700002003204700002103224700002003245700002103265700002003286700001603306700002503322700002103347700001903368700002203387700002003409700002403429700001603453700002003469700002203489700002203511700002003533700002003553700002903573700002103602700001703623700002603640856003603666 2019 eng d a1524-453900aBlood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease.0 aBlood Leukocyte DNA Methylation Predicts Risk of Future Myocardi c2019 08 20 a645-6570 v1403 aBACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts.
METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts.
RESULTS: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts.
CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.
10aAdult10aAged10aCohort Studies10aCoronary Disease10aCpG Islands10aDNA Methylation10aEurope10aFemale10aGenome-Wide Association Study10aHumans10aIncidence10aLeukocytes10aMale10aMiddle Aged10aMyocardial Infarction10aPopulation Groups10aPrognosis10aProspective Studies10aRisk10aUnited States1 aAgha, Golareh1 aMendelson, Michael, M1 aWard-Caviness, Cavin, K1 aJoehanes, Roby1 aHuan, Tianxiao1 aGondalia, Rahul1 aSalfati, Elias1 aBrody, Jennifer, A1 aFiorito, Giovanni1 aBressler, Jan1 aChen, Brian, H1 aLigthart, Symen1 aGuarrera, Simonetta1 aColicino, Elena1 aJust, Allan, C1 aWahl, Simone1 aGieger, Christian1 aVandiver, Amy, R1 aTanaka, Toshiko1 aHernandez, Dena, G1 aPilling, Luke, C1 aSingleton, Andrew, B1 aSacerdote, Carlotta1 aKrogh, Vittorio1 aPanico, Salvatore1 aTumino, Rosario1 aLi, Yun1 aZhang, Guosheng1 aStewart, James, D1 aFloyd, James, S1 aWiggins, Kerri, L1 aRotter, Jerome, I1 aMulthaup, Michael1 aBakulski, Kelly1 aHorvath, Steven1 aTsao, Philip, S1 aAbsher, Devin, M1 aVokonas, Pantel1 aHirschhorn, Joel1 aFallin, Daniele1 aLiu, Chunyu1 aBandinelli, Stefania1 aBoerwinkle, Eric1 aDehghan, Abbas1 aSchwartz, Joel, D1 aPsaty, Bruce, M1 aFeinberg, Andrew, P1 aHou, Lifang1 aFerrucci, Luigi1 aSotoodehnia, Nona1 aMatullo, Giuseppe1 aPeters, Annette1 aFornage, Myriam1 aAssimes, Themistocles, L1 aWhitsel, Eric, A1 aLevy, Daniel1 aBaccarelli, Andrea, A uhttps://chs-nhlbi.org/node/850704340nas a2200733 4500008004100000022001400041245013200055210006900187260001300256300001200269490000700281520227500288100001602563700002202579700002002601700002502621700002302646700001302669700002702682700001902709700001602728700002602744700001902770700001702789700002202806700002002828700001702848700002802865700002102893700002402914700001702938700002402955700001802979700002602997700002003023700002003043700002103063700002403084700002003108700002203128700002303150700002403173700002003197700001603217700001803233700001803251700001503269700002003284700002103304700002103325700001503346700001803361700001603379700002303395700001703418700001603435700001803451700002703469700001703496700002003513700002003533700001703553856003603570 2020 eng d a2574-830000aWhole Blood DNA Methylation Signatures of Diet Are Associated With Cardiovascular Disease Risk Factors and All-Cause Mortality.0 aWhole Blood DNA Methylation Signatures of Diet Are Associated Wi c2020 Aug ae0027660 v133 aBACKGROUND: DNA methylation patterns associated with habitual diet have not been well studied.
METHODS: Diet quality was characterized using a Mediterranean-style diet score and the Alternative Healthy Eating Index score. We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400 000 CpGs (cytosine-guanine dinucleotides) in 5 population-based cohorts including 6662 European ancestry, 2702 African ancestry, and 360 Hispanic ancestry participants. For diet-associated CpGs identified in epigenome-wide analyses, we conducted Mendelian randomization (MR) analysis to examine their relations to cardiovascular disease risk factors and examined their longitudinal associations with all-cause mortality.
RESULTS: We identified 30 CpGs associated with either Mediterranean-style diet score or Alternative Healthy Eating Index, or both, in European ancestry participants. Among these CpGs, 12 CpGs were significantly associated with all-cause mortality (Bonferroni corrected <1.6×10). Hypermethylation of cg18181703 () was associated with higher scores of both Mediterranean-style diet score and Alternative Healthy Eating Index and lower risk for all-cause mortality (=5.7×10). Ten additional diet-associated CpGs were nominally associated with all-cause mortality (<0.05). MR analysis revealed 8 putatively causal associations for 6 CpGs with 4 cardiovascular disease risk factors (body mass index, triglycerides, high-density lipoprotein cholesterol concentrations, and type 2 diabetes mellitus; Bonferroni corrected MR <4.5×10). For example, hypermethylation of cg11250194 () was associated with lower triglyceride concentrations (MR, =1.5×10).and hypermethylation of cg02079413 (; ) was associated with body mass index (corrected MR, =1×10).
CONCLUSIONS: Habitual diet quality was associated with differential peripheral leukocyte DNA methylation levels of 30 CpGs, most of which were also associated with multiple health outcomes, in European ancestry individuals. These findings demonstrate that integrative genomic analysis of dietary information may reveal molecular targets for disease prevention and treatment.
1 aMa, Jiantao1 aRebholz, Casey, M1 aBraun, Kim, V E1 aReynolds, Lindsay, M1 aAslibekyan, Stella1 aXia, Rui1 aBiligowda, Niranjan, G1 aHuan, Tianxiao1 aLiu, Chunyu1 aMendelson, Michael, M1 aJoehanes, Roby1 aHu, Emily, A1 aVitolins, Mara, Z1 aWood, Alexis, C1 aLohman, Kurt1 aOchoa-Rosales, Carolina1 avan Meurs, Joyce1 aUitterlinden, Andre1 aLiu, Yongmei1 aElhadad, Mohamed, A1 aHeier, Margit1 aWaldenberger, Melanie1 aPeters, Annette1 aColicino, Elena1 aWhitsel, Eric, A1 aBaldassari, Antoine1 aGharib, Sina, A1 aSotoodehnia, Nona1 aBrody, Jennifer, A1 aSitlani, Colleen, M1 aTanaka, Toshiko1 aHill, David1 aCorley, Janie1 aDeary, Ian, J1 aZhang, Yan1 aSchöttker, Ben1 aBrenner, Hermann1 aWalker, Maura, E1 aYe, Shumao1 aNguyen, Steve1 aPankow, Jim1 aDemerath, Ellen, W1 aZheng, Yinan1 aHou, Lifang1 aLiang, Liming1 aLichtenstein, Alice, H1 aHu, Frank, B1 aFornage, Myriam1 aVoortman, Trudy1 aLevy, Daniel uhttps://chs-nhlbi.org/node/844603954nas a2200805 4500008004100000022001400041245007700055210006900132260001300201300001100214490000700225520175800232653001501990653002802005653002002033653002402053653001602077653001102093653000902104653001402113100001902127700001802146700002002164700002802184700001602212700002302228700002102251700001502272700002402287700002802311700002002339700001702359700002602376700002002402700001602422700001402438700001602452700002002468700001902488700002002507700001802527700002602545700002202571700002302593700002102616700002302637700002002660700001902680700002002699700002202719700002402741700001702765700002202782700002002804700002602824700001802850700002002868700001402888700002202902700002702924700001602951700002502967700002002992700002103012700002303033700001803056700002103074700001703095856003603112 2022 eng d a1474-972600aIntegrative analysis of clinical and epigenetic biomarkers of mortality.0 aIntegrative analysis of clinical and epigenetic biomarkers of mo c2022 Jun ae136080 v213 aDNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow-up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p < 1 × 10 , of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5% increase in the C-index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta = 1.2, P = 4.1 × 10 ) and negatively associated with longevity (Beta = -1.9, P = 0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune- and cancer-related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.
10aBiomarkers10aCardiovascular Diseases10aDNA Methylation10aEpigenesis, Genetic10aEpigenomics10aHumans10aMale10aNeoplasms1 aHuan, Tianxiao1 aNguyen, Steve1 aColicino, Elena1 aOchoa-Rosales, Carolina1 aHill, David1 aBrody, Jennifer, A1 aSoerensen, Mette1 aZhang, Yan1 aBaldassari, Antoine1 aElhadad, Mohamed, Ahmed1 aToshiko, Tanaka1 aZheng, Yinan1 aDomingo-Relloso, Arce1 aLee, Dong, Heon1 aMa, Jiantao1 aYao, Chen1 aLiu, Chunyu1 aHwang, Shih-Jen1 aJoehanes, Roby1 aFornage, Myriam1 aBressler, Jan1 avan Meurs, Joyce, B J1 aDebrabant, Birgit1 aMengel-From, Jonas1 aHjelmborg, Jacob1 aChristensen, Kaare1 aVokonas, Pantel1 aSchwartz, Joel1 aGahrib, Sina, A1 aSotoodehnia, Nona1 aSitlani, Colleen, M1 aKunze, Sonja1 aGieger, Christian1 aPeters, Annette1 aWaldenberger, Melanie1 aDeary, Ian, J1 aFerrucci, Luigi1 aQu, Yishu1 aGreenland, Philip1 aLloyd-Jones, Donald, M1 aHou, Lifang1 aBandinelli, Stefania1 aVoortman, Trudy1 aHermann, Brenner1 aBaccarelli, Andrea1 aWhitsel, Eric1 aPankow, James, S1 aLevy, Daniel uhttps://chs-nhlbi.org/node/909403534nas a2200649 4500008004100000245010900041210006900150260001600219520168900235100002201924700001601946700002001962700002201982700001402004700002202018700001602040700002202056700002402078700002002102700002202122700001702144700002402161700001802185700002102203700002302224700002402247700001902271700002102290700002002311700001902331700002202350700002002372700001902392700002002411700001702431700001902448700001702467700002502484700002402509700001902533700002302552700001902575700002302594700002002617700002102637700001802658700002002676700002202696700002402718700002102742700002002763700001802783700001402801700001702815700001602832856003602848 2023 eng d00aGenome-Wide Interaction Analysis with DASH Diet Score Identified Novel Loci for Systolic Blood Pressure.0 aGenomeWide Interaction Analysis with DASH Diet Score Identified c2023 Nov 113 aOBJECTIVE: We examined interactions between genotype and a Dietary Approaches to Stop Hypertension (DASH) diet score in relation to systolic blood pressure (SBP).
METHODS: We analyzed up to 9,420,585 biallelic imputed single nucleotide polymorphisms (SNPs) in up to 127,282 individuals of six population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (CHARGE; n=35,660) and UK Biobank (n=91,622) and performed European population-specific and cross-population meta-analyses.
RESULTS: We identified three loci in European-specific analyses and an additional four loci in cross-population analyses at P for interaction < 5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency = 0.03) and the DASH diet score (P for interaction = 4e-8; P for heterogeneity = 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (P for interaction = 9.4e-7) and 0.20±0.06 mm Hg (P for interaction = 0.001) in CHARGE and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with -expression quantitative trait loci (eQTL) variants (P = 4e-273) and -DNA methylation quantitative trait loci (mQTL) variants (P = 1e-300). While the closest gene for rs117878928 is , the highest narrow sense heritability accounted by SNPs potentially interacting with the DASH diet score in this locus was for gene at 15q25.1.
CONCLUSION: We demonstrated gene-DASH diet score interaction effects on SBP in several loci. Studies with larger diverse populations are needed to validate our findings.
1 aGuirette, Melanie1 aLan, Jessie1 aMcKeown, Nicola1 aBrown, Michael, R1 aChen, Han1 ade Vries, Paul, S1 aKim, Hyunju1 aRebholz, Casey, M1 aMorrison, Alanna, C1 aBartz, Traci, M1 aFretts, Amanda, M1 aGuo, Xiuqing1 aLemaitre, Rozenn, N1 aLiu, Ching-Ti1 aNoordam, Raymond1 ade Mutsert, Renée1 aRosendaal, Frits, R1 aWang, Carol, A1 aBeilin, Lawrence1 aMori, Trevor, A1 aOddy, Wendy, H1 aPennell, Craig, E1 aChai, Jin, Fang1 aWhitton, Clare1 avan Dam, Rob, M1 aLiu, Jianjun1 aTai, Shyong, E1 aSim, Xueling1 aNeuhouser, Marian, L1 aKooperberg, Charles1 aTinker, Lesley1 aFranceschini, Nora1 aHuan, Tianxiao1 aWinkler, Thomas, W1 aBentley, Amy, R1 aGauderman, James1 aHeerkens, Luc1 aTanaka, Toshiko1 avan Rooij, Jeroen1 aMunroe, Patricia, B1 aWarren, Helen, R1 aVoortman, Trudy1 aChen, Honglei1 aRao, D, C1 aLevy, Daniel1 aMa, Jiantao uhttps://chs-nhlbi.org/node/9583