05814nas a2201345 4500008004100000022001400041245014200055210006900197260001300266300001300279490000700292520193700299653002202236653003002258653003402288653002002322653001802342653001102360653002802371653002902399653003602428653004202464100001902506700002002525700001902545700001402564700001802578700001702596700001802613700002602631700001902657700002202676700002002698700003102718700002302749700002102772700001602793700001302809700002102822700001802843700001702861700002402878700002302902700001802925700002402943700002602967700001902993700002303012700002003035700002303055700002603078700001503104700002203119700002203141700001903163700002203182700001903204700001603223700001803239700002103257700002103278700002303299700001803322700001803340700002303358700002203381700002503403700002303428700001903451700001903470700002503489700002403514700002203538700001803560700001703578700001903595700001403614700002403628700001603652700002503668700002403693700002003717700001603737700001503753700002103768700002103789700002503810700002203835700002003857700002103877700002003898700001703918700002003935700002303955700002403978700002404002700002004026700002004046700002204066700002204088700002104110700002004131700002104151700002204172700002204194700001504216700002304231700002204254710002004276710002204296710002304318710002204341710006904363856003604432 2014 eng d a1553-740400aMeta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes.0 aMetaanalysis of genomewide association studies in African Americ c2014 Aug ae10045170 v103 a
Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)
10aAfrican Americans10aDiabetes Mellitus, Type 210aGenome-Wide Association Study10aHLA-B27 Antigen10aHMGA2 Protein10aHumans10aKCNQ1 Potassium Channel10aMutant Chimeric Proteins10aPolymorphism, Single Nucleotide10aTranscription Factor 7-Like 2 Protein1 aC Y Ng, Maggie1 aShriner, Daniel1 aChen, Brian, H1 aLi, Jiang1 aChen, Wei-Min1 aGuo, Xiuqing1 aLiu, Jiankang1 aBielinski, Suzette, J1 aYanek, Lisa, R1 aNalls, Michael, A1 aComeau, Mary, E1 aRasmussen-Torvik, Laura, J1 aJensen, Richard, A1 aEvans, Daniel, S1 aSun, Yan, V1 aAn, Ping1 aPatel, Sanjay, R1 aLu, Yingchang1 aLong, Jirong1 aArmstrong, Loren, L1 aWagenknecht, Lynne1 aYang, Lingyao1 aSnively, Beverly, M1 aPalmer, Nicholette, D1 aMudgal, Poorva1 aLangefeld, Carl, D1 aKeene, Keith, L1 aFreedman, Barry, I1 aMychaleckyj, Josyf, C1 aNayak, Uma1 aRaffel, Leslie, J1 aGoodarzi, Mark, O1 aChen, Y-D, Ida1 aTaylor, Herman, A1 aCorrea, Adolfo1 aSims, Mario1 aCouper, David1 aPankow, James, S1 aBoerwinkle, Eric1 aAdeyemo, Adebowale1 aDoumatey, Ayo1 aChen, Guanjie1 aMathias, Rasika, A1 aVaidya, Dhananjay1 aSingleton, Andrew, B1 aZonderman, Alan, B1 aIgo, Robert, P1 aSedor, John, R1 aKabagambe, Edmond, K1 aSiscovick, David, S1 aMcKnight, Barbara1 aRice, Kenneth1 aLiu, Yongmei1 aHsueh, Wen-Chi1 aZhao, Wei1 aBielak, Lawrence, F1 aKraja, Aldi1 aProvince, Michael, A1 aBottinger, Erwin, P1 aGottesman, Omri1 aCai, Qiuyin1 aZheng, Wei1 aBlot, William, J1 aLowe, William, L1 aPacheco, Jennifer, A1 aCrawford, Dana, C1 aGrundberg, Elin1 aRich, Stephen, S1 aHayes, Geoffrey1 aShu, Xiao-Ou1 aLoos, Ruth, J F1 aBorecki, Ingrid, B1 aPeyser, Patricia, A1 aCummings, Steven, R1 aPsaty, Bruce, M1 aFornage, Myriam1 aIyengar, Sudha, K1 aEvans, Michele, K1 aBecker, Diane, M1 aKao, Linda, W H1 aWilson, James, G1 aRotter, Jerome, I1 aSale, Michèle, M1 aLiu, Simin1 aRotimi, Charles, N1 aBowden, Donald, W1 aFIND Consortium1 aeMERGE Consortium1 aDIAGRAM Consortium1 aMuTHER Consortium1 aMEta-analysis of type 2 DIabetes in African Americans Consortium uhttps://chs-nhlbi.org/node/658505220nas 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/734904760nas 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/8507