%0 Journal Article %J Nat Commun %D 2022 %T DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases. %A Wielscher, Matthias %A Mandaviya, Pooja R %A Kuehnel, Brigitte %A Joehanes, Roby %A Mustafa, Rima %A Robinson, Oliver %A Zhang, Yan %A Bodinier, Barbara %A Walton, Esther %A Mishra, Pashupati P %A Schlosser, Pascal %A Wilson, Rory %A Tsai, Pei-Chien %A Palaniswamy, Saranya %A Marioni, Riccardo E %A Fiorito, Giovanni %A Cugliari, Giovanni %A Karhunen, Ville %A Ghanbari, Mohsen %A Psaty, Bruce M %A Loh, Marie %A Bis, Joshua C %A Lehne, Benjamin %A Sotoodehnia, Nona %A Deary, Ian J %A Chadeau-Hyam, Marc %A Brody, Jennifer A %A Cardona, Alexia %A Selvin, Elizabeth %A Smith, Alicia K %A Miller, Andrew H %A Torres, Mylin A %A Marouli, Eirini %A Gào, Xin %A van Meurs, Joyce B J %A Graf-Schindler, Johanna %A Rathmann, Wolfgang %A Koenig, Wolfgang %A Peters, Annette %A Weninger, Wolfgang %A Farlik, Matthias %A Zhang, Tao %A Chen, Wei %A Xia, Yujing %A Teumer, Alexander %A Nauck, Matthias %A Grabe, Hans J %A Doerr, Macus %A Lehtimäki, Terho %A Guan, Weihua %A Milani, Lili %A Tanaka, Toshiko %A Fisher, Krista %A Waite, Lindsay L %A Kasela, Silva %A Vineis, Paolo %A Verweij, Niek %A van der Harst, Pim %A Iacoviello, Licia %A Sacerdote, Carlotta %A Panico, Salvatore %A Krogh, Vittorio %A Tumino, Rosario %A Tzala, Evangelia %A Matullo, Giuseppe %A Hurme, Mikko A %A Raitakari, Olli T %A Colicino, Elena %A Baccarelli, Andrea A %A Kähönen, Mika %A Herzig, Karl-Heinz %A Li, Shengxu %A Conneely, Karen N %A Kooner, Jaspal S %A Köttgen, Anna %A Heijmans, Bastiaan T %A Deloukas, Panos %A Relton, Caroline %A Ong, Ken K %A Bell, Jordana T %A Eric Boerwinkle %A Elliott, Paul %A Brenner, Hermann %A Beekman, Marian %A Levy, Daniel %A Waldenberger, Melanie %A Chambers, John C %A Dehghan, Abbas %A Jarvelin, Marjo-Riitta %K C-Reactive Protein %K CpG Islands %K DNA Methylation %K Humans %K Inflammation %K Nucleotide Motifs %X

We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.

%B Nat Commun %V 13 %P 2408 %8 2022 May 03 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35504910?dopt=Abstract %R 10.1038/s41467-022-29792-6 %0 Journal Article %J Am J Hum Genet %D 2017 %T DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation. %A Richard, Melissa A %A Huan, Tianxiao %A Ligthart, Symen %A Gondalia, Rahul %A Jhun, Min A %A Brody, Jennifer A %A Irvin, Marguerite R %A Marioni, Riccardo %A Shen, Jincheng %A Tsai, Pei-Chien %A Montasser, May E %A Jia, Yucheng %A Syme, Catriona %A Salfati, Elias L %A Eric Boerwinkle %A Guan, Weihua %A Mosley, Thomas H %A Bressler, Jan %A Morrison, Alanna C %A Liu, Chunyu %A Mendelson, Michael M %A Uitterlinden, André G %A van Meurs, Joyce B %A Franco, Oscar H %A Zhang, Guosheng %A Li, Yun %A Stewart, James D %A Bis, Joshua C %A Psaty, Bruce M %A Chen, Yii-Der Ida %A Kardia, Sharon L R %A Zhao, Wei %A Turner, Stephen T %A Absher, Devin %A Aslibekyan, Stella %A Starr, John M %A McRae, Allan F %A Hou, Lifang %A Just, Allan C %A Schwartz, Joel D %A Vokonas, Pantel S %A Menni, Cristina %A Spector, Tim D %A Shuldiner, Alan %A Damcott, Coleen M %A Rotter, Jerome I %A Palmas, Walter %A Liu, Yongmei %A Paus, Tomáš %A Horvath, Steve %A O'Connell, Jeffrey R %A Guo, Xiuqing %A Pausova, Zdenka %A Assimes, Themistocles L %A Sotoodehnia, Nona %A Smith, Jennifer A %A Arnett, Donna K %A Deary, Ian J %A Baccarelli, Andrea A %A Bell, Jordana T %A Whitsel, Eric %A Dehghan, Abbas %A Levy, Daniel %A Fornage, Myriam %K Aged %K Blood Pressure %K CpG Islands %K Cross-Sectional Studies %K DNA Methylation %K Epigenesis, Genetic %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Mendelian Randomization Analysis %K Middle Aged %K Nerve Tissue Proteins %K Quantitative Trait Loci %K Tetraspanins %X

Genome-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; replication: N = 7,182, p < 1.6 × 10). The replicated methylation sites are heritable (h > 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.

%B Am J Hum Genet %V 101 %P 888-902 %8 2017 Dec 07 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/29198723?dopt=Abstract %R 10.1016/j.ajhg.2017.09.028 %0 Journal Article %J Aging (Albany NY) %D 2016 %T DNA methylation-based measures of biological age: meta-analysis predicting time to death. %A Chen, Brian H %A Marioni, Riccardo E %A Colicino, Elena %A Peters, Marjolein J %A Ward-Caviness, Cavin K %A Tsai, Pei-Chien %A Roetker, Nicholas S %A Just, Allan C %A Demerath, Ellen W %A Guan, Weihua %A Bressler, Jan %A Fornage, Myriam %A Studenski, Stephanie %A Vandiver, Amy R %A Moore, Ann Zenobia %A Tanaka, Toshiko %A Kiel, Douglas P %A Liang, Liming %A Vokonas, Pantel %A Schwartz, Joel %A Lunetta, Kathryn L %A Murabito, Joanne M %A Bandinelli, Stefania %A Hernandez, Dena G %A Melzer, David %A Nalls, Michael %A Pilling, Luke C %A Price, Timothy R %A Singleton, Andrew B %A Gieger, Christian %A Holle, Rolf %A Kretschmer, Anja %A Kronenberg, Florian %A Kunze, Sonja %A Linseisen, Jakob %A Meisinger, Christine %A Rathmann, Wolfgang %A Waldenberger, Melanie %A Visscher, Peter M %A Shah, Sonia %A Wray, Naomi R %A McRae, Allan F %A Franco, Oscar H %A Hofman, Albert %A Uitterlinden, André G %A Absher, Devin %A Assimes, Themistocles %A Levine, Morgan E %A Lu, Ake T %A Tsao, Philip S %A Hou, Lifang %A Manson, JoAnn E %A Carty, Cara L %A LaCroix, Andrea Z %A Reiner, Alexander P %A Spector, Tim D %A Feinberg, Andrew P %A Levy, Daniel %A Baccarelli, Andrea %A van Meurs, Joyce %A Bell, Jordana T %A Peters, Annette %A Deary, Ian J %A Pankow, James S %A Ferrucci, Luigi %A Horvath, Steve %K Aging %K DNA Methylation %K Epigenesis, Genetic %K Female %K Humans %K Logistic Models %K Male %K Mortality %K Racial Groups %K Risk Factors %K Survival Analysis %K T-Lymphocyte Subsets %X

Estimates of biological age based on DNA methylation patterns, often referred to as "epigenetic age", "DNAm age", have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were predictive of mortality (p≤8.2x10, independent of chronological age, even after adjusting for additional risk factors (p<5.4x10, and within the racial/ethnic groups that we examined (non-Hispanic whites, Hispanics, African Americans). Epigenetic age estimates that incorporated information on blood cell composition led to the smallest p-values for time to death (p=7.5x10). Overall, this study a) strengthens the evidence that epigenetic age predicts all-cause mortality above and beyond chronological age and traditional risk factors, and b) demonstrates that epigenetic age estimates that incorporate information on blood cell counts lead to highly significant associations with all-cause mortality.

%B Aging (Albany NY) %V 8 %P 1844-1865 %8 2016 Sep 28 %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/27690265?dopt=Abstract %R 10.18632/aging.101020