@article {7349, title = {DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases.}, journal = {Genome Biol}, volume = {17}, year = {2016}, month = {2016 Dec 12}, pages = {255}, abstract = {

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 {\texttimes} 10(-7)) in the discovery panel of European ancestry and replicated (P < 2.29 {\texttimes} 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 {\texttimes} 10(-5)), ten (17\%) CpG sites were associated with a nearby genetic variant (P < 2.50 {\texttimes} 10(-3)), and 51 (88\%) were also associated with at least one related cardiometabolic entity (P < 9.58 {\texttimes} 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.

}, issn = {1474-760X}, doi = {10.1186/s13059-016-1119-5}, author = {Ligthart, Symen and Marzi, Carola and Aslibekyan, Stella and Mendelson, Michael M and Conneely, Karen N and Tanaka, Toshiko and Colicino, Elena and Waite, Lindsay L and Joehanes, Roby and Guan, Weihua and Brody, Jennifer A and Elks, Cathy and Marioni, Riccardo and Jhun, Min A and Agha, Golareh and Bressler, Jan and Ward-Caviness, Cavin K and Chen, Brian H and Huan, Tianxiao and Bakulski, Kelly and Salfati, Elias L and Fiorito, Giovanni and Wahl, Simone and Schramm, Katharina and Sha, Jin and Hernandez, Dena G and Just, Allan C and Smith, Jennifer A and Sotoodehnia, Nona and Pilling, Luke C and Pankow, James S and Tsao, Phil S and Liu, Chunyu and Zhao, Wei and Guarrera, Simonetta and Michopoulos, Vasiliki J and Smith, Alicia K and Peters, Marjolein J and Melzer, David and Vokonas, Pantel and Fornage, Myriam and Prokisch, Holger and Bis, Joshua C and Chu, Audrey Y and Herder, Christian and Grallert, Harald and Yao, Chen and Shah, Sonia and McRae, Allan F and Lin, Honghuang and Horvath, Steve and Fallin, Daniele and Hofman, Albert and Wareham, Nicholas J and Wiggins, Kerri L and Feinberg, Andrew P and Starr, John M and Visscher, Peter M and Murabito, Joanne M and Kardia, Sharon L R and Absher, Devin M and Binder, Elisabeth B and Singleton, Andrew B and Bandinelli, Stefania and Peters, Annette and Waldenberger, Melanie and Matullo, Giuseppe and Schwartz, Joel D and Demerath, Ellen W and Uitterlinden, Andr{\'e} G and van Meurs, Joyce B J and Franco, Oscar H and Chen, Yii-Der Ida and Levy, Daniel and Turner, Stephen T and Deary, Ian J and Ressler, Kerry J and Dupuis, Jos{\'e}e and Ferrucci, Luigi and Ong, Ken K and Assimes, Themistocles L and Boerwinkle, Eric and Koenig, Wolfgang and Arnett, Donna K and Baccarelli, Andrea A and Benjamin, Emelia J and Dehghan, Abbas} } @article {7816, title = {DNA methylation age is associated with an altered hemostatic profile in a multi-ethnic meta-analysis.}, journal = {Blood}, year = {2018}, month = {2018 Jul 24}, abstract = {

Many hemostatic factors are associated with age and age-related diseases, however much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we used European and African-ancestry participants who were meta-analyzed separately and combined via a random effects meta-analysis. All other measures only included participants of European-ancestry. We found that 1-year higher extrinsic epigenetic age as compared to chronological age was associated with higher fibrinogen (0.004 g/L per year; 95\% CI: 0.001, 0.007; P = 0.01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL per year; 95\% CI: 0.07, 0.20; P = 6.6x10-5) concentrations as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the three fibrinogen subunit-encoding genes (FGA, FGG, and FGB), in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a pro-coagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

}, issn = {1528-0020}, doi = {10.1182/blood-2018-02-831347}, author = {Ward-Caviness, Cavin K and Huffman, Jennifer E and Evertt, Karl and Germain, Marine and van Dongen, Jenny and Hill, W David and Jhun, Min A and Brody, Jennifer A and Ghanbari, Mohsen and Du, Lei and Roetker, Nicholas S and de Vries, Paul S and Waldenberger, Melanie and Gieger, Christian and Wolf, Petra and Prokisch, Holger and Koenig, Wolfgang and O{\textquoteright}Donnell, Christopher J and Levy, Daniel and Liu, Chunyu and Truong, Vinh and Wells, Philip S and Tr{\'e}gou{\"e}t, David-Alexandre and Tang, Weihong and Morrison, Alanna C and Boerwinkle, Eric and Wiggins, Kerri L and McKnight, Barbara and Guo, Xiuqing and Psaty, Bruce M and Sotoodenia, Nona and Boomsa, Dorret I and Willemsen, Gonneke and Ligthart, Lannie and Deary, Ian J and Zhao, Wei and Ware, Erin B and Kardia, Sharon L R and van Meurs, Joyce B J and Uitterlinden, Andr{\'e} G and Franco, Oscar H and Eriksson, Per and Franco-Cereceda, Anders and Pankow, James S and Johnson, Andrew D and Gagnon, France and Morange, Pierre-Emmanuel and de Geus, Eco J C and Starr, John M and Smith, Jennifer A and Dehghan, Abbas and Bj{\"o}rck, Hanna M and Smith, Nicholas L and Peters, Annette} } @article {7924, title = {Genome-Wide Association Trans-Ethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels.}, journal = {Circulation}, year = {2018}, month = {2018 Nov 20}, abstract = {

BACKGROUND: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.

METHODS: We meta-analyzed genome-wide association results from 46,354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated approximately 35 million imputed variants with natural-log transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization (MR) analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.

RESULTS: We identified 13 novel genome-wide significant (p<=2.5x10) associations; 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. MR suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.

CONCLUSIONS: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.

}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.118.034532}, author = {Sabater-Lleal, Maria and Huffman, Jennifer E and de Vries, Paul S and Marten, Jonathan and Mastrangelo, Michael A and Song, Ci and Pankratz, Nathan and Ward-Caviness, Cavin K and Yanek, Lisa R and Trompet, Stella and Delgado, Graciela E and Guo, Xiuqing and Bartz, Traci M and Martinez-Perez, Angel and Germain, Marine and de Haan, Hugoline G and Ozel, Ayse B and Polasek, Ozren and Smith, Albert V and Eicher, John D and Reiner, Alex P and Tang, Weihong and Davies, Neil M and Stott, David J and Rotter, Jerome I and Tofler, Geoffrey H and Boerwinkle, Eric and de Maat, Moniek P M and Kleber, Marcus E and Welsh, Paul and Brody, Jennifer A and Chen, Ming-Huei and Vaidya, Dhananjay and Soria, Jos{\'e} Manuel and Suchon, Pierre and van Hylckama Vlieg, Astrid and Desch, Karl C and Kolcic, Ivana and Joshi, Peter K and Launer, Lenore J and Harris, Tamara B and Campbell, Harry and Rudan, Igor and Becker, Diane M and Li, Jun Z and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Hofman, Albert and Franco, Oscar H and Cushman, Mary and Psaty, Bruce M and Morange, Pierre-Emmanuel and McKnight, Barbara and Chong, Michael R and Fernandez-Cadenas, Israel and Rosand, Jonathan and Lindgren, Arne and Gudnason, Vilmundur and Wilson, James F and Hayward, Caroline and Ginsburg, David and Fornage, Myriam and Rosendaal, Frits R and Souto, Juan Carlos and Becker, Lewis C and Jenny, Nancy S and M{\"a}rz, Winfried and Jukema, J Wouter and Dehghan, Abbas and Tr{\'e}gou{\"e}t, David-Alexandre and Morrison, Alanna C and Johnson, Andrew D and O{\textquoteright}Donnell, Christopher J and Strachan, David P and Lowenstein, Charles J and Smith, Nicholas L} } @article {8507, title = {Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease.}, journal = {Circulation}, volume = {140}, year = {2019}, month = {2019 08 20}, pages = {645-657}, abstract = {

BACKGROUND: 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.

}, keywords = {Adult, Aged, Cohort Studies, Coronary Disease, CpG Islands, DNA Methylation, Europe, Female, Genome-Wide Association Study, Humans, Incidence, Leukocytes, Male, Middle Aged, Myocardial Infarction, Population Groups, Prognosis, Prospective Studies, Risk, United States}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.118.039357}, author = {Agha, Golareh and Mendelson, Michael M and Ward-Caviness, Cavin K and Joehanes, Roby and Huan, Tianxiao and Gondalia, Rahul and Salfati, Elias and Brody, Jennifer A and Fiorito, Giovanni and Bressler, Jan and Chen, Brian H and Ligthart, Symen and Guarrera, Simonetta and Colicino, Elena and Just, Allan C and Wahl, Simone and Gieger, Christian and Vandiver, Amy R and Tanaka, Toshiko and Hernandez, Dena G and Pilling, Luke C and Singleton, Andrew B and Sacerdote, Carlotta and Krogh, Vittorio and Panico, Salvatore and Tumino, Rosario and Li, Yun and Zhang, Guosheng and Stewart, James D and Floyd, James S and Wiggins, Kerri L and Rotter, Jerome I and Multhaup, Michael and Bakulski, Kelly and Horvath, Steven and Tsao, Philip S and Absher, Devin M and Vokonas, Pantel and Hirschhorn, Joel and Fallin, M Daniele and Liu, Chunyu and Bandinelli, Stefania and Boerwinkle, Eric and Dehghan, Abbas and Schwartz, Joel D and Psaty, Bruce M and Feinberg, Andrew P and Hou, Lifang and Ferrucci, Luigi and Sotoodehnia, Nona and Matullo, Giuseppe and Peters, Annette and Fornage, Myriam and Assimes, Themistocles L and Whitsel, Eric A and Levy, Daniel and Baccarelli, Andrea A} } @article {7988, title = {A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology.}, journal = {Blood}, volume = {133}, year = {2019}, month = {2019 Feb 28}, pages = {967-977}, abstract = {

Factor VII (FVII) is an important component of the coagulation cascade. Few genetic loci regulating FVII activity and/or levels have been discovered to date. We conducted a meta-analysis of 9 genome-wide association studies of plasma FVII levels (7 FVII activity and 2 FVII antigen) among 27 495 participants of European and African ancestry. Each study performed ancestry-specific association analyses. Inverse variance weighted meta-analysis was performed within each ancestry group and then combined for a -ancestry meta-analysis. Our primary analysis included the 7 studies that measured FVII activity, and a secondary analysis included all 9 studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using small-interfering RNA and then measuring messenger RNA and FVII protein expression. Lastly, we used meta-analysis results to perform Mendelian randomization analysis to estimate the causal effect of FVII activity on coronary artery disease, ischemic stroke (IS), and venous thromboembolism. We identified 2 novel ( and ) and 6 known loci associated with FVII activity, explaining 19.0\% of the phenotypic variance. Adding FVII antigen data to the meta-analysis did not result in the discovery of further loci. Silencing in HuH7 cells upregulated FVII, whereas silencing downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at and contribute to FVII activity by regulating expression levels. FVII activity appears to contribute to the etiology of IS in the general population.

}, issn = {1528-0020}, doi = {10.1182/blood-2018-05-849240}, author = {de Vries, Paul S and Sabater-Lleal, Maria and Huffman, Jennifer E and Marten, Jonathan and Song, Ci and Pankratz, Nathan and Bartz, Traci M and de Haan, Hugoline G and Delgado, Graciela E and Eicher, John D and Martinez-Perez, Angel and Ward-Caviness, Cavin K and Brody, Jennifer A and Chen, Ming-Huei and de Maat, Moniek P M and Fr{\r a}nberg, Mattias and Gill, Dipender and Kleber, Marcus E and Rivadeneira, Fernando and Soria, Jos{\'e} Manuel and Tang, Weihong and Tofler, Geoffrey H and Uitterlinden, Andr{\'e} G and van Hylckama Vlieg, Astrid and Seshadri, Sudha and Boerwinkle, Eric and Davies, Neil M and Giese, Anne-Katrin and Ikram, M Kamran and Kittner, Steven J and McKnight, Barbara and Psaty, Bruce M and Reiner, Alex P and Sargurupremraj, Muralidharan and Taylor, Kent D and Fornage, Myriam and Hamsten, Anders and M{\"a}rz, Winfried and Rosendaal, Frits R and Souto, Juan Carlos and Dehghan, Abbas and Johnson, Andrew D and Morrison, Alanna C and O{\textquoteright}Donnell, Christopher J and Smith, Nicholas L} } @article {8050, title = {Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease.}, journal = {PLoS One}, volume = {14}, year = {2019}, month = {2019}, pages = {e0216222}, abstract = {

BACKGROUND: Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.

METHODS AND FINDINGS: We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95\% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.

CONCLUSIONS: A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0216222}, author = {Ward-Caviness, Cavin K and de Vries, Paul S and Wiggins, Kerri L and Huffman, Jennifer E and Yanek, Lisa R and Bielak, Lawrence F and Giulianini, Franco and Guo, Xiuqing and Kleber, Marcus E and Kacprowski, Tim and Gro{\ss}, Stefan and Petersman, Astrid and Davey Smith, George and Hartwig, Fernando P and Bowden, Jack and Hemani, Gibran and M{\"u}ller-Nuraysid, Martina and Strauch, Konstantin and Koenig, Wolfgang and Waldenberger, Melanie and Meitinger, Thomas and Pankratz, Nathan and Boerwinkle, Eric and Tang, Weihong and Fu, Yi-Ping and Johnson, Andrew D and Song, Ci and de Maat, Moniek P M and Uitterlinden, Andr{\'e} G and Franco, Oscar H and Brody, Jennifer A and McKnight, Barbara and Chen, Yii-Der Ida and Psaty, Bruce M and Mathias, Rasika A and Becker, Diane M and Peyser, Patricia A and Smith, Jennifer A and Bielinski, Suzette J and Ridker, Paul M and Taylor, Kent D and Yao, Jie and Tracy, Russell and Delgado, Graciela and Trompet, Stella and Sattar, Naveed and Jukema, J Wouter and Becker, Lewis C and Kardia, Sharon L R and Rotter, Jerome I and M{\"a}rz, Winfried and D{\"o}rr, Marcus and Chasman, Daniel I and Dehghan, Abbas and O{\textquoteright}Donnell, Christopher J and Smith, Nicholas L and Peters, Annette and Morrison, Alanna C} }