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1.  DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases 
Ligthart, Symen | Marzi, Carola | Aslibekyan, Stella | Mendelson, Michael M. | Conneely, Karen N. | Tanaka, Toshiko | Colicino, Elena | Waite, Lindsay L. | Joehanes, Roby | Guan, Weihua | Brody, Jennifer A. | Elks, Cathy | Marioni, Riccardo | Jhun, Min A. | Agha, Golareh | Bressler, Jan | Ward-Caviness, Cavin K. | Chen, Brian H. | Huan, Tianxiao | Bakulski, Kelly | Salfati, Elias L. | Fiorito, Giovanni | Wahl, Simone | Schramm, Katharina | Sha, Jin | Hernandez, Dena G. | Just, Allan C. | Smith, Jennifer A. | Sotoodehnia, Nona | Pilling, Luke C. | Pankow, James S. | Tsao, Phil S. | Liu, Chunyu | Zhao, Wei | Guarrera, Simonetta | Michopoulos, Vasiliki J. | Smith, Alicia K. | Peters, Marjolein J. | Melzer, David | Vokonas, Pantel | Fornage, Myriam | Prokisch, Holger | Bis, Joshua C. | Chu, Audrey Y. | Herder, Christian | Grallert, Harald | Yao, Chen | Shah, Sonia | McRae, Allan F. | Lin, Honghuang | Horvath, Steve | Fallin, Daniele | Hofman, Albert | Wareham, Nicholas J. | Wiggins, Kerri L. | Feinberg, Andrew P. | Starr, John M. | Visscher, Peter M. | Murabito, Joanne M. | Kardia, Sharon L. R. | Absher, Devin M. | Binder, Elisabeth B. | Singleton, Andrew B. | Bandinelli, Stefania | Peters, Annette | Waldenberger, Melanie | Matullo, Giuseppe | Schwartz, Joel D. | Demerath, Ellen W. | Uitterlinden, André G. | van Meurs, Joyce B. J. | Franco, Oscar H. | Chen, Yii-Der Ida | Levy, Daniel | Turner, Stephen T. | Deary, Ian J. | Ressler, Kerry J. | Dupuis, Josée | Ferrucci, Luigi | Ong, Ken K. | Assimes, Themistocles L. | Boerwinkle, Eric | Koenig, Wolfgang | Arnett, Donna K. | Baccarelli, Andrea A. | Benjamin, Emelia J. | Dehghan, Abbas
Genome Biology  2016;17:255.
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.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-016-1119-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13059-016-1119-5
PMCID: PMC5151130  PMID: 27955697
Inflammation; DNA methylation; Epigenome-wide association study; C-reactive protein; Body mass index; Diabetes; Coronary heart disease
2.  Prognostic Value of Cardiac Troponin T and Sex in Patients Undergoing Elective Percutaneous Coronary Intervention 
Background
In patients with stable coronary artery disease undergoing elective percutaneous coronary intervention, the prognostic value of high‐sensitivity cardiac troponin T (hs‐cTnT) and the influence of sex remain poorly defined.
Methods and Results
Consecutive patients with stable coronary artery disease who underwent elective percutaneous coronary intervention were included. Primary endpoint was all‐cause mortality. Unadjusted hazard ratio (HR) in overall and sex‐specific population and multivariable adjusted HR were calculated by using Cox proportional hazard models. In a total of 5626 patients, elevated hs‐cTnT levels, more than the sex‐specific 99th percentile upper reference limit of normal (URL), were observed in 2221 patients (39%) at baseline. During follow‐up (median, 14.5 months; 25th–75th percentiles, 6.4–27.2 months), 265 patients died. Mortality was higher in patients with the sex‐specific 99th percentile URL compared to those with normal hs‐cTnT (17.3% vs 3.4%; HR=6.10; 95% CI, 4.58–8.14; P<0.001). hs‐cTnT was an independent predictor of mortality in multivariable adjusted models. The C‐statistic was significantly increased by adding hs‐cTnT to the basic prediction model for mortality (0.793–0.815; P<0.001). There was a significant interaction between hs‐cTnT and sex on mortality. Differences in all‐cause mortality between patients with more than the sex‐specific 99th percentile URL and those with normal hs‐cTnT were numerically larger in male than female patients (male, HR=6.45; 95% CI, 4.68–8.87, P<0.001; female, HR=4.29, 95% CI, 2.36–9.03; P<0.001).
Conclusions
In patients with stable coronary artery disease undergoing elective percutaneous coronary intervention, preprocedural hs‐cTnT was a strong predictor of mortality in both men and women.
doi:10.1161/JAHA.116.004464
PMCID: PMC5210430  PMID: 27895042
percutaneous coronary intervention; sex; stable coronary artery disease; troponin T; Biomarkers; Chronic Ischemic Heart Disease; Percutaneous Coronary Intervention
3.  Epigenetic Signatures at AQP3 and SOCS3 Engage in Low-Grade Inflammation across Different Tissues 
PLoS ONE  2016;11(11):e0166015.
Background
Elevated levels of C-reactive protein (CRP, determined by a high-sensitivity assay) indicate low-grade inflammation which is implicated in many age-related disorders. Epigenetic studies on CRP might discover molecular mechanisms underlying CRP regulation. We aimed to identify DNA methylation sites related to CRP concentrations in cells and tissues regulating low-grade inflammation.
Results
Genome-wide DNA methylation was measured in peripheral blood in 1,741 participants of the KORA F4 study using Illumina HumanMethylation450 BeadChip arrays. Four CpG sites (located at BCL3, AQP3, SOCS3, and cg19821297 intergenic at chromosome 19p13.2, P ≤ 1.01E-07) were significantly hypomethylated at high CRP concentrations independent of various confounders including age, sex, BMI, smoking, and white blood cell composition. Findings were not sex-specific. CRP-related top genes were enriched in JAK/STAT pathways (Benjamini-Hochberg corrected P < 0.05). Results were followed-up in three studies using DNA from peripheral blood (EPICOR, n = 503) and adipose tissue (TwinsUK, n = 368) measured as described above and from liver tissue (LMU liver cohort, n = 286) measured by MALDI-TOF mass spectrometry using EpiTYPER. CpG sites at the AQP3 locus (significant p-values in peripheral blood = 1.72E-03 and liver tissue = 1.51E-03) and the SOCS3 locus (p-values in liver < 2.82E-05) were associated with CRP in the validation panels.
Conclusions
Epigenetic modifications seem to engage in low-grade inflammation, possibly via JAK/STAT mediated pathways. Results suggest a shared relevance across different tissues at the AQP3 locus and highlight a role of DNA methylation for CRP regulation at the SOCS3 locus.
doi:10.1371/journal.pone.0166015
PMCID: PMC5100881  PMID: 27824951
4.  Recalibration of the ACC/AHA Risk Score in Two Population-Based German Cohorts 
PLoS ONE  2016;11(10):e0164688.
Background
The 2013 ACC/AHA guidelines introduced an algorithm for risk assessment of atherosclerotic cardiovascular disease (ASCVD) within 10 years. In Germany, risk assessment with the ESC SCORE is limited to cardiovascular mortality. Applicability of the novel ACC/AHA risk score to the German population has not yet been assessed. We therefore sought to recalibrate and evaluate the ACC/AHA risk score in two German cohorts and to compare it to the ESC SCORE.
Methods
We studied 5,238 participants from the KORA surveys S3 (1994–1995) and S4 (1999–2001) and 4,208 subjects from the Heinz Nixdorf Recall (HNR) Study (2000–2003). There were 383 (7.3%) and 271 (6.4%) first non-fatal or fatal ASCVD events within 10 years in KORA and in HNR, respectively. Risk scores were evaluated in terms of calibration and discrimination performance.
Results
The original ACC/AHA risk score overestimated 10-year ASCVD rates by 37% in KORA and 66% in HNR. After recalibration, miscalibration diminished to 8% underestimation in KORA and 12% overestimation in HNR. Discrimination performance of the ACC/AHA risk score was not affected by the recalibration (KORA: C = 0.78, HNR: C = 0.74). The ESC SCORE overestimated by 5% in KORA and by 85% in HNR. The corresponding C-statistic was 0.82 in KORA and 0.76 in HNR.
Conclusions
The recalibrated ACC/AHA risk score showed strongly improved calibration compared to the original ACC/AHA risk score. Predicting only cardiovascular mortality, discrimination performance of the commonly used ESC SCORE remained somewhat superior to the ACC/AHA risk score. Nevertheless, the recalibrated ACC/AHA risk score may provide a meaningful tool for estimating 10-year risk of fatal and non-fatal cardiovascular disease in Germany.
doi:10.1371/journal.pone.0164688
PMCID: PMC5061315  PMID: 27732641
5.  Molecular Characterization of the NLRC4 Expression in Relation to Interleukin-18 Levels 
Background
Interleukin-18 (IL-18) is a pleiotropic cytokine centrally involved in the cytokine cascade with complex immunomodulatory functions in innate and acquired immunity. Circulating IL-18 concentrations are associated with type 2 diabetes, cardiovascular events and diverse inflammatory and autoimmune disorders.
Methods and Results
To identify causal variants affecting circulating IL-18 concentrations, we applied various omics and molecular biology approaches. By GWAS, we confirmed association of IL-18 levels with a SNP in the untranslated exon 2 of the inflammasome component NLRC4 (NLR family, CARD domain containing 4) gene on chromosome 2 (rs385076, P=2.4×10−45). Subsequent molecular analyses by gene expression analysis and reporter gene assays indicated an effect of rs385076 on NLRC4 expression and differential isoform usage by modulating binding of the transcription factor PU.1.
Conclusions
Our study provides evidence for the functional causality of SNP rs385076 within the NLRC4 gene in relation to IL-18 activation.
doi:10.1161/CIRCGENETICS.115.001079
PMCID: PMC4618032  PMID: 26362438
gene expression; transcription factors; gene regulation; genetic variation; Interleukin 18; Inflammasome; PU.1; NLRC4
6.  Dataset of the associations of aldosterone to renin ratio with MR-proANP and MR-proADM 
Data in Brief  2016;8:1395-1399.
This article contains data related to the research article entitled “Altered relation of the renin-aldosterone system and vasoactive peptides in type 2 diabetes: the KORA F4 study” (Then et al., 2016) [1] and describes the association of the aldosterone to renin ratio with midregional-pro atrial natriuretic peptide (MR-proANP) and midregional-pro adrenomedullin (MR-proADM) in 1261 participants from the KORA F4 cohort.
doi:10.1016/j.dib.2016.08.008
PMCID: PMC4995539  PMID: 27595128
Aldosterone to renin ratio; MR-proANP; MR-proADM; Diabetes
7.  Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function 
Pattaro, Cristian | Teumer, Alexander | Gorski, Mathias | Chu, Audrey Y. | Li, Man | Mijatovic, Vladan | Garnaas, Maija | Tin, Adrienne | Sorice, Rossella | Li, Yong | Taliun, Daniel | Olden, Matthias | Foster, Meredith | Yang, Qiong | Chen, Ming-Huei | Pers, Tune H. | Johnson, Andrew D. | Ko, Yi-An | Fuchsberger, Christian | Tayo, Bamidele | Nalls, Michael | Feitosa, Mary F. | Isaacs, Aaron | Dehghan, Abbas | d’Adamo, Pio | Adeyemo, Adebowale | Dieffenbach, Aida Karina | Zonderman, Alan B. | Nolte, Ilja M. | van der Most, Peter J. | Wright, Alan F. | Shuldiner, Alan R. | Morrison, Alanna C. | Hofman, Albert | Smith, Albert V. | Dreisbach, Albert W. | Franke, Andre | Uitterlinden, Andre G. | Metspalu, Andres | Tonjes, Anke | Lupo, Antonio | Robino, Antonietta | Johansson, Åsa | Demirkan, Ayse | Kollerits, Barbara | Freedman, Barry I. | Ponte, Belen | Oostra, Ben A. | Paulweber, Bernhard | Krämer, Bernhard K. | Mitchell, Braxton D. | Buckley, Brendan M. | Peralta, Carmen A. | Hayward, Caroline | Helmer, Catherine | Rotimi, Charles N. | Shaffer, Christian M. | Müller, Christian | Sala, Cinzia | van Duijn, Cornelia M. | Saint-Pierre, Aude | Ackermann, Daniel | Shriner, Daniel | Ruggiero, Daniela | Toniolo, Daniela | Lu, Yingchang | Cusi, Daniele | Czamara, Darina | Ellinghaus, David | Siscovick, David S. | Ruderfer, Douglas | Gieger, Christian | Grallert, Harald | Rochtchina, Elena | Atkinson, Elizabeth J. | Holliday, Elizabeth G. | Boerwinkle, Eric | Salvi, Erika | Bottinger, Erwin P. | Murgia, Federico | Rivadeneira, Fernando | Ernst, Florian | Kronenberg, Florian | Hu, Frank B. | Navis, Gerjan J. | Curhan, Gary C. | Ehret, George B. | Homuth, Georg | Coassin, Stefan | Thun, Gian-Andri | Pistis, Giorgio | Gambaro, Giovanni | Malerba, Giovanni | Montgomery, Grant W. | Eiriksdottir, Gudny | Jacobs, Gunnar | Li, Guo | Wichmann, H.-Erich | Campbell, Harry | Schmidt, Helena | Wallaschofski, Henri | Völzke, Henry | Brenner, Hermann | Kroemer, Heyo K. | Kramer, Holly | Lin, Honghuang | Leach, I. Mateo | Ford, Ian | Guessous, Idris | Rudan, Igor | Prokopenko, Inga | Borecki, Ingrid | Heid, Iris M. | Kolcic, Ivana | Persico, Ivana | Jukema, J. Wouter | Wilson, James F. | Felix, Janine F. | Divers, Jasmin | Lambert, Jean-Charles | Stafford, Jeanette M. | Gaspoz, Jean-Michel | Smith, Jennifer A. | Faul, Jessica D. | Wang, Jie Jin | Ding, Jingzhong | Hirschhorn, Joel N. | Attia, John | Whitfield, John B. | Chalmers, John | Viikari, Jorma | Coresh, Josef | Denny, Joshua C. | Karjalainen, Juha | Fernandes, Jyotika K. | Endlich, Karlhans | Butterbach, Katja | Keene, Keith L. | Lohman, Kurt | Portas, Laura | Launer, Lenore J. | Lyytikäinen, Leo-Pekka | Yengo, Loic | Franke, Lude | Ferrucci, Luigi | Rose, Lynda M. | Kedenko, Lyudmyla | Rao, Madhumathi | Struchalin, Maksim | Kleber, Marcus E. | Cavalieri, Margherita | Haun, Margot | Cornelis, Marilyn C. | Ciullo, Marina | Pirastu, Mario | de Andrade, Mariza | McEvoy, Mark A. | Woodward, Mark | Adam, Martin | Cocca, Massimiliano | Nauck, Matthias | Imboden, Medea | Waldenberger, Melanie | Pruijm, Menno | Metzger, Marie | Stumvoll, Michael | Evans, Michele K. | Sale, Michele M. | Kähönen, Mika | Boban, Mladen | Bochud, Murielle | Rheinberger, Myriam | Verweij, Niek | Bouatia-Naji, Nabila | Martin, Nicholas G. | Hastie, Nick | Probst-Hensch, Nicole | Soranzo, Nicole | Devuyst, Olivier | Raitakari, Olli | Gottesman, Omri | Franco, Oscar H | Polasek, Ozren | Gasparini, Paolo | Munroe, Patricia B. | Ridker, Paul M. | Mitchell, Paul | Muntner, Paul | Meisinger, Christa | Smit, Johannes H. | Kovacs, Peter | Wild, Philipp S. | Froguel, Philippe | Rettig, Rainer | Magi, Reedik | Biffar, Reiner | Schmidt, Reinhold | Middelberg, Rita PS | Carroll, Robert J. | Penninx, Brenda W. | Scott, Rodney J. | Katz, Ronit | Sedaghat, Sanaz | Wild, Sarah H. | Kardia, Sharon L.R. | Ulivi, Sheila | Hwang, Shih-Jen | Enroth, Stefan | Kloiber, Stefan | Trompet, Stella | Stengel, Benedicte | Hancock, Stephen J. | Turner, Stephen T. | Rosas, Sylvia E. | Stracke, Sylvia | Harris, Tamara B. | Zeller, Tanja | Zemunik, Tatijana | Lehtimäki, Terho | Illig, Thomas | Aspelund, Thor | Nikopensius, Tiit | Esko, Tonu | Tanaka, Toshiko | Gyllensten, Ulf | Völker, Uwe | Emilsson, Valur | Vitart, Veronique | Aalto, Ville | Gudnason, Vilmundur | Chouraki, Vincent | Chen, Wei-Min | Igl, Wilmar | März, Winfried | Koenig, Wolfgang | Lieb, Wolfgang | Loos, Ruth J. F. | Liu, Yongmei | Snieder, Harold | Pramstaller, Peter P. | Parsa, Afshin | O’Connell, Jeffrey R. | Susztak, Katalin | Hamet, Pavel | Tremblay, Johanne | de Boer, Ian H. | Böger, Carsten A. | Goessling, Wolfram | Chasman, Daniel I. | Köttgen, Anna | Kao, WH Linda | Fox, Caroline S.
Nature communications  2016;7:10023.
Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, nineteen associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biologic pathways.
doi:10.1038/ncomms10023
PMCID: PMC4735748  PMID: 26831199
8.  Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study 
Winkler, Thomas W. | Justice, Anne E. | Graff, Mariaelisa | Barata, Llilda | Feitosa, Mary F. | Chu, Su | Czajkowski, Jacek | Esko, Tõnu | Fall, Tove | Kilpeläinen, Tuomas O. | Lu, Yingchang | Mägi, Reedik | Mihailov, Evelin | Pers, Tune H. | Rüeger, Sina | Teumer, Alexander | Ehret, Georg B. | Ferreira, Teresa | Heard-Costa, Nancy L. | Karjalainen, Juha | Lagou, Vasiliki | Mahajan, Anubha | Neinast, Michael D. | Prokopenko, Inga | Simino, Jeannette | Teslovich, Tanya M. | Jansen, Rick | Westra, Harm-Jan | White, Charles C. | Absher, Devin | Ahluwalia, Tarunveer S. | Ahmad, Shafqat | Albrecht, Eva | Alves, Alexessander Couto | Bragg-Gresham, Jennifer L. | de Craen, Anton J. M. | Bis, Joshua C. | Bonnefond, Amélie | Boucher, Gabrielle | Cadby, Gemma | Cheng, Yu-Ching | Chiang, Charleston W. K. | Delgado, Graciela | Demirkan, Ayse | Dueker, Nicole | Eklund, Niina | Eiriksdottir, Gudny | Eriksson, Joel | Feenstra, Bjarke | Fischer, Krista | Frau, Francesca | Galesloot, Tessel E. | Geller, Frank | Goel, Anuj | Gorski, Mathias | Grammer, Tanja B. | Gustafsson, Stefan | Haitjema, Saskia | Hottenga, Jouke-Jan | Huffman, Jennifer E. | Jackson, Anne U. | Jacobs, Kevin B. | Johansson, Åsa | Kaakinen, Marika | Kleber, Marcus E. | Lahti, Jari | Mateo Leach, Irene | Lehne, Benjamin | Liu, Youfang | Lo, Ken Sin | Lorentzon, Mattias | Luan, Jian'an | Madden, Pamela A. F. | Mangino, Massimo | McKnight, Barbara | Medina-Gomez, Carolina | Monda, Keri L. | Montasser, May E. | Müller, Gabriele | Müller-Nurasyid, Martina | Nolte, Ilja M. | Panoutsopoulou, Kalliope | Pascoe, Laura | Paternoster, Lavinia | Rayner, Nigel W. | Renström, Frida | Rizzi, Federica | Rose, Lynda M. | Ryan, Kathy A. | Salo, Perttu | Sanna, Serena | Scharnagl, Hubert | Shi, Jianxin | Smith, Albert Vernon | Southam, Lorraine | Stančáková, Alena | Steinthorsdottir, Valgerdur | Strawbridge, Rona J. | Sung, Yun Ju | Tachmazidou, Ioanna | Tanaka, Toshiko | Thorleifsson, Gudmar | Trompet, Stella | Pervjakova, Natalia | Tyrer, Jonathan P. | Vandenput, Liesbeth | van der Laan, Sander W | van der Velde, Nathalie | van Setten, Jessica | van Vliet-Ostaptchouk, Jana V. | Verweij, Niek | Vlachopoulou, Efthymia | Waite, Lindsay L. | Wang, Sophie R. | Wang, Zhaoming | Wild, Sarah H. | Willenborg, Christina | Wilson, James F. | Wong, Andrew | Yang, Jian | Yengo, Loïc | Yerges-Armstrong, Laura M. | Yu, Lei | Zhang, Weihua | Zhao, Jing Hua | Andersson, Ehm A. | Bakker, Stephan J. L. | Baldassarre, Damiano | Banasik, Karina | Barcella, Matteo | Barlassina, Cristina | Bellis, Claire | Benaglio, Paola | Blangero, John | Blüher, Matthias | Bonnet, Fabrice | Bonnycastle, Lori L. | Boyd, Heather A. | Bruinenberg, Marcel | Buchman, Aron S | Campbell, Harry | Chen, Yii-Der Ida | Chines, Peter S. | Claudi-Boehm, Simone | Cole, John | Collins, Francis S. | de Geus, Eco J. C. | de Groot, Lisette C. P. G. M. | Dimitriou, Maria | Duan, Jubao | Enroth, Stefan | Eury, Elodie | Farmaki, Aliki-Eleni | Forouhi, Nita G. | Friedrich, Nele | Gejman, Pablo V. | Gigante, Bruna | Glorioso, Nicola | Go, Alan S. | Gottesman, Omri | Gräßler, Jürgen | Grallert, Harald | Grarup, Niels | Gu, Yu-Mei | Broer, Linda | Ham, Annelies C. | Hansen, Torben | Harris, Tamara B. | Hartman, Catharina A. | Hassinen, Maija | Hastie, Nicholas | Hattersley, Andrew T. | Heath, Andrew C. | Henders, Anjali K. | Hernandez, Dena | Hillege, Hans | Holmen, Oddgeir | Hovingh, Kees G | Hui, Jennie | Husemoen, Lise L. | Hutri-Kähönen, Nina | Hysi, Pirro G. | Illig, Thomas | De Jager, Philip L. | Jalilzadeh, Shapour | Jørgensen, Torben | Jukema, J. Wouter | Juonala, Markus | Kanoni, Stavroula | Karaleftheri, Maria | Khaw, Kay Tee | Kinnunen, Leena | Kittner, Steven J. | Koenig, Wolfgang | Kolcic, Ivana | Kovacs, Peter | Krarup, Nikolaj T. | Kratzer, Wolfgang | Krüger, Janine | Kuh, Diana | Kumari, Meena | Kyriakou, Theodosios | Langenberg, Claudia | Lannfelt, Lars | Lanzani, Chiara | Lotay, Vaneet | Launer, Lenore J. | Leander, Karin | Lindström, Jaana | Linneberg, Allan | Liu, Yan-Ping | Lobbens, Stéphane | Luben, Robert | Lyssenko, Valeriya | Männistö, Satu | Magnusson, Patrik K. | McArdle, Wendy L. | Menni, Cristina | Merger, Sigrun | Milani, Lili | Montgomery, Grant W. | Morris, Andrew P. | Narisu, Narisu | Nelis, Mari | Ong, Ken K. | Palotie, Aarno | Pérusse, Louis | Pichler, Irene | Pilia, Maria G. | Pouta, Anneli | Rheinberger, Myriam | Ribel-Madsen, Rasmus | Richards, Marcus | Rice, Kenneth M. | Rice, Treva K. | Rivolta, Carlo | Salomaa, Veikko | Sanders, Alan R. | Sarzynski, Mark A. | Scholtens, Salome | Scott, Robert A. | Scott, William R. | Sebert, Sylvain | Sengupta, Sebanti | Sennblad, Bengt | Seufferlein, Thomas | Silveira, Angela | Slagboom, P. Eline | Smit, Jan H. | Sparsø, Thomas H. | Stirrups, Kathleen | Stolk, Ronald P. | Stringham, Heather M. | Swertz, Morris A | Swift, Amy J. | Syvänen, Ann-Christine | Tan, Sian-Tsung | Thorand, Barbara | Tönjes, Anke | Tremblay, Angelo | Tsafantakis, Emmanouil | van der Most, Peter J. | Völker, Uwe | Vohl, Marie-Claude | Vonk, Judith M. | Waldenberger, Melanie | Walker, Ryan W. | Wennauer, Roman | Widén, Elisabeth | Willemsen, Gonneke | Wilsgaard, Tom | Wright, Alan F. | Zillikens, M. Carola | van Dijk, Suzanne C. | van Schoor, Natasja M. | Asselbergs, Folkert W. | de Bakker, Paul I. W. | Beckmann, Jacques S. | Beilby, John | Bennett, David A. | Bergman, Richard N. | Bergmann, Sven | Böger, Carsten A. | Boehm, Bernhard O. | Boerwinkle, Eric | Boomsma, Dorret I. | Bornstein, Stefan R. | Bottinger, Erwin P. | Bouchard, Claude | Chambers, John C. | Chanock, Stephen J. | Chasman, Daniel I. | Cucca, Francesco | Cusi, Daniele | Dedoussis, George | Erdmann, Jeanette | Eriksson, Johan G. | Evans, Denis A. | de Faire, Ulf | Farrall, Martin | Ferrucci, Luigi | Ford, Ian | Franke, Lude | Franks, Paul W. | Froguel, Philippe | Gansevoort, Ron T. | Gieger, Christian | Grönberg, Henrik | Gudnason, Vilmundur | Gyllensten, Ulf | Hall, Per | Hamsten, Anders | van der Harst, Pim | Hayward, Caroline | Heliövaara, Markku | Hengstenberg, Christian | Hicks, Andrew A | Hingorani, Aroon | Hofman, Albert | Hu, Frank | Huikuri, Heikki V. | Hveem, Kristian | James, Alan L. | Jordan, Joanne M. | Jula, Antti | Kähönen, Mika | Kajantie, Eero | Kathiresan, Sekar | Kiemeney, Lambertus A. L. M. | Kivimaki, Mika | Knekt, Paul B. | Koistinen, Heikki A. | Kooner, Jaspal S. | Koskinen, Seppo | Kuusisto, Johanna | Maerz, Winfried | Martin, Nicholas G | Laakso, Markku | Lakka, Timo A. | Lehtimäki, Terho | Lettre, Guillaume | Levinson, Douglas F. | Lind, Lars | Lokki, Marja-Liisa | Mäntyselkä, Pekka | Melbye, Mads | Metspalu, Andres | Mitchell, Braxton D. | Moll, Frans L. | Murray, Jeffrey C. | Musk, Arthur W. | Nieminen, Markku S. | Njølstad, Inger | Ohlsson, Claes | Oldehinkel, Albertine J. | Oostra, Ben A. | Palmer, Lyle J | Pankow, James S. | Pasterkamp, Gerard | Pedersen, Nancy L. | Pedersen, Oluf | Penninx, Brenda W. | Perola, Markus | Peters, Annette | Polašek, Ozren | Pramstaller, Peter P. | Psaty, Bruce M. | Qi, Lu | Quertermous, Thomas | Raitakari, Olli T. | Rankinen, Tuomo | Rauramaa, Rainer | Ridker, Paul M. | Rioux, John D. | Rivadeneira, Fernando | Rotter, Jerome I. | Rudan, Igor | den Ruijter, Hester M. | Saltevo, Juha | Sattar, Naveed | Schunkert, Heribert | Schwarz, Peter E. H. | Shuldiner, Alan R. | Sinisalo, Juha | Snieder, Harold | Sørensen, Thorkild I. A. | Spector, Tim D. | Staessen, Jan A. | Stefania, Bandinelli | Thorsteinsdottir, Unnur | Stumvoll, Michael | Tardif, Jean-Claude | Tremoli, Elena | Tuomilehto, Jaakko | Uitterlinden, André G. | Uusitupa, Matti | Verbeek, André L. M. | Vermeulen, Sita H. | Viikari, Jorma S. | Vitart, Veronique | Völzke, Henry | Vollenweider, Peter | Waeber, Gérard | Walker, Mark | Wallaschofski, Henri | Wareham, Nicholas J. | Watkins, Hugh | Zeggini, Eleftheria | Chakravarti, Aravinda | Clegg, Deborah J. | Cupples, L. Adrienne | Gordon-Larsen, Penny | Jaquish, Cashell E. | Rao, D. C. | Abecasis, Goncalo R. | Assimes, Themistocles L. | Barroso, Inês | Berndt, Sonja I. | Boehnke, Michael | Deloukas, Panos | Fox, Caroline S. | Groop, Leif C. | Hunter, David J. | Ingelsson, Erik | Kaplan, Robert C. | McCarthy, Mark I. | Mohlke, Karen L. | O'Connell, Jeffrey R. | Schlessinger, David | Strachan, David P. | Stefansson, Kari | van Duijn, Cornelia M. | Hirschhorn, Joel N. | Lindgren, Cecilia M. | Heid, Iris M. | North, Kari E. | Borecki, Ingrid B. | Kutalik, Zoltán | Loos, Ruth J. F.
PLoS Genetics  2016;12(6):e1006166.
doi:10.1371/journal.pgen.1006166
PMCID: PMC4927064  PMID: 27355579
9.  Relationship of Thoracic Adipose Tissue Depots with Coronary Atherosclerosis and Circulating Inflammatory Biomarkers 
Obesity (Silver Spring, Md.)  2015;23(6):1178-1184.
Objective
Our aim was to determine the relationship of various thoracic fat depots to the presence and extent of coronary artery plaque and circulating biomarkers.
Methods
In 342 patients (52±11 years, 61% male, BMI 29.1±5.9 kg/m2) with coronary CT angiography, we measured the fat volume in four thoracic depots (pericoronary, epicardial, periaortic, extracardiac), assessed coronary plaque and determined the circulating level of C-reactive protein, tumor necrosis factor alpha, plasminogen activator inhibitor-1, monocyte chemoattractant-1, and adiponectin. Extent of coronary plaque was classified into 3 groups: 0, 1–3 and >3 segments.
Results
Patients with plaque (n=169, 49%) had higher volumes of all 4 fat depots as compared to patients without plaque (all p<0.01), despite similar BMI (p=0.18). Extracardiac fat was most strongly correlated with BMI (r=0.45, p<0.001), while pericoronary fat was least (r=0.21, p<0.001). Only pericoronary fat remained associated with coronary plaque in adjusted analyses. Inflammatory biomarkers showed a positive correlation with pericoronary fat (all p<0.0001), whereas adiponectin was not associated to this fat compartment (p=0.60) and showed a negative correlation with all other fat depots (all p<0.001).
Conclusion
Pericoronary fat is independently associated with CAD. Its correlation with inflammatory biomarkers suggests that while systemic inflammation plays a role in the pathogenesis of CAD, there are additional local effects that may exist.
doi:10.1002/oby.21080
PMCID: PMC4446160  PMID: 25960369
pericoronary fat; coronary atherosclerosis; cardiac computed tomography
10.  Lipoprotein‐Associated Phospholipase A2 Activity Is a Marker of Risk But Not a Useful Target for Treatment in Patients With Stable Coronary Heart Disease 
Background
We evaluated lipoprotein‐associated phospholipase A2 (Lp‐PLA 2) activity in patients with stable coronary heart disease before and during treatment with darapladib, a selective Lp‐PLA 2 inhibitor, in relation to outcomes and the effects of darapladib in the STABILITY trial.
Methods and Results
Plasma Lp‐PLA 2 activity was determined at baseline (n=14 500); at 1 month (n=13 709); serially (n=100) at 3, 6, and 18 months; and at the end of treatment. Adjusted Cox regression models evaluated associations between Lp‐PLA 2 activity levels and outcomes. At baseline, the median Lp‐PLA 2 level was 172.4 μmol/min per liter (interquartile range 143.1–204.2 μmol/min per liter). Comparing the highest and lowest Lp‐PLA 2 quartile groups, the hazard ratios were 1.50 (95% CI 1.23–1.82) for the primary composite end point (cardiovascular death, myocardial infarction, or stroke), 1.95 (95% CI 1.29–2.93) for hospitalization for heart failure, 1.42 (1.07–1.89) for cardiovascular death, and 1.37 (1.03–1.81) for myocardial infarction after adjustment for baseline characteristics, standard laboratory variables, and other prognostic biomarkers. Treatment with darapladib led to a ≈65% persistent reduction in median Lp‐PLA 2 activity. There were no associations between on‐treatment Lp‐PLA 2 activity or changes of Lp‐PLA 2 activity and outcomes, and there were no significant interactions between baseline and on‐treatment Lp‐PLA 2 activity or changes in Lp‐PLA 2 activity levels and the effects of darapladib on outcomes.
Conclusions
Although high Lp‐PLA 2 activity was associated with increased risk of cardiovascular events, pharmacological lowering of Lp‐PLA 2 activity by ≈65% did not significantly reduce cardiovascular events in patients with stable coronary heart disease, regardless of the baseline level or the magnitude of change of Lp‐PLA 2 activity.
Clinical Trial Registration
URL: https://www.clinicaltrials.gov. Unique identifier: NCT00799903.
doi:10.1161/JAHA.116.003407
PMCID: PMC4937279  PMID: 27329448
atherosclerosis; coronary disease; inflammation; lipoprotein; myocardial infarction; Biomarkers; Coronary Artery Disease; Pharmacology; Treatment; Risk Factors
11.  Troponin I and cardiovascular risk prediction in the general population: the BiomarCaRE consortium 
European Heart Journal  2016;37(30):2428-2437.
Aims
Our aims were to evaluate the distribution of troponin I concentrations in population cohorts across Europe, to characterize the association with cardiovascular outcomes, to determine the predictive value beyond the variables used in the ESC SCORE, to test a potentially clinically relevant cut-off value, and to evaluate the improved eligibility for statin therapy based on elevated troponin I concentrations retrospectively.
Methods and results
Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project, we analysed individual level data from 10 prospective population-based studies including 74 738 participants. We investigated the value of adding troponin I levels to conventional risk factors for prediction of cardiovascular disease by calculating measures of discrimination (C-index) and net reclassification improvement (NRI). We further tested the clinical implication of statin therapy based on troponin concentration in 12 956 individuals free of cardiovascular disease in the JUPITER study. Troponin I remained an independent predictor with a hazard ratio of 1.37 for cardiovascular mortality, 1.23 for cardiovascular disease, and 1.24 for total mortality. The addition of troponin I information to a prognostic model for cardiovascular death constructed of ESC SCORE variables increased the C-index discrimination measure by 0.007 and yielded an NRI of 0.048, whereas the addition to prognostic models for cardiovascular disease and total mortality led to lesser C-index discrimination and NRI increment. In individuals above 6 ng/L of troponin I, a concentration near the upper quintile in BiomarCaRE (5.9 ng/L) and JUPITER (5.8 ng/L), rosuvastatin therapy resulted in higher absolute risk reduction compared with individuals <6 ng/L of troponin I, whereas the relative risk reduction was similar.
Conclusion
In individuals free of cardiovascular disease, the addition of troponin I to variables of established risk score improves prediction of cardiovascular death and cardiovascular disease.
doi:10.1093/eurheartj/ehw172
PMCID: PMC4982535  PMID: 27174290
High-sensitivity assayed troponin I; Cardiovascular risk; Mortality; Biomarker for Cardiovascular Risk Assessment in Europe; MONICA Risk Genetics Archiving and Monograph
12.  Age- and Sex-Specific Causal Effects of Adiposity on Cardiovascular Risk Factors 
Fall, Tove | Hägg, Sara | Ploner, Alexander | Mägi, Reedik | Fischer, Krista | Draisma, Harmen H.M. | Sarin, Antti-Pekka | Benyamin, Beben | Ladenvall, Claes | Åkerlund, Mikael | Kals, Mart | Esko, Tõnu | Nelson, Christopher P. | Kaakinen, Marika | Huikari, Ville | Mangino, Massimo | Meirhaeghe, Aline | Kristiansson, Kati | Nuotio, Marja-Liisa | Kobl, Michael | Grallert, Harald | Dehghan, Abbas | Kuningas, Maris | de Vries, Paul S. | de Bruijn, Renée F.A.G. | Willems, Sara M. | Heikkilä, Kauko | Silventoinen, Karri | Pietiläinen, Kirsi H. | Legry, Vanessa | Giedraitis, Vilmantas | Goumidi, Louisa | Syvänen, Ann-Christine | Strauch, Konstantin | Koenig, Wolfgang | Lichtner, Peter | Herder, Christian | Palotie, Aarno | Menni, Cristina | Uitterlinden, André G. | Kuulasmaa, Kari | Havulinna, Aki S. | Moreno, Luis A. | Gonzalez-Gross, Marcela | Evans, Alun | Tregouet, David-Alexandre | Yarnell, John W.G. | Virtamo, Jarmo | Ferrières, Jean | Veronesi, Giovanni | Perola, Markus | Arveiler, Dominique | Brambilla, Paolo | Lind, Lars | Kaprio, Jaakko | Hofman, Albert | Stricker, Bruno H. | van Duijn, Cornelia M. | Ikram, M. Arfan | Franco, Oscar H. | Cottel, Dominique | Dallongeville, Jean | Hall, Alistair S. | Jula, Antti | Tobin, Martin D. | Penninx, Brenda W. | Peters, Annette | Gieger, Christian | Samani, Nilesh J. | Montgomery, Grant W. | Whitfield, John B. | Martin, Nicholas G. | Groop, Leif | Spector, Tim D. | Magnusson, Patrik K. | Amouyel, Philippe | Boomsma, Dorret I. | Nilsson, Peter M. | Järvelin, Marjo-Riitta | Lyssenko, Valeriya | Metspalu, Andres | Strachan, David P. | Salomaa, Veikko | Ripatti, Samuli | Pedersen, Nancy L. | Prokopenko, Inga | McCarthy, Mark I. | Ingelsson, Erik
Diabetes  2015;64(5):1841-1852.
Observational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese individuals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 individuals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both nonstratified analysis (P = 2.8 × 10−107) and stratified analyses (all P < 3.3 × 10−30). We found evidence of a causal effect of adiposity on blood pressure, fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the <55-year stratum. Further, we found evidence of a smaller causal effect on total cholesterol (P for difference = 0.015) in the ≥55-year stratum than in the <55-year stratum, a finding that could be explained by biology, survival bias, or differential medication. In conclusion, this study extends previous knowledge of the effects of adiposity by providing sex- and age-specific causal estimates on cardiovascular risk factors.
doi:10.2337/db14-0988
PMCID: PMC4407863  PMID: 25712996
13.  Objectively Measured Walking Duration and Sedentary Behaviour and Four-Year Mortality in Older People 
PLoS ONE  2016;11(4):e0153779.
Background
Physical activity is an important component of health. Recommendations based on sensor measurements are sparse in older people. The aim of this study was to analyse the effect of objectively measured walking and sedentary duration on four-year mortality in community-dwelling older people.
Methods
Between March 2009 and April 2010, physical activity of 1271 participants (≥65 years, 56.4% men) from Southern Germany was measured over one week using a thigh-worn uni-axial accelerometer (activPAL; PAL Technologies, Glasgow, Scotland). Mortality was assessed during a four-year follow-up. Cox-proportional-hazards models were used to estimate the associations between walking (including low to high intensity) and sedentary duration with mortality. Models were adjusted for age and sex, additional epidemiological variables, and selected biomarkers.
Results
An inverse relationship between walking duration and mortality with a minimum risk for the 3rd quartile (102.2 to128.4 minutes walking daily) was found even after multivariate adjustment with HRs for quartiles 2 to 4 compared to quartile 1 of 0.45 (95%-CI: 0.26; 0.76), 0.18 (95%-CI: 0.08; 0.41), 0.39 (95%-CI: 0.19; 0.78), respectively. For sedentary duration an age- and sex-adjusted increased mortality risk was observed for the 4th quartile (daily sedentary duration ≥1137.2 min.) (HR 2.05, 95%-CI: 1.13; 3.73), which diminished, however, after full adjustment (HR 1.63, 95%-CI: 0.88; 3.02). Furthermore, our results suggest effect modification between walking and sedentary duration, such that in people with low walking duration a high sedentary duration was noted as an independent factor for increased mortality.
Conclusions
In summary, walking duration was clearly associated with four-year overall mortality in community-dwelling older people.
doi:10.1371/journal.pone.0153779
PMCID: PMC4833405  PMID: 27082963
14.  Delivery Mode, Duration of Labor, and Cord Blood Adiponectin, Leptin, and C-Reactive Protein: Results of the Population-Based Ulm Birth Cohort Studies 
PLoS ONE  2016;11(2):e0149918.
Background
Numerous studies have reported associations between delivery mode and health outcomes in infancy and later life. Previous smaller studies indicated a relationship between delivery mode and newborn inflammation potentially constituting a mediating factor. We aimed to determine the influence of delivery mode and duration of labor on cord blood concentrations of adiponectin, leptin, and high-sensitivity C-reactive protein (hs-CRP).
Methods
In the Ulm SPATZ Health Study, 934 singleton newborns and their mothers were recruited during their hospital stay in the University Medical Center Ulm, Southern Germany, from 04/2012-05/2013. Inflammatory biomarkers were measured by ELISAs (n = 836). Delivery mode was analyzed categorically (elective cesarean (reference), active labor delivery: emergency cesarean, assisted vaginal, and spontaneous vaginal); duration of labor continuously. Following log-transformation, linear regression was used to estimate geometric means ratios (GMR) adjusted for potential confounders for the effects of delivery mode and duration of labor on each biomarker separately. Independent replication was sought in the similarly conducted Ulm Birth Cohort Study recruited from 11/2000-11/2001.
Results
Individually, active labor delivery modes as well as increasing duration of labor were associated with higher leptin and hs-CRP concentrations. After mutual adjustment, the associations with delivery modes were attenuated but those for duration of labor remained statistically significant (GMR (95%CI) 1.10 (1.00; 1.21) and 1.15 (1.04; 1.27) for leptin and hs-CRP per hour of labor, respectively). No significant adjusted associations were observed between delivery modes and adiponectin concentrations. These findings were replicated in an independent birth cohort study.
Conclusions
Cord blood leptin and hs-CRP concentrations were associated with duration of labor rather than delivery mode. Further research is warranted to investigate these associations with additional cytokines involved in inflammatory response to delineate the inflammatory profile. Subsequently, research on determinants of these associations and their role in development of chronic disease is needed.
doi:10.1371/journal.pone.0149918
PMCID: PMC4763096  PMID: 26900695
15.  Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels 
Kilpeläinen, Tuomas O. | Carli, Jayne F. Martin | Skowronski, Alicja A. | Sun, Qi | Kriebel, Jennifer | Feitosa, Mary F | Hedman, Åsa K. | Drong, Alexander W. | Hayes, James E. | Zhao, Jinghua | Pers, Tune H. | Schick, Ursula | Grarup, Niels | Kutalik, Zoltán | Trompet, Stella | Mangino, Massimo | Kristiansson, Kati | Beekman, Marian | Lyytikäinen, Leo-Pekka | Eriksson, Joel | Henneman, Peter | Lahti, Jari | Tanaka, Toshiko | Luan, Jian'an | Greco M, Fabiola Del | Pasko, Dorota | Renström, Frida | Willems, Sara M. | Mahajan, Anubha | Rose, Lynda M. | Guo, Xiuqing | Liu, Yongmei | Kleber, Marcus E. | Pérusse, Louis | Gaunt, Tom | Ahluwalia, Tarunveer S. | Ju Sung, Yun | Ramos, Yolande F. | Amin, Najaf | Amuzu, Antoinette | Barroso, Inês | Bellis, Claire | Blangero, John | Buckley, Brendan M. | Böhringer, Stefan | I Chen, Yii-Der | de Craen, Anton J. N. | Crosslin, David R. | Dale, Caroline E. | Dastani, Zari | Day, Felix R. | Deelen, Joris | Delgado, Graciela E. | Demirkan, Ayse | Finucane, Francis M. | Ford, Ian | Garcia, Melissa E. | Gieger, Christian | Gustafsson, Stefan | Hallmans, Göran | Hankinson, Susan E. | Havulinna, Aki S | Herder, Christian | Hernandez, Dena | Hicks, Andrew A. | Hunter, David J. | Illig, Thomas | Ingelsson, Erik | Ioan-Facsinay, Andreea | Jansson, John-Olov | Jenny, Nancy S. | Jørgensen, Marit E. | Jørgensen, Torben | Karlsson, Magnus | Koenig, Wolfgang | Kraft, Peter | Kwekkeboom, Joanneke | Laatikainen, Tiina | Ladwig, Karl-Heinz | LeDuc, Charles A. | Lowe, Gordon | Lu, Yingchang | Marques-Vidal, Pedro | Meisinger, Christa | Menni, Cristina | Morris, Andrew P. | Myers, Richard H. | Männistö, Satu | Nalls, Mike A. | Paternoster, Lavinia | Peters, Annette | Pradhan, Aruna D. | Rankinen, Tuomo | Rasmussen-Torvik, Laura J. | Rathmann, Wolfgang | Rice, Treva K. | Brent Richards, J | Ridker, Paul M. | Sattar, Naveed | Savage, David B. | Söderberg, Stefan | Timpson, Nicholas J. | Vandenput, Liesbeth | van Heemst, Diana | Uh, Hae-Won | Vohl, Marie-Claude | Walker, Mark | Wichmann, Heinz-Erich | Widén, Elisabeth | Wood, Andrew R. | Yao, Jie | Zeller, Tanja | Zhang, Yiying | Meulenbelt, Ingrid | Kloppenburg, Margreet | Astrup, Arne | Sørensen, Thorkild I. A. | Sarzynski, Mark A. | Rao, D. C. | Jousilahti, Pekka | Vartiainen, Erkki | Hofman, Albert | Rivadeneira, Fernando | Uitterlinden, André G. | Kajantie, Eero | Osmond, Clive | Palotie, Aarno | Eriksson, Johan G. | Heliövaara, Markku | Knekt, Paul B. | Koskinen, Seppo | Jula, Antti | Perola, Markus | Huupponen, Risto K. | Viikari, Jorma S. | Kähönen, Mika | Lehtimäki, Terho | Raitakari, Olli T. | Mellström, Dan | Lorentzon, Mattias | Casas, Juan P. | Bandinelli, Stefanie | März, Winfried | Isaacs, Aaron | van Dijk, Ko W. | van Duijn, Cornelia M. | Harris, Tamara B. | Bouchard, Claude | Allison, Matthew A. | Chasman, Daniel I. | Ohlsson, Claes | Lind, Lars | Scott, Robert A. | Langenberg, Claudia | Wareham, Nicholas J. | Ferrucci, Luigi | Frayling, Timothy M. | Pramstaller, Peter P. | Borecki, Ingrid B. | Waterworth, Dawn M. | Bergmann, Sven | Waeber, Gérard | Vollenweider, Peter | Vestergaard, Henrik | Hansen, Torben | Pedersen, Oluf | Hu, Frank B. | Eline Slagboom, P | Grallert, Harald | Spector, Tim D. | Jukema, J.W. | Klein, Robert J. | Schadt, Erik E | Franks, Paul W. | Lindgren, Cecilia M. | Leibel, Rudolph L. | Loos, Ruth J. F.
Nature Communications  2016;7:10494.
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.
This meta-analysis of genome-wide association studies identifies four genetic loci associated with circulating leptin levels independent of adiposity. Examination in mouse adipose tissue explants provides functional support for the leptin-associated loci.
doi:10.1038/ncomms10494
PMCID: PMC4740377  PMID: 26833098
16.  Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function 
Pattaro, Cristian | Teumer, Alexander | Gorski, Mathias | Chu, Audrey Y. | Li, Man | Mijatovic, Vladan | Garnaas, Maija | Tin, Adrienne | Sorice, Rossella | Li, Yong | Taliun, Daniel | Olden, Matthias | Foster, Meredith | Yang, Qiong | Chen, Ming-Huei | Pers, Tune H. | Johnson, Andrew D. | Ko, Yi-An | Fuchsberger, Christian | Tayo, Bamidele | Nalls, Michael | Feitosa, Mary F. | Isaacs, Aaron | Dehghan, Abbas | d'Adamo, Pio | Adeyemo, Adebowale | Dieffenbach, Aida Karina | Zonderman, Alan B. | Nolte, Ilja M. | van der Most, Peter J. | Wright, Alan F. | Shuldiner, Alan R. | Morrison, Alanna C. | Hofman, Albert | Smith, Albert V. | Dreisbach, Albert W. | Franke, Andre | Uitterlinden, Andre G. | Metspalu, Andres | Tonjes, Anke | Lupo, Antonio | Robino, Antonietta | Johansson, Åsa | Demirkan, Ayse | Kollerits, Barbara | Freedman, Barry I. | Ponte, Belen | Oostra, Ben A. | Paulweber, Bernhard | Krämer, Bernhard K. | Mitchell, Braxton D. | Buckley, Brendan M. | Peralta, Carmen A. | Hayward, Caroline | Helmer, Catherine | Rotimi, Charles N. | Shaffer, Christian M. | Müller, Christian | Sala, Cinzia | van Duijn, Cornelia M. | Saint-Pierre, Aude | Ackermann, Daniel | Shriner, Daniel | Ruggiero, Daniela | Toniolo, Daniela | Lu, Yingchang | Cusi, Daniele | Czamara, Darina | Ellinghaus, David | Siscovick, David S. | Ruderfer, Douglas | Gieger, Christian | Grallert, Harald | Rochtchina, Elena | Atkinson, Elizabeth J. | Holliday, Elizabeth G. | Boerwinkle, Eric | Salvi, Erika | Bottinger, Erwin P. | Murgia, Federico | Rivadeneira, Fernando | Ernst, Florian | Kronenberg, Florian | Hu, Frank B. | Navis, Gerjan J. | Curhan, Gary C. | Ehret, George B. | Homuth, Georg | Coassin, Stefan | Thun, Gian-Andri | Pistis, Giorgio | Gambaro, Giovanni | Malerba, Giovanni | Montgomery, Grant W. | Eiriksdottir, Gudny | Jacobs, Gunnar | Li, Guo | Wichmann, H-Erich | Campbell, Harry | Schmidt, Helena | Wallaschofski, Henri | Völzke, Henry | Brenner, Hermann | Kroemer, Heyo K. | Kramer, Holly | Lin, Honghuang | Leach, I. Mateo | Ford, Ian | Guessous, Idris | Rudan, Igor | Prokopenko, Inga | Borecki, Ingrid | Heid, Iris M. | Kolcic, Ivana | Persico, Ivana | Jukema, J. Wouter | Wilson, James F. | Felix, Janine F. | Divers, Jasmin | Lambert, Jean-Charles | Stafford, Jeanette M. | Gaspoz, Jean-Michel | Smith, Jennifer A. | Faul, Jessica D. | Wang, Jie Jin | Ding, Jingzhong | Hirschhorn, Joel N. | Attia, John | Whitfield, John B. | Chalmers, John | Viikari, Jorma | Coresh, Josef | Denny, Joshua C. | Karjalainen, Juha | Fernandes, Jyotika K. | Endlich, Karlhans | Butterbach, Katja | Keene, Keith L. | Lohman, Kurt | Portas, Laura | Launer, Lenore J. | Lyytikäinen, Leo-Pekka | Yengo, Loic | Franke, Lude | Ferrucci, Luigi | Rose, Lynda M. | Kedenko, Lyudmyla | Rao, Madhumathi | Struchalin, Maksim | Kleber, Marcus E. | Cavalieri, Margherita | Haun, Margot | Cornelis, Marilyn C. | Ciullo, Marina | Pirastu, Mario | de Andrade, Mariza | McEvoy, Mark A. | Woodward, Mark | Adam, Martin | Cocca, Massimiliano | Nauck, Matthias | Imboden, Medea | Waldenberger, Melanie | Pruijm, Menno | Metzger, Marie | Stumvoll, Michael | Evans, Michele K. | Sale, Michele M. | Kähönen, Mika | Boban, Mladen | Bochud, Murielle | Rheinberger, Myriam | Verweij, Niek | Bouatia-Naji, Nabila | Martin, Nicholas G. | Hastie, Nick | Probst-Hensch, Nicole | Soranzo, Nicole | Devuyst, Olivier | Raitakari, Olli | Gottesman, Omri | Franco, Oscar H. | Polasek, Ozren | Gasparini, Paolo | Munroe, Patricia B. | Ridker, Paul M. | Mitchell, Paul | Muntner, Paul | Meisinger, Christa | Smit, Johannes H. | Kovacs, Peter | Wild, Philipp S. | Froguel, Philippe | Rettig, Rainer | Mägi, Reedik | Biffar, Reiner | Schmidt, Reinhold | Middelberg, Rita P. S. | Carroll, Robert J. | Penninx, Brenda W. | Scott, Rodney J. | Katz, Ronit | Sedaghat, Sanaz | Wild, Sarah H. | Kardia, Sharon L. R. | Ulivi, Sheila | Hwang, Shih-Jen | Enroth, Stefan | Kloiber, Stefan | Trompet, Stella | Stengel, Benedicte | Hancock, Stephen J. | Turner, Stephen T. | Rosas, Sylvia E. | Stracke, Sylvia | Harris, Tamara B. | Zeller, Tanja | Zemunik, Tatijana | Lehtimäki, Terho | Illig, Thomas | Aspelund, Thor | Nikopensius, Tiit | Esko, Tonu | Tanaka, Toshiko | Gyllensten, Ulf | Völker, Uwe | Emilsson, Valur | Vitart, Veronique | Aalto, Ville | Gudnason, Vilmundur | Chouraki, Vincent | Chen, Wei-Min | Igl, Wilmar | März, Winfried | Koenig, Wolfgang | Lieb, Wolfgang | Loos, Ruth J. F. | Liu, Yongmei | Snieder, Harold | Pramstaller, Peter P. | Parsa, Afshin | O'Connell, Jeffrey R. | Susztak, Katalin | Hamet, Pavel | Tremblay, Johanne | de Boer, Ian H. | Böger, Carsten A. | Goessling, Wolfram | Chasman, Daniel I. | Köttgen, Anna | Kao, W. H. Linda | Fox, Caroline S.
Nature Communications  2016;7:10023.
Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.
doi:10.1038/ncomms10023
PMCID: PMC4735748  PMID: 26831199
17.  Genetic Determinants of Circulating Interleukin-1 Receptor Antagonist Levels and Their Association With Glycemic Traits 
Diabetes  2014;63(12):4343-4359.
The proinflammatory cytokine interleukin (IL)-1β is implicated in the development of insulin resistance and β-cell dysfunction, whereas higher circulating levels of IL-1 receptor antagonist (IL-1RA), an endogenous inhibitor of IL-1β, has been suggested to improve glycemia and β-cell function in patients with type 2 diabetes. To elucidate the protective role of IL-1RA, this study aimed to identify genetic determinants of circulating IL-1RA concentration and to investigate their associations with immunological and metabolic variables related to cardiometabolic risk. In the analysis of seven discovery and four replication cohort studies, two single nucleotide polymorphisms (SNPs) were independently associated with circulating IL-1RA concentration (rs4251961 at the IL1RN locus [n = 13,955, P = 2.76 × 10−21] and rs6759676, closest gene locus IL1F10 [n = 13,994, P = 1.73 × 10−17]). The proportion of the variance in IL-1RA explained by both SNPs combined was 2.0%. IL-1RA–raising alleles of both SNPs were associated with lower circulating C-reactive protein concentration. The IL-1RA–raising allele of rs6759676 was also associated with lower fasting insulin levels and lower HOMA insulin resistance. In conclusion, we show that circulating IL-1RA levels are predicted by two independent SNPs at the IL1RN and IL1F10 loci and that genetically raised IL-1RA may be protective against the development of insulin resistance.
doi:10.2337/db14-0731
PMCID: PMC4237993  PMID: 24969107
18.  Coffee consumption and NAFLD: a community based study on 1223 subjects 
BMC Research Notes  2015;8:640.
Background
Objective of the present cross-sectional study was to investigate the impact of caffeine consumption on fatty liver and serum alanine aminotransferase (ALT) concentrations in a random population sample.
Methods
All subjects (n = 1452; 789 women, 663 men; average age 42.3 ± 12.8 years) underwent ultrasonographic examination of the liver and completed a standardized questionnaire regarding personal and lifestyle data, in particular relating to coffee consumption and past medical history. In addition, anthropometric data were documented and laboratory examinations performed. Statistical interpretation of the data was performed descriptively and by means of bivariate and multivariate analysis.
Results
Data of the present study demonstrated a significant association between hepatic steatosis male gender (p < 0.0001), advanced age (p < 0.0001) and elevated body-mass index (BMI; p < 0.0001). No association between caffeine consumption and fatty liver was identified. An association between caffeine consumption and elevated serum ALT concentrations was not identified.
Conclusions
The findings of the present study provide no evidence for an association between caffeine consumption and either the prevalence of hepatic steatosis or serum ALT concentrations.
doi:10.1186/s13104-015-1645-3
PMCID: PMC4632464  PMID: 26530296
Caffeine; Hepatic steatosis; Fatty liver; Alanine aminotransferase; Population-based cross-sectional study
19.  Psoriasis and cardiometabolic traits: modest association but distinct genetic architectures 
Psoriasis has been linked to cardiometabolic diseases, but epidemiological findings are inconsistent. We investigated the association between psoriasis and cardiometabolic outcomes in a German cross-sectional study (n=4.185) and a prospective cohort of German Health Insurance beneficiaries (n=1.811.098). A potential genetic overlap was explored using genome-wide data from >22.000 coronary artery disease (CAD) and >4.000 psoriasis cases, and with a dense genotyping study of cardiometabolic risk loci on 927 psoriasis cases and 3.717 controls. Controlling for major confounders, in the cross-sectional analysis psoriasis was significantly associated with type 2 diabetes (T2D, adjusted odd’s ratio OR=2.36; 95% confidence interval CI=1.26–4.41) and myocardial infarction (MI, OR=2.26, 95% CI=1.03–4.96). In the longitudinal study, psoriasis slightly increased the risk for incident T2D (adjusted relative risk RR=1.11; 95%CI=1.08–1.14) and MI (RR=1.14; 95%CI=1.06–1.22), with highest risk increments in systemically treated psoriasis, which accounted for 11 and 17 excess cases of T2D and MI per 10,000 person-years. Except for weak signals from within the MHC, there was no evidence for genetic risk loci shared between psoriasis and cardiometabolic traits. Our findings suggest that psoriasis, in particular severe psoriasis, increases risk for T2D and MI, and that the genetic architecture of psoriasis and cardiometabolic traits is largely distinct.
doi:10.1038/jid.2015.8
PMCID: PMC4402117  PMID: 25599394
20.  The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study 
Winkler, Thomas W. | Justice, Anne E. | Graff, Mariaelisa | Barata, Llilda | Feitosa, Mary F. | Chu, Su | Czajkowski, Jacek | Esko, Tõnu | Fall, Tove | Kilpeläinen, Tuomas O. | Lu, Yingchang | Mägi, Reedik | Mihailov, Evelin | Pers, Tune H. | Rüeger, Sina | Teumer, Alexander | Ehret, Georg B. | Ferreira, Teresa | Heard-Costa, Nancy L. | Karjalainen, Juha | Lagou, Vasiliki | Mahajan, Anubha | Neinast, Michael D. | Prokopenko, Inga | Simino, Jeannette | Teslovich, Tanya M. | Jansen, Rick | Westra, Harm-Jan | White, Charles C. | Absher, Devin | Ahluwalia, Tarunveer S. | Ahmad, Shafqat | Albrecht, Eva | Alves, Alexessander Couto | Bragg-Gresham, Jennifer L. | de Craen, Anton J. M. | Bis, Joshua C. | Bonnefond, Amélie | Boucher, Gabrielle | Cadby, Gemma | Cheng, Yu-Ching | Chiang, Charleston W. K. | Delgado, Graciela | Demirkan, Ayse | Dueker, Nicole | Eklund, Niina | Eiriksdottir, Gudny | Eriksson, Joel | Feenstra, Bjarke | Fischer, Krista | Frau, Francesca | Galesloot, Tessel E. | Geller, Frank | Goel, Anuj | Gorski, Mathias | Grammer, Tanja B. | Gustafsson, Stefan | Haitjema, Saskia | Hottenga, Jouke-Jan | Huffman, Jennifer E. | Jackson, Anne U. | Jacobs, Kevin B. | Johansson, Åsa | Kaakinen, Marika | Kleber, Marcus E. | Lahti, Jari | Leach, Irene Mateo | Lehne, Benjamin | Liu, Youfang | Lo, Ken Sin | Lorentzon, Mattias | Luan, Jian'an | Madden, Pamela A. F. | Mangino, Massimo | McKnight, Barbara | Medina-Gomez, Carolina | Monda, Keri L. | Montasser, May E. | Müller, Gabriele | Müller-Nurasyid, Martina | Nolte, Ilja M. | Panoutsopoulou, Kalliope | Pascoe, Laura | Paternoster, Lavinia | Rayner, Nigel W. | Renström, Frida | Rizzi, Federica | Rose, Lynda M. | Ryan, Kathy A. | Salo, Perttu | Sanna, Serena | Scharnagl, Hubert | Shi, Jianxin | Smith, Albert Vernon | Southam, Lorraine | Stančáková, Alena | Steinthorsdottir, Valgerdur | Strawbridge, Rona J. | Sung, Yun Ju | Tachmazidou, Ioanna | Tanaka, Toshiko | Thorleifsson, Gudmar | Trompet, Stella | Pervjakova, Natalia | Tyrer, Jonathan P. | Vandenput, Liesbeth | van der Laan, Sander W | van der Velde, Nathalie | van Setten, Jessica | van Vliet-Ostaptchouk, Jana V. | Verweij, Niek | Vlachopoulou, Efthymia | Waite, Lindsay L. | Wang, Sophie R. | Wang, Zhaoming | Wild, Sarah H. | Willenborg, Christina | Wilson, James F. | Wong, Andrew | Yang, Jian | Yengo, Loïc | Yerges-Armstrong, Laura M. | Yu, Lei | Zhang, Weihua | Zhao, Jing Hua | Andersson, Ehm A. | Bakker, Stephan J. L. | Baldassarre, Damiano | Banasik, Karina | Barcella, Matteo | Barlassina, Cristina | Bellis, Claire | Benaglio, Paola | Blangero, John | Blüher, Matthias | Bonnet, Fabrice | Bonnycastle, Lori L. | Boyd, Heather A. | Bruinenberg, Marcel | Buchman, Aron S | Campbell, Harry | Chen, Yii-Der Ida | Chines, Peter S. | Claudi-Boehm, Simone | Cole, John | Collins, Francis S. | de Geus, Eco J. C. | de Groot, Lisette C. P. G. M. | Dimitriou, Maria | Duan, Jubao | Enroth, Stefan | Eury, Elodie | Farmaki, Aliki-Eleni | Forouhi, Nita G. | Friedrich, Nele | Gejman, Pablo V. | Gigante, Bruna | Glorioso, Nicola | Go, Alan S. | Gottesman, Omri | Gräßler, Jürgen | Grallert, Harald | Grarup, Niels | Gu, Yu-Mei | Broer, Linda | Ham, Annelies C. | Hansen, Torben | Harris, Tamara B. | Hartman, Catharina A. | Hassinen, Maija | Hastie, Nicholas | Hattersley, Andrew T. | Heath, Andrew C. | Henders, Anjali K. | Hernandez, Dena | Hillege, Hans | Holmen, Oddgeir | Hovingh, Kees G | Hui, Jennie | Husemoen, Lise L. | Hutri-Kähönen, Nina | Hysi, Pirro G. | Illig, Thomas | De Jager, Philip L. | Jalilzadeh, Shapour | Jørgensen, Torben | Jukema, J. 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PLoS Genetics  2015;11(10):e1005378.
Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.
Author Summary
Adult body size and body shape differ substantially between men and women and change over time. More than 100 genetic variants that influence body mass index (measure of body size) or waist-to-hip ratio (measure of body shape) have been identified. While there is evidence that some genetic loci affect body shape differently in men than in women, little is known about whether genetic effects differ in older compared to younger adults, and whether such changes differ between men and women. Therefore, we conducted a systematic genome-wide search, including 114 studies (>320,000 individuals), to specifically identify genetic loci with age- and or sex-dependent effects on body size and shape. We identified 15 loci of which the effect on BMI was different in older compared to younger adults, whereas we found no evidence for loci with different effects in men compared to women. The opposite was seen for body shape as we identified 44 loci of which the effect on waist-to-hip ratio differed between men and women, but no difference between younger and older adults were observed. Our observations may provide new insights into the biology that underlies weight change with age or the sexual dimorphism of body shape.
doi:10.1371/journal.pgen.1005378
PMCID: PMC4591371  PMID: 26426971
21.  Midregional-proAtrial Natriuretic Peptide and High Sensitive Troponin T Strongly Predict Adverse Outcome in Patients Undergoing Percutaneous Repair of Mitral Valve Regurgitation 
PLoS ONE  2015;10(9):e0137464.
Background
It is not known whether biomarkers of hemodynamic stress, myocardial necrosis, and renal function might predict adverse outcome in patients undergoing percutaneous repair of severe mitral valve insufficiency. Thus, we aimed to assess the predictive value of various established and emerging biomarkers for major adverse cardiovascular events (MACE) in these patients.
Methods
Thirty-four patients with symptomatic severe mitral valve insufficiency with a mean STS-Score for mortality of 12.6% and a mean logistic EuroSCORE of 19.7% undergoing MitraClip therapy were prospectively included in this study. Plasma concentrations of mid regional-proatrial natriuretic peptide (MR-proANP), Cystatin C, high-sensitive C-reactive protein (hsCRP), high-sensitive troponin T (hsTnT), N-terminal B-type natriuretic peptide (NT-proBNP), galectin-3, and soluble ST-2 (interleukin 1 receptor-like 1) were measured directly before procedure. MACE was defined as cardiovascular death and hospitalization for heart failure (HF).
Results
During a median follow-up of 211 days (interquartile range 133 to 333 days), 9 patients (26.5%) experienced MACE (death: 7 patients, rehospitalization for HF: 2 patients). Thirty day MACE-rate was 5.9% (death: 2 patients, no rehospitalization for HF). Baseline concentrations of hsTnT (Median 92.6 vs 25.2 ng/L), NT-proBNP (Median 11251 vs 1974 pg/mL) and MR-proANP (Median 755.6 vs 318.3 pmol/L, all p<0.001) were clearly higher in those experiencing an event vs event-free patients, while other clinical variables including STS-Score and logistic EuroSCORE did not differ significantly. In Kaplan-Meier analyses, NT-proBNP and in particular hsTnT and MR-proANP above the median discriminated between those experiencing an event vs event-free patients. This was further corroborated by C-statistics where areas under the ROC curve for prediction of MACE using the respective median values were 0.960 for MR-proANP, 0.907 for NT-proBNP, and 0.822 for hsTnT.
Conclusions
MR-proANP and hsTnT strongly predict cardiovascular death and rehospitalization for HF in patients undergoing percutaneous repair of mitral valve insufficiency. Both markers might be useful components in new scoring systems to better predict short- and potentially long-term mortality and morbidity after MitraClip procedure.
doi:10.1371/journal.pone.0137464
PMCID: PMC4569129  PMID: 26368980
22.  Subclinical and clinical hypothyroidism and non-alcoholic fatty liver disease: a cross-sectional study of a random population sample aged 18 to 65 years 
Background
Non-alcoholic fatty liver disease (NAFLD) is one of the most common disorders of the liver worldwide. Recently, a correlation between thyroid dysfunction and NAFLD has been discussed. Objective of the present study was to investigate the association between thyroid dysfunction and hepatic steatosis.
Methods
Data from 2,445 subjects (51.7 % females) aged 18 to 65 years participating in a population-based cross-sectional study were assessed based on a standardized questionnaire and documentation of physical, biochemical and ultrasonographic findings. After application of exclusion criteria, a total of 1,276 subjects were included in the study collective. The influence of potential factors on the development of hepatic steatosis was assessed using multivariate logistic regression.
Results
The prevalence of hepatic steatosis in the study collective was 27.4 % (n = 349). The serum thyroxin (TT4) concentration in subjects with hepatic steatosis was reduced (p = 0.0004). Adjusting for age, or BMI, there was an increased prevalence of hepatic steatosis in subjects with reduced TT4 concentrations (p = 0.0143; p = <.0001).
Conclusions
The findings of the present study confirm an association between both subclinical and clinical hypothyroidism and hepatic steatosis
doi:10.1186/s12902-015-0030-5
PMCID: PMC4536732  PMID: 26276551
NAFLD; Thyroid; Hypothyroidism; NASH; Cross-sectional studies
23.  New genetic loci link adipose and insulin biology to body fat distribution 
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James F | Witteman, Jacqueline C | Adair, Linda S | Bochud, Murielle | Boehm, Bernhard O | Bornstein, Stefan R | Bouchard, Claude | Cauchi, Stéphane | Caulfield, Mark J | Chambers, John C | Chasman, Daniel I | Cooper, Richard S | Dedoussis, George | Ferrucci, Luigi | Froguel, Philippe | Grabe, Hans-Jörgen | Hamsten, Anders | Hui, Jennie | Hveem, Kristian | Jöckel, Karl-Heinz | Kivimaki, Mika | Kuh, Diana | Laakso, Markku | Liu, Yongmei | März, Winfried | Munroe, Patricia B | Njølstad, Inger | Oostra, Ben A | Palmer, Colin NA | Pedersen, Nancy L | Perola, Markus | Pérusse, Louis | Peters, Ulrike | Power, Chris | Quertermous, Thomas | Rauramaa, Rainer | Rivadeneira, Fernando | Saaristo, Timo E | Saleheen, Danish | Sinisalo, Juha | Slagboom, P Eline | Snieder, Harold | Spector, Tim D | Stefansson, Kari | Stumvoll, Michael | Tuomilehto, Jaakko | Uitterlinden, André G | Uusitupa, Matti | van der Harst, Pim | Veronesi, Giovanni | Walker, Mark | Wareham, Nicholas J | Watkins, Hugh | Wichmann, 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Nature  2015;518(7538):187-196.
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, we conducted genome-wide association meta-analyses of waist and hip circumference-related traits in up to 224,459 individuals. We identified 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and an additional 19 loci newly associated with related waist and hip circumference measures (P<5×10−8). Twenty of the 49 WHRadjBMI loci showed significant sexual dimorphism, 19 of which displayed a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation, and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
doi:10.1038/nature14132
PMCID: PMC4338562  PMID: 25673412
24.  Large Multiethnic Candidate Gene Study for C-Reactive Protein Levels: Identification of a Novel Association at CD36 in African Americans 
Human genetics  2014;133(8):985-995.
C-reactive protein (CRP) is a heritable biomarker of systemic inflammation and a predictor of cardiovascular disease (CVD). Large-scale genetic association studies for CRP have largely focused on individuals of European descent. We sought to uncover novel genetic variants for CRP in a multi-ethnic sample using the ITMAT Broad-CARe (IBC) array, a custom 50,000 SNP gene-centric array having dense coverage of over 2,000 candidate CVD genes. We performed analyses on 7570 African Americans (AA) from the Candidate gene Association Resource (CARe) study and race-combined meta-analyses that included 29,939 additional individuals of European descent from CARe, the Women’s Health Initiative (WHI) and KORA studies. We observed array-wide significance (p<2.2×10−6) for four loci in AA, three of which have been reported previously in individuals of European descent (IL6R, p=2.0×10−6; CRP, p=4.2×10−71; APOE, p=1.6×10−6). The fourth significant locus, CD36 (p=1.6×10−6), was observed at a functional variant (rs3211938) that is extremely rare in individuals of European descent. We replicated the CD36 finding (p=1.8×10−5) in an independent sample of 8041 AA women from WHI; a meta-analysis combining the CARe and WHI AA results at rs3211938 reached genome-wide significance (p=1.5×10−10). In the race-combined meta-analyses, 13 loci reached significance, including ten (CRP, TOMM40/APOE/APOC1, HNF1A, LEPR, GCKR, IL6R, IL1RN, NLRP3, HNF4A and BAZ1B/BCL7B) previously associated with CRP, and one (ARNTL) previously reported to be nominally associated with CRP. Two novel loci were also detected (RPS6KB1, p=2.0×10−6; CD36, p=1.4×10−6). These results highlight both shared and unique genetic risk factors for CRP in AA compared to populations of European descent.
doi:10.1007/s00439-014-1439-z
PMCID: PMC4104766  PMID: 24643644
C-reactive protein; Inflammation; Multi-ethnic; Candidate gene
25.  Air Pollution from Road Traffic and Systemic Inflammation in Adults: A Cross-Sectional Analysis in the European ESCAPE Project 
Environmental Health Perspectives  2015;123(8):785-791.
Background
Exposure to particulate matter air pollution (PM) has been associated with cardiovascular diseases.
Objectives
In this study we evaluated whether annual exposure to ambient air pollution is associated with systemic inflammation, which is hypothesized to be an intermediate step to cardiovascular disease.
Methods
Six cohorts of adults from Central and Northern Europe were used in this cross-sectional study as part of the larger ESCAPE project (European Study of Cohorts for Air Pollution Effects). Data on levels of blood markers for systemic inflammation—high-sensitivity C-reactive protein (CRP) and fibrinogen—were available for 22,561 and 17,428 persons, respectively. Land use regression models were used to estimate cohort participants’ long-term exposure to various size fractions of PM, soot, and nitrogen oxides (NOx). In addition, traffic intensity on the closest street and traffic load within 100 m from home were used as indicators of traffic air pollution exposure.
Results
Particulate air pollution was not associated with systemic inflammation. However, cohort participants living on a busy (> 10,000 vehicles/day) road had elevated CRP values (10.2%; 95% CI: 2.4, 18.8%, compared with persons living on a quiet residential street with < 1,000 vehicles/day). Annual NOx concentration was also positively associated with levels of CRP (3.2%; 95% CI: 0.3, 6.1 per 20 μg/m3), but the effect estimate was more sensitive to model adjustments. For fibrinogen, no consistent associations were observed.
Conclusions
Living close to busy traffic was associated with increased CRP concentrations, a known risk factor for cardiovascular diseases. However, it remains unclear which specific air pollutants are responsible for the association.
Citation
Lanki T, Hampel R, Tiittanen P, Andrich S, Beelen R, Brunekreef B, Dratva J, De Faire U, Fuks KB, Hoffmann B, Imboden M, Jousilahti P, Koenig W, Mahabadi AA, Künzli N, Pedersen NL, Penell J, Pershagen G, Probst-Hensch NM, Schaffner E, Schindler C, Sugiri D, Swart WJ, Tsai MY, Turunen AW, Weinmayr G, Wolf K, Yli-Tuomi T, Peters A. 2015. Air pollution from road traffic and systemic inflammation in adults: a cross-sectional analysis in the European ESCAPE project. Environ Health Perspect 123:785–791; http://dx.doi.org/10.1289/ehp.1408224
doi:10.1289/ehp.1408224
PMCID: PMC4529004  PMID: 25816055

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