%0 Journal Article %J Hum Mol Genet %D 2021 %T Genome-wide association study of circulating interleukin 6 levels identifies novel loci. %A Ahluwalia, Tarunveer S %A Prins, Bram P %A Abdollahi, Mohammadreza %A Armstrong, Nicola J %A Aslibekyan, Stella %A Bain, Lisa %A Jefferis, Barbara %A Baumert, Jens %A Beekman, Marian %A Ben-Shlomo, Yoav %A Bis, Joshua C %A Mitchell, Braxton D %A de Geus, Eco %A Delgado, Graciela E %A Marek, Diana %A Eriksson, Joel %A Kajantie, Eero %A Kanoni, Stavroula %A Kemp, John P %A Lu, Chen %A Marioni, Riccardo E %A McLachlan, Stela %A Milaneschi, Yuri %A Nolte, Ilja M %A Petrelis, Alexandros M %A Porcu, Eleonora %A Sabater-Lleal, Maria %A Naderi, Elnaz %A Seppälä, Ilkka %A Shah, Tina %A Singhal, Gaurav %A Standl, Marie %A Teumer, Alexander %A Thalamuthu, Anbupalam %A Thiering, Elisabeth %A Trompet, Stella %A Ballantyne, Christie M %A Benjamin, Emelia J %A Casas, Juan P %A Toben, Catherine %A Dedoussis, George %A Deelen, Joris %A Durda, Peter %A Engmann, Jorgen %A Feitosa, Mary F %A Grallert, Harald %A Hammarstedt, Ann %A Harris, Sarah E %A Homuth, Georg %A Hottenga, Jouke-Jan %A Jalkanen, Sirpa %A Jamshidi, Yalda %A Jawahar, Magdalene C %A Jess, Tine %A Kivimaki, Mika %A Kleber, Marcus E %A Lahti, Jari %A Liu, Yongmei %A Marques-Vidal, Pedro %A Mellström, Dan %A Mooijaart, Simon P %A Müller-Nurasyid, Martina %A Penninx, Brenda %A Revez, Joana A %A Rossing, Peter %A Räikkönen, Katri %A Sattar, Naveed %A Scharnagl, Hubert %A Sennblad, Bengt %A Silveira, Angela %A Pourcain, Beate St %A Timpson, Nicholas J %A Trollor, Julian %A van Dongen, Jenny %A van Heemst, Diana %A Visvikis-Siest, Sophie %A Vollenweider, Peter %A Völker, Uwe %A Waldenberger, Melanie %A Willemsen, Gonneke %A Zabaneh, Delilah %A Morris, Richard W %A Arnett, Donna K %A Baune, Bernhard T %A Boomsma, Dorret I %A Chang, Yen-Pei C %A Deary, Ian J %A Deloukas, Panos %A Eriksson, Johan G %A Evans, David M %A Ferreira, Manuel A %A Gaunt, Tom %A Gudnason, Vilmundur %A Hamsten, Anders %A Heinrich, Joachim %A Hingorani, Aroon %A Humphries, Steve E %A Jukema, J Wouter %A Koenig, Wolfgang %A Kumari, Meena %A Kutalik, Zoltán %A Lawlor, Deborah A %A Lehtimäki, Terho %A Marz, Winfried %A Mather, Karen A %A Naitza, Silvia %A Nauck, Matthias %A Ohlsson, Claes %A Price, Jackie F %A Raitakari, Olli %A Rice, Ken %A Sachdev, Perminder S %A Slagboom, Eline %A Sørensen, Thorkild I A %A Spector, Tim %A Stacey, David %A Stathopoulou, Maria G %A Tanaka, Toshiko %A Wannamethee, S Goya %A Whincup, Peter %A Rotter, Jerome I %A Dehghan, Abbas %A Eric Boerwinkle %A Psaty, Bruce M %A Snieder, Harold %A Alizadeh, Behrooz Z %K Cohort Studies %K Gene Expression Regulation %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K HLA-DRB1 Chains %K Humans %K Interleukin 1 Receptor Antagonist Protein %K Interleukin-1 %K Interleukin-6 %K Polymorphism, Single Nucleotide %K Receptors, Interleukin-6 %K White People %X

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

%B Hum Mol Genet %V 30 %P 393-409 %8 2021 Apr 27 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/33517400?dopt=Abstract %R 10.1093/hmg/ddab023 %0 Journal Article %J Blood %D 2018 %T DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta-analysis. %A Ward-Caviness, Cavin K %A Huffman, Jennifer E %A Everett, Karl %A Germain, Marine %A van Dongen, Jenny %A Hill, W David %A Jhun, Min A %A Brody, Jennifer A %A Ghanbari, Mohsen %A Du, Lei %A Roetker, Nicholas S %A de Vries, Paul S %A Waldenberger, Melanie %A Gieger, Christian %A Wolf, Petra %A Prokisch, Holger %A Koenig, Wolfgang %A O'Donnell, Christopher J %A Levy, Daniel %A Liu, Chunyu %A Truong, Vinh %A Wells, Philip S %A Trégouët, David-Alexandre %A Tang, Weihong %A Morrison, Alanna C %A Eric Boerwinkle %A Wiggins, Kerri L %A McKnight, Barbara %A Guo, Xiuqing %A Psaty, Bruce M %A Sotoodenia, Nona %A Boomsma, Dorret I %A Willemsen, Gonneke %A Ligthart, Lannie %A Deary, Ian J %A Zhao, Wei %A Ware, Erin B %A Kardia, Sharon L R %A van Meurs, Joyce B J %A Uitterlinden, André G %A Franco, Oscar H %A Eriksson, Per %A Franco-Cereceda, Anders %A Pankow, James S %A Johnson, Andrew D %A Gagnon, France %A Morange, Pierre-Emmanuel %A de Geus, Eco J C %A Starr, John M %A Smith, Jennifer A %A Dehghan, Abbas %A Björck, Hanna M %A Smith, Nicholas L %A Peters, Annette %K Aging %K DNA Methylation %K Epigenesis, Genetic %K Hemostasis %K Humans %X

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 performed European and African ancestry-specific meta-analyses which were then combined via a random effects meta-analysis. For all other measures we could not estimate ancestry-specific effects and used a single fixed effects meta-analysis. We found that 1-year higher extrinsic epigenetic age as compared with chronological age was associated with higher fibrinogen (0.004 g/L/y; 95% confidence interval, 0.001-0.007; = .01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL/y; 95% confidence interval, 0.07-0.20; = 6.6 10) 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 () and the 3 fibrinogen subunit-encoding genes (, , and ) in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a procoagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

%B Blood %V 132 %P 1842-1850 %8 2018 Oct 25 %G eng %N 17 %1 https://www.ncbi.nlm.nih.gov/pubmed/30042098?dopt=Abstract %R 10.1182/blood-2018-02-831347 %0 Journal Article %J PLoS One %D 2014 %T No evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index: results from meta-analyses of 80,607 subjects. %A Baumert, Jens %A Huang, Jie %A McKnight, Barbara %A Sabater-Lleal, Maria %A Steri, Maristella %A Chu, Audrey Y %A Trompet, Stella %A Lopez, Lorna M %A Fornage, Myriam %A Teumer, Alexander %A Tang, Weihong %A Rudnicka, Alicja R %A Mälarstig, Anders %A Hottenga, Jouke-Jan %A Kavousi, Maryam %A Lahti, Jari %A Tanaka, Toshiko %A Hayward, Caroline %A Huffman, Jennifer E %A Morange, Pierre-Emmanuel %A Rose, Lynda M %A Basu, Saonli %A Rumley, Ann %A Stott, David J %A Buckley, Brendan M %A de Craen, Anton J M %A Sanna, Serena %A Masala, Marco %A Biffar, Reiner %A Homuth, Georg %A Silveira, Angela %A Sennblad, Bengt %A Goel, Anuj %A Watkins, Hugh %A Müller-Nurasyid, Martina %A Rückerl, Regina %A Taylor, Kent %A Chen, Ming-Huei %A de Geus, Eco J C %A Hofman, Albert %A Witteman, Jacqueline C M %A de Maat, Moniek P M %A Palotie, Aarno %A Davies, Gail %A Siscovick, David S %A Kolcic, Ivana %A Wild, Sarah H %A Song, Jaejoon %A McArdle, Wendy L %A Ford, Ian %A Sattar, Naveed %A Schlessinger, David %A Grotevendt, Anne %A Franzosi, Maria Grazia %A Illig, Thomas %A Waldenberger, Melanie %A Lumley, Thomas %A Tofler, Geoffrey H %A Willemsen, Gonneke %A Uitterlinden, André G %A Rivadeneira, Fernando %A Räikkönen, Katri %A Chasman, Daniel I %A Folsom, Aaron R %A Lowe, Gordon D %A Westendorp, Rudi G J %A Slagboom, P Eline %A Cucca, Francesco %A Wallaschofski, Henri %A Strawbridge, Rona J %A Seedorf, Udo %A Koenig, Wolfgang %A Bis, Joshua C %A Mukamal, Kenneth J %A van Dongen, Jenny %A Widen, Elisabeth %A Franco, Oscar H %A Starr, John M %A Liu, Kiang %A Ferrucci, Luigi %A Polasek, Ozren %A Wilson, James F %A Oudot-Mellakh, Tiphaine %A Campbell, Harry %A Navarro, Pau %A Bandinelli, Stefania %A Eriksson, Johan %A Boomsma, Dorret I %A Dehghan, Abbas %A Clarke, Robert %A Hamsten, Anders %A Eric Boerwinkle %A Jukema, J Wouter %A Naitza, Silvia %A Ridker, Paul M %A Völzke, Henry %A Deary, Ian J %A Reiner, Alexander P %A Trégouët, David-Alexandre %A O'Donnell, Christopher J %A Strachan, David P %A Peters, Annette %A Smith, Nicholas L %K Alcohol Drinking %K Body Mass Index %K Fibrinogen %K Gene-Environment Interaction %K Genomics %K Humans %K Smoking %X

Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2 × 10(-8). This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.

%B PLoS One %V 9 %P e111156 %8 2014 %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/25551457?dopt=Abstract %R 10.1371/journal.pone.0111156