%0 Journal Article %J Eur J Hum Genet %D 2016 %T Association of the IGF1 gene with fasting insulin levels. %A Willems, Sara M %A Cornes, Belinda K %A Brody, Jennifer A %A Morrison, Alanna C %A Lipovich, Leonard %A Dauriz, Marco %A Chen, Yuning %A Liu, Ching-Ti %A Rybin, Denis V %A Richard A Gibbs %A Donna M Muzny %A Pankow, James S %A Psaty, Bruce M %A Eric Boerwinkle %A Rotter, Jerome I %A Siscovick, David S %A Vasan, Ramachandran S %A Kaplan, Robert C %A Isaacs, Aaron %A Dupuis, Josée %A van Duijn, Cornelia M %A Meigs, James B %K Adult %K Aged %K Fasting %K Female %K Humans %K Insulin %K Insulin-Like Growth Factor I %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X
Insulin-like growth factor 1 (IGF-I) has been associated with insulin resistance. Genome-wide association studies (GWASs) of fasting insulin (FI) identified single-nucleotide variants (SNVs) near the IGF1 gene, raising two hypotheses: (1) these associations are mediated by IGF-I levels and (2) these noncoding variants either tag other functional variants in the region or are directly functional. In our study, analyses including 5141 individuals from population-based cohorts suggest that FI associations near IGF1 are not mediated by IGF-I. Analyses of targeted sequencing data in 3539 individuals reveal a large number of novel rare variants at the IGF1 locus and show a FI association with a subset of rare nonsynonymous variants (PSKAT=5.7 × 10(-4)). Conditional analyses suggest that this association is partly explained by the GWAS signal and the presence of a residual independent rare variant effect (Pconditional=0.019). Annotation using ENCODE data suggests that the GWAS variants may have a direct functional role in insulin biology. In conclusion, our study provides insight into variation present at the IGF1 locus and into the genetic architecture underlying FI levels, suggesting that FI associations of SNVs near IGF1 are not mediated by IGF-I and suggesting a role for both rare nonsynonymous and common functional variants in insulin biology.
%B Eur J Hum Genet %V 24 %P 1337-43 %8 2016 Aug %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/26860063?dopt=Abstract %R 10.1038/ejhg.2016.4 %0 Journal Article %J Nature %D 2015 %T Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. %A Do, Ron %A Stitziel, Nathan O %A Won, Hong-Hee %A Jørgensen, Anders Berg %A Duga, Stefano %A Angelica Merlini, Pier %A Kiezun, Adam %A Farrall, Martin %A Goel, Anuj %A Zuk, Or %A Guella, Illaria %A Asselta, Rosanna %A Lange, Leslie A %A Peloso, Gina M %A Auer, Paul L %A Girelli, Domenico %A Martinelli, Nicola %A Farlow, Deborah N %A DePristo, Mark A %A Roberts, Robert %A Stewart, Alexander F R %A Saleheen, Danish %A Danesh, John %A Epstein, Stephen E %A Sivapalaratnam, Suthesh %A Hovingh, G Kees %A Kastelein, John J %A Samani, Nilesh J %A Schunkert, Heribert %A Erdmann, Jeanette %A Shah, Svati H %A Kraus, William E %A Davies, Robert %A Nikpay, Majid %A Johansen, Christopher T %A Wang, Jian %A Hegele, Robert A %A Hechter, Eliana %A Marz, Winfried %A Kleber, Marcus E %A Huang, Jie %A Johnson, Andrew D %A Li, Mingyao %A Burke, Greg L %A Gross, Myron %A Liu, Yongmei %A Assimes, Themistocles L %A Heiss, Gerardo %A Lange, Ethan M %A Folsom, Aaron R %A Taylor, Herman A %A Olivieri, Oliviero %A Hamsten, Anders %A Clarke, Robert %A Reilly, Dermot F %A Yin, Wu %A Rivas, Manuel A %A Donnelly, Peter %A Rossouw, Jacques E %A Psaty, Bruce M %A Herrington, David M %A Wilson, James G %A Rich, Stephen S %A Bamshad, Michael J %A Tracy, Russell P %A Cupples, L Adrienne %A Rader, Daniel J %A Reilly, Muredach P %A Spertus, John A %A Cresci, Sharon %A Hartiala, Jaana %A Tang, W H Wilson %A Hazen, Stanley L %A Allayee, Hooman %A Reiner, Alex P %A Carlson, Christopher S %A Kooperberg, Charles %A Jackson, Rebecca D %A Eric Boerwinkle %A Lander, Eric S %A Schwartz, Stephen M %A Siscovick, David S %A McPherson, Ruth %A Tybjaerg-Hansen, Anne %A Abecasis, Gonçalo R %A Watkins, Hugh %A Nickerson, Deborah A %A Ardissino, Diego %A Sunyaev, Shamil R %A O'Donnell, Christopher J %A Altshuler, David %A Gabriel, Stacey %A Kathiresan, Sekar %K Age Factors %K Age of Onset %K Alleles %K Apolipoprotein A-V %K Apolipoproteins A %K Case-Control Studies %K Cholesterol, LDL %K Coronary Artery Disease %K Exome %K Female %K Genetic Predisposition to Disease %K Genetics, Population %K Heterozygote %K Humans %K Male %K Middle Aged %K Mutation %K Myocardial Infarction %K National Heart, Lung, and Blood Institute (U.S.) %K Receptors, LDL %K Triglycerides %K United States %XMyocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.
%B Nature %V 518 %P 102-6 %8 2015 Feb 05 %G eng %N 7537 %1 https://www.ncbi.nlm.nih.gov/pubmed/25487149?dopt=Abstract %R 10.1038/nature13917 %0 Journal Article %J Nat Commun %D 2015 %T Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. %A Wessel, Jennifer %A Chu, Audrey Y %A Willems, Sara M %A Wang, Shuai %A Yaghootkar, Hanieh %A Brody, Jennifer A %A Dauriz, Marco %A Hivert, Marie-France %A Raghavan, Sridharan %A Lipovich, Leonard %A Hidalgo, Bertha %A Fox, Keolu %A Huffman, Jennifer E %A An, Ping %A Lu, Yingchang %A Rasmussen-Torvik, Laura J %A Grarup, Niels %A Ehm, Margaret G %A Li, Li %A Baldridge, Abigail S %A Stančáková, Alena %A Abrol, Ravinder %A Besse, Céline %A Boland, Anne %A Bork-Jensen, Jette %A Fornage, Myriam %A Freitag, Daniel F %A Garcia, Melissa E %A Guo, Xiuqing %A Hara, Kazuo %A Isaacs, Aaron %A Jakobsdottir, Johanna %A Lange, Leslie A %A Layton, Jill C %A Li, Man %A Hua Zhao, Jing %A Meidtner, Karina %A Morrison, Alanna C %A Nalls, Mike A %A Peters, Marjolein J %A Sabater-Lleal, Maria %A Schurmann, Claudia %A Silveira, Angela %A Smith, Albert V %A Southam, Lorraine %A Stoiber, Marcus H %A Strawbridge, Rona J %A Taylor, Kent D %A Varga, Tibor V %A Allin, Kristine H %A Amin, Najaf %A Aponte, Jennifer L %A Aung, Tin %A Barbieri, Caterina %A Bihlmeyer, Nathan A %A Boehnke, Michael %A Bombieri, Cristina %A Bowden, Donald W %A Burns, Sean M %A Chen, Yuning %A Chen, Yii-DerI %A Cheng, Ching-Yu %A Correa, Adolfo %A Czajkowski, Jacek %A Dehghan, Abbas %A Ehret, Georg B %A Eiriksdottir, Gudny %A Escher, Stefan A %A Farmaki, Aliki-Eleni %A Frånberg, Mattias %A Gambaro, Giovanni %A Giulianini, Franco %A Goddard, William A %A Goel, Anuj %A Gottesman, Omri %A Grove, Megan L %A Gustafsson, Stefan %A Hai, Yang %A Hallmans, Goran %A Heo, Jiyoung %A Hoffmann, Per %A Ikram, Mohammad K %A Jensen, Richard A %A Jørgensen, Marit E %A Jørgensen, Torben %A Karaleftheri, Maria %A Khor, Chiea C %A Kirkpatrick, Andrea %A Kraja, Aldi T %A Kuusisto, Johanna %A Lange, Ethan M %A Lee, I T %A Lee, Wen-Jane %A Leong, Aaron %A Liao, Jiemin %A Liu, Chunyu %A Liu, Yongmei %A Lindgren, Cecilia M %A Linneberg, Allan %A Malerba, Giovanni %A Mamakou, Vasiliki %A Marouli, Eirini %A Maruthur, Nisa M %A Matchan, Angela %A McKean-Cowdin, Roberta %A McLeod, Olga %A Metcalf, Ginger A %A Mohlke, Karen L %A Muzny, Donna M %A Ntalla, Ioanna %A Palmer, Nicholette D %A Pasko, Dorota %A Peter, Andreas %A Rayner, Nigel W %A Renstrom, Frida %A Rice, Ken %A Sala, Cinzia F %A Sennblad, Bengt %A Serafetinidis, Ioannis %A Smith, Jennifer A %A Soranzo, Nicole %A Speliotes, Elizabeth K %A Stahl, Eli A %A Stirrups, Kathleen %A Tentolouris, Nikos %A Thanopoulou, Anastasia %A Torres, Mina %A Traglia, Michela %A Tsafantakis, Emmanouil %A Javad, Sundas %A Yanek, Lisa R %A Zengini, Eleni %A Becker, Diane M %A Bis, Joshua C %A Brown, James B %A Cupples, L Adrienne %A Hansen, Torben %A Ingelsson, Erik %A Karter, Andrew J %A Lorenzo, Carlos %A Mathias, Rasika A %A Norris, Jill M %A Peloso, Gina M %A Sheu, Wayne H-H %A Toniolo, Daniela %A Vaidya, Dhananjay %A Varma, Rohit %A Wagenknecht, Lynne E %A Boeing, Heiner %A Bottinger, Erwin P %A Dedoussis, George %A Deloukas, Panos %A Ferrannini, Ele %A Franco, Oscar H %A Franks, Paul W %A Gibbs, Richard A %A Gudnason, Vilmundur %A Hamsten, Anders %A Harris, Tamara B %A Hattersley, Andrew T %A Hayward, Caroline %A Hofman, Albert %A Jansson, Jan-Håkan %A Langenberg, Claudia %A Launer, Lenore J %A Levy, Daniel %A Oostra, Ben A %A O'Donnell, Christopher J %A O'Rahilly, Stephen %A Padmanabhan, Sandosh %A Pankow, James S %A Polasek, Ozren %A Province, Michael A %A Rich, Stephen S %A Ridker, Paul M %A Rudan, Igor %A Schulze, Matthias B %A Smith, Blair H %A Uitterlinden, André G %A Walker, Mark %A Watkins, Hugh %A Wong, Tien Y %A Zeggini, Eleftheria %A Laakso, Markku %A Borecki, Ingrid B %A Chasman, Daniel I %A Pedersen, Oluf %A Psaty, Bruce M %A Tai, E Shyong %A van Duijn, Cornelia M %A Wareham, Nicholas J %A Waterworth, Dawn M %A Boerwinkle, Eric %A Kao, W H Linda %A Florez, Jose C %A Loos, Ruth J F %A Wilson, James G %A Frayling, Timothy M %A Siscovick, David S %A Dupuis, Josée %A Rotter, Jerome I %A Meigs, James B %A Scott, Robert A %A Goodarzi, Mark O %K Black People %K Blood Glucose %K Diabetes Mellitus, Type 2 %K Exome %K Fasting %K Genetic Association Studies %K Genetic Loci %K Genetic Predisposition to Disease %K Genetic Variation %K Glucagon-Like Peptide-1 Receptor %K Glucose-6-Phosphatase %K Humans %K Insulin %K Mutation Rate %K Oligonucleotide Array Sequence Analysis %K Polymorphism, Single Nucleotide %K White People %XFasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
%B Nat Commun %V 6 %P 5897 %8 2015 Jan 29 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/25631608?dopt=Abstract %R 10.1038/ncomms6897 %0 Journal Article %J Circ Cardiovasc Genet %D 2014 %T Association of levels of fasting glucose and insulin with rare variants at the chromosome 11p11.2-MADD locus: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. %A Cornes, Belinda K %A Brody, Jennifer A %A Nikpoor, Naghmeh %A Morrison, Alanna C %A Chu, Huan %A Ahn, Byung Soo %A Wang, Shuai %A Dauriz, Marco %A Barzilay, Joshua I %A Dupuis, Josée %A Florez, Jose C %A Coresh, Josef %A Richard A Gibbs %A Kao, W H Linda %A Liu, Ching-Ti %A McKnight, Barbara %A Donna M Muzny %A Pankow, James S %A Reid, Jeffrey G %A White, Charles C %A Johnson, Andrew D %A Wong, Tien Y %A Psaty, Bruce M %A Eric Boerwinkle %A Rotter, Jerome I %A Siscovick, David S %A Sladek, Robert %A Meigs, James B %K Aged %K Aged, 80 and over %K Aging %K Blood Glucose %K Chromosomes, Human, Pair 11 %K Cohort Studies %K Death Domain Receptor Signaling Adaptor Proteins %K Diabetes Mellitus, Type 2 %K Fasting %K Female %K Gene Frequency %K Genetic Variation %K Genome-Wide Association Study %K Genomics %K Guanine Nucleotide Exchange Factors %K Heart Diseases %K Humans %K Insulin %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Sequence Analysis, DNA %XBACKGROUND: Common variation at the 11p11.2 locus, encompassing MADD, ACP2, NR1H3, MYBPC3, and SPI1, has been associated in genome-wide association studies with fasting glucose and insulin (FI). In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study, we sequenced 5 gene regions at 11p11.2 to identify rare, potentially functional variants influencing fasting glucose or FI levels.
METHODS AND RESULTS: Sequencing (mean depth, 38×) across 16.1 kb in 3566 individuals without diabetes mellitus identified 653 variants, 79.9% of which were rare (minor allele frequency <1%) and novel. We analyzed rare variants in 5 gene regions with FI or fasting glucose using the sequence kernel association test. At NR1H3, 53 rare variants were jointly associated with FI (P=2.73×10(-3)); of these, 7 were predicted to have regulatory function and showed association with FI (P=1.28×10(-3)). Conditioning on 2 previously associated variants at MADD (rs7944584, rs10838687) did not attenuate this association, suggesting that there are >2 independent signals at 11p11.2. One predicted regulatory variant, chr11:47227430 (hg18; minor allele frequency=0.00068), contributed 20.6% to the overall sequence kernel association test score at NR1H3, lies in intron 2 of NR1H3, and is a predicted binding site for forkhead box A1 (FOXA1), a transcription factor associated with insulin regulation. In human HepG2 hepatoma cells, the rare chr11:47227430 A allele disrupted FOXA1 binding and reduced FOXA1-dependent transcriptional activity.
CONCLUSIONS: Sequencing at 11p11.2-NR1H3 identified rare variation associated with FI. One variant, chr11:47227430, seems to be functional, with the rare A allele reducing transcription factor FOXA1 binding and FOXA1-dependent transcriptional activity.
%B Circ Cardiovasc Genet %V 7 %P 374-382 %8 2014 Jun %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/24951664?dopt=Abstract %R 10.1161/CIRCGENETICS.113.000169 %0 Journal Article %J Am J Hum Genet %D 2014 %T Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. %A Peloso, Gina M %A Auer, Paul L %A Bis, Joshua C %A Voorman, Arend %A Morrison, Alanna C %A Stitziel, Nathan O %A Brody, Jennifer A %A Khetarpal, Sumeet A %A Crosby, Jacy R %A Fornage, Myriam %A Isaacs, Aaron %A Jakobsdottir, Johanna %A Feitosa, Mary F %A Davies, Gail %A Huffman, Jennifer E %A Manichaikul, Ani %A Davis, Brian %A Lohman, Kurt %A Joon, Aron Y %A Smith, Albert V %A Grove, Megan L %A Zanoni, Paolo %A Redon, Valeska %A Demissie, Serkalem %A Lawson, Kim %A Peters, Ulrike %A Carlson, Christopher %A Jackson, Rebecca D %A Ryckman, Kelli K %A Mackey, Rachel H %A Robinson, Jennifer G %A Siscovick, David S %A Schreiner, Pamela J %A Mychaleckyj, Josyf C %A Pankow, James S %A Hofman, Albert %A Uitterlinden, André G %A Harris, Tamara B %A Taylor, Kent D %A Stafford, Jeanette M %A Reynolds, Lindsay M %A Marioni, Riccardo E %A Dehghan, Abbas %A Franco, Oscar H %A Patel, Aniruddh P %A Lu, Yingchang %A Hindy, George %A Gottesman, Omri %A Bottinger, Erwin P %A Melander, Olle %A Orho-Melander, Marju %A Loos, Ruth J F %A Duga, Stefano %A Merlini, Piera Angelica %A Farrall, Martin %A Goel, Anuj %A Asselta, Rosanna %A Girelli, Domenico %A Martinelli, Nicola %A Shah, Svati H %A Kraus, William E %A Li, Mingyao %A Rader, Daniel J %A Reilly, Muredach P %A McPherson, Ruth %A Watkins, Hugh %A Ardissino, Diego %A Zhang, Qunyuan %A Wang, Judy %A Tsai, Michael Y %A Taylor, Herman A %A Correa, Adolfo %A Griswold, Michael E %A Lange, Leslie A %A Starr, John M %A Rudan, Igor %A Eiriksdottir, Gudny %A Launer, Lenore J %A Ordovas, Jose M %A Levy, Daniel %A Chen, Y-D Ida %A Reiner, Alexander P %A Hayward, Caroline %A Polasek, Ozren %A Deary, Ian J %A Borecki, Ingrid B %A Liu, Yongmei %A Gudnason, Vilmundur %A Wilson, James G %A van Duijn, Cornelia M %A Kooperberg, Charles %A Rich, Stephen S %A Psaty, Bruce M %A Rotter, Jerome I %A O'Donnell, Christopher J %A Rice, Kenneth %A Eric Boerwinkle %A Kathiresan, Sekar %A Cupples, L Adrienne %K 1-Alkyl-2-acetylglycerophosphocholine Esterase %K Adult %K Aged %K Alleles %K Animals %K Black People %K Cholesterol, HDL %K Cholesterol, LDL %K Cohort Studies %K Coronary Disease %K Female %K Gene Frequency %K Genetic Association Studies %K Genetic Code %K Genetic Variation %K Humans %K Linear Models %K Male %K Mice %K Mice, Inbred C57BL %K Microtubule-Associated Proteins %K Middle Aged %K Phenotype %K Sequence Analysis, DNA %K Subtilisins %K Triglycerides %K White People %XLow-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.
%B Am J Hum Genet %V 94 %P 223-32 %8 2014 Feb 06 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/24507774?dopt=Abstract %R 10.1016/j.ajhg.2014.01.009 %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 %XPlasma 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 %0 Journal Article %J PLoS One %D 2013 %T Best practices and joint calling of the HumanExome BeadChip: the CHARGE Consortium. %A Grove, Megan L %A Yu, Bing %A Cochran, Barbara J %A Haritunians, Talin %A Bis, Joshua C %A Taylor, Kent D %A Hansen, Mark %A Borecki, Ingrid B %A Cupples, L Adrienne %A Fornage, Myriam %A Gudnason, Vilmundur %A Harris, Tamara B %A Kathiresan, Sekar %A Kraaij, Robert %A Launer, Lenore J %A Levy, Daniel %A Liu, Yongmei %A Mosley, Thomas %A Peloso, Gina M %A Psaty, Bruce M %A Rich, Stephen S %A Rivadeneira, Fernando %A Siscovick, David S %A Smith, Albert V %A Uitterlinden, Andre %A van Duijn, Cornelia M %A Wilson, James G %A O'Donnell, Christopher J %A Rotter, Jerome I %A Boerwinkle, Eric %K Aging %K Alleles %K Cluster Analysis %K Cohort Studies %K Exome %K Female %K Gene Frequency %K Genomics %K Genotype %K Heart %K Humans %K Male %K Oligonucleotide Array Sequence Analysis %K Polymorphism, Single Nucleotide %K Racial Groups %K Sample Size %K Self Report %K Sequence Analysis, DNA %XGenotyping arrays are a cost effective approach when typing previously-identified genetic polymorphisms in large numbers of samples. One limitation of genotyping arrays with rare variants (e.g., minor allele frequency [MAF] <0.01) is the difficulty that automated clustering algorithms have to accurately detect and assign genotype calls. Combining intensity data from large numbers of samples may increase the ability to accurately call the genotypes of rare variants. Approximately 62,000 ethnically diverse samples from eleven Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium cohorts were genotyped with the Illumina HumanExome BeadChip across seven genotyping centers. The raw data files for the samples were assembled into a single project for joint calling. To assess the quality of the joint calling, concordance of genotypes in a subset of individuals having both exome chip and exome sequence data was analyzed. After exclusion of low performing SNPs on the exome chip and non-overlap of SNPs derived from sequence data, genotypes of 185,119 variants (11,356 were monomorphic) were compared in 530 individuals that had whole exome sequence data. A total of 98,113,070 pairs of genotypes were tested and 99.77% were concordant, 0.14% had missing data, and 0.09% were discordant. We report that joint calling allows the ability to accurately genotype rare variation using array technology when large sample sizes are available and best practices are followed. The cluster file from this experiment is available at www.chargeconsortium.com/main/exomechip.
%B PLoS One %V 8 %P e68095 %8 2013 %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/23874508?dopt=Abstract %R 10.1371/journal.pone.0068095 %0 Journal Article %J Metabolism %D 2010 %T Common INSIG2 polymorphisms are associated with age-related changes in body size and high-density lipoprotein cholesterol from young adulthood to middle age. %A Fornage, Myriam %A Papanicolaou, George %A Lewis, Cora E %A Boerwinkle, Eric %A Siscovick, David S %K Adolescent %K Adult %K Age Factors %K Body Mass Index %K Body Size %K Cholesterol, HDL %K Cross-Sectional Studies %K Female %K Humans %K Intracellular Signaling Peptides and Proteins %K Male %K Membrane Proteins %K Polymorphism, Single Nucleotide %K Young Adult %XInsulin-induced gene 2 (INSIG2) plays an important role in the regulation of cholesterol and fatty acids synthesis. A polymorphism, rs7566605, located 10 kilobases upstream of the INSIG2 gene, was identified in a genomewide association study of obesity. We conducted an association study of 12 INSIG2 tag-single nucleotide polymorphisms with longitudinal measures of body size (body mass index and waist circumference) and lipid metabolism (plasma high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides levels). We investigated their interaction with age in 4304 Coronary Artery Risk Development in Young Adults participants (49.5% blacks, 50.5% whites) followed prospectively for 20 years. rs7566605 was not associated with variation in body size or lipid metabolism at any age in either racial group. However, rs1352083 and rs10185316 were associated with age-related decline in high-density lipoprotein cholesterol in whites (P = .0005 and .04, respectively). A similar trend was observed in blacks who consistently maintained a body mass index less than 25 kg/m(2) over the study period. These data support a role of INSIG2 sequence variation in the regulation of cholesterol metabolism.
%B Metabolism %V 59 %P 1084-91 %8 2010 Aug %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/20045156?dopt=Abstract %R 10.1016/j.metabol.2009.11.005 %0 Journal Article %J PLoS Genet %D 2010 %T Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six Loci influencing serum magnesium levels. %A Meyer, Tamra E %A Verwoert, Germaine C %A Hwang, Shih-Jen %A Glazer, Nicole L %A Smith, Albert V %A van Rooij, Frank J A %A Ehret, Georg B %A Boerwinkle, Eric %A Felix, Janine F %A Leak, Tennille S %A Harris, Tamara B %A Yang, Qiong %A Dehghan, Abbas %A Aspelund, Thor %A Katz, Ronit %A Homuth, Georg %A Kocher, Thomas %A Rettig, Rainer %A Ried, Janina S %A Gieger, Christian %A Prucha, Hanna %A Pfeufer, Arne %A Meitinger, Thomas %A Coresh, Josef %A Hofman, Albert %A Sarnak, Mark J %A Chen, Yii-Der Ida %A Uitterlinden, André G %A Chakravarti, Aravinda %A Psaty, Bruce M %A van Duijn, Cornelia M %A Kao, W H Linda %A Witteman, Jacqueline C M %A Gudnason, Vilmundur %A Siscovick, David S %A Fox, Caroline S %A Köttgen, Anna %K Adult %K Aged %K Female %K Genome-Wide Association Study %K Humans %K Magnesium %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Potassium %K Sodium %K White People %XMagnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using approximately 2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p<5 x 10(-8)) or suggestive associations (p<4 x 10(-7)) were evaluated for replication in an additional 8,463 subjects of European descent. The association of common variants at six genomic regions (in or near MUC1, ATP2B1, DCDC5, TRPM6, SHROOM3, and MDS1) with serum magnesium levels was genome-wide significant when meta-analyzed with the replication dataset. All initially significant SNPs from the CHARGE Consortium showed nominal association with clinically defined hypomagnesemia, two showed association with kidney function, two with bone mineral density, and one of these also associated with fasting glucose levels. Common variants in CNNM2, a magnesium transporter studied only in model systems to date, as well as in CNNM3 and CNNM4, were also associated with magnesium concentrations in this study. We observed no associations with serum sodium or potassium levels exceeding p<4 x 10(-7). Follow-up studies of newly implicated genomic loci may provide additional insights into the regulation and homeostasis of human serum magnesium levels.
%B PLoS Genet %V 6 %8 2010 Aug 05 %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/20700443?dopt=Abstract %R 10.1371/journal.pgen.1001045 %0 Journal Article %J Diabetes Care %D 2010 %T Interactions of dietary whole-grain intake with fasting glucose- and insulin-related genetic loci in individuals of European descent: a meta-analysis of 14 cohort studies. %A Nettleton, Jennifer A %A McKeown, Nicola M %A Kanoni, Stavroula %A Lemaitre, Rozenn N %A Hivert, Marie-France %A Ngwa, Julius %A van Rooij, Frank J A %A Sonestedt, Emily %A Wojczynski, Mary K %A Ye, Zheng %A Tanaka, Tosh %A Garcia, Melissa %A Anderson, Jennifer S %A Follis, Jack L %A Djousse, Luc %A Mukamal, Kenneth %A Papoutsakis, Constantina %A Mozaffarian, Dariush %A Zillikens, M Carola %A Bandinelli, Stefania %A Bennett, Amanda J %A Borecki, Ingrid B %A Feitosa, Mary F %A Ferrucci, Luigi %A Forouhi, Nita G %A Groves, Christopher J %A Hallmans, Goran %A Harris, Tamara %A Hofman, Albert %A Houston, Denise K %A Hu, Frank B %A Johansson, Ingegerd %A Kritchevsky, Stephen B %A Langenberg, Claudia %A Launer, Lenore %A Liu, Yongmei %A Loos, Ruth J %A Nalls, Michael %A Orho-Melander, Marju %A Renstrom, Frida %A Rice, Kenneth %A Riserus, Ulf %A Rolandsson, Olov %A Rotter, Jerome I %A Saylor, Georgia %A Sijbrands, Eric J G %A Sjogren, Per %A Smith, Albert %A Steingrímsdóttir, Laufey %A Uitterlinden, André G %A Wareham, Nicholas J %A Prokopenko, Inga %A Pankow, James S %A van Duijn, Cornelia M %A Florez, Jose C %A Witteman, Jacqueline C M %A Dupuis, Josée %A Dedoussis, George V %A Ordovas, Jose M %A Ingelsson, Erik %A Cupples, L Adrienne %A Siscovick, David S %A Franks, Paul W %A Meigs, James B %K Adult %K Aged %K Blood Glucose %K Edible Grain %K Fasting %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Humans %K Insulin %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K White People %XOBJECTIVE: Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin.
RESEARCH DESIGN AND METHODS: Via meta-analysis of data from 14 cohorts comprising ∼ 48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value <0.0028 (0.05 of 18 tests) as statistically significant.
RESULTS: Greater whole-grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (β [95% CI] per 1-serving-greater whole-grain intake: -0.009 mmol/l glucose [-0.013 to -0.005], P < 0.0001 and -0.011 pmol/l [ln] insulin [-0.015 to -0.007], P = 0.0003). No interactions met our multiple testing-adjusted statistical significance threshold. The strongest SNP interaction with whole-grain intake was rs780094 (GCKR) for fasting insulin (P = 0.006), where greater whole-grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele.
CONCLUSIONS: Our results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.
%B Diabetes Care %V 33 %P 2684-91 %8 2010 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/20693352?dopt=Abstract %R 10.2337/dc10-1150 %0 Journal Article %J Atherosclerosis %D 2007 %T Sequence variation in the soluble epoxide hydrolase gene and subclinical coronary atherosclerosis: interaction with cigarette smoking. %A Wei, Qi %A Doris, Peter A %A Pollizotto, Martin V %A Eric Boerwinkle %A Jacobs, David R %A Siscovick, David S %A Fornage, Myriam %K Adolescent %K Adult %K Black or African American %K Coronary Artery Disease %K Epoxide Hydrolases %K Female %K Gene Frequency %K Haplotypes %K Humans %K Linkage Disequilibrium %K Male %K Polymorphism, Single Nucleotide %K Prospective Studies %K Risk Factors %K Smoking %K Solubility %K White People %XSoluble epoxide hydrolase (EPHX2) catalyses the degradation of the vasoactive and anti-inflammatory epoxyeicosatrienoic acids and may play a role in the pathophysiology of atherosclerosis. 1337 African-Americans and 1645 Whites from the CARDIA study were genotyped for 22 and 15 EPHX2 single nucleotide polymorphisms (SNPs), respectively, to examine the associations of common EPHX2 haplotypes and genotypes with presence of coronary artery calcified plaque (CAC). The potential influence of cigarette smoking, which increases EPHX2 gene expression, on these associations was also assessed. In African-Americans, a common haplotype uniquely tagged by the R287Q polymorphism was associated with significantly greater risk for CAC (OR=1.7; 95% CI=1.04-3.0). In Whites, a common haplotype uniquely tagged by a polymorphism in Intron 11 of the gene was associated with significantly greater risk for CAC (OR=1.3; 95% CI=1.02-1.6). These haplotype-tagging polymorphisms also showed significant associations with CAC in individual SNP analyses, and these relationships were significantly modified by smoking. This detailed investigation of the association of EPHX2 genetic variation with CAC supports EPHX2's emerging role as a risk factor for atherosclerosis, whose effects are influenced by smoking.
%B Atherosclerosis %V 190 %P 26-34 %8 2007 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/16545818?dopt=Abstract %R 10.1016/j.atherosclerosis.2006.02.021 %0 Journal Article %J Eur J Cardiovasc Prev Rehabil %D 2004 %T Parental history of stroke and myocardial infarction predicts coronary artery calcification: The Coronary Artery Risk Development in Young Adults (CARDIA) study. %A Fornage, Myriam %A Lopez, David S %A Roseman, Jeffrey M %A Siscovick, David S %A Wong, Nathan D %A Eric Boerwinkle %K Adolescent %K Adult %K Black or African American %K Calcinosis %K Coronary Artery Disease %K Fathers %K Female %K Humans %K Male %K Mothers %K Myocardial Infarction %K Prospective Studies %K Stroke %K White People %XBACKGROUND: Few studies have examined the relationship between parental history of stroke and myocardial infarction (MI) and subclinical atherosclerosis, especially among young, asymptomatic individuals. This study investigates the association between coronary artery calcification (CAC) and parental history of stroke and MI in African-Americans and Caucasians from the CARDIA study.
METHODS: Parental history of stroke and MI was determined by self-administered family history questionnaire at baseline and Year 5 examinations. Presence of coronary calcification was determined by computed tomography on 3041 individuals, age 32 to 47, including 1375 African-Americans and 1666 Caucasians. Analyses were restricted to individuals free of clinically manifest coronary heart disease (CHD) and stroke.
RESULTS: Parental history of stroke is associated with a two-fold greater risk of CAC in African-Americans, and this relationship is independent from established CHD risk factors (95% CI=1.14-3.43). There is no relationship between parental history of stroke and CAC status in Caucasians. Parental history of MI is associated with a two-fold greater risk of CAC in Caucasians (95% CI=1.38-2.92). The impact of parental history of MI in African-Americans is lower (OR=1.65; 95% CI=1.01-2.69) and no longer statistically significant after adjusting for known CHD risk factors.
CONCLUSIONS: The identification of individuals with a parental history of stroke and MI provides important information for clinicians by which to target primary prevention efforts. Further characterization of familial factors, especially genetic factors, contributing to increased risk of CAC will shed light on the basis of the observed associations.
%B Eur J Cardiovasc Prev Rehabil %V 11 %P 421-6 %8 2004 Oct %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/15616417?dopt=Abstract %R 10.1097/01.hjr.0000129744.61087.b4 %0 Journal Article %J Circulation %D 2003 %T From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. %A Naghavi, Morteza %A Libby, Peter %A Falk, Erling %A Casscells, S Ward %A Litovsky, Silvio %A Rumberger, John %A Badimon, Juan Jose %A Stefanadis, Christodoulos %A Moreno, Pedro %A Pasterkamp, Gerard %A Fayad, Zahi %A Stone, Peter H %A Waxman, Sergio %A Raggi, Paolo %A Madjid, Mohammad %A Zarrabi, Alireza %A Burke, Allen %A Yuan, Chun %A Fitzgerald, Peter J %A Siscovick, David S %A de Korte, Chris L %A Aikawa, Masanori %A Juhani Airaksinen, K E %A Assmann, Gerd %A Becker, Christoph R %A Chesebro, James H %A Farb, Andrew %A Galis, Zorina S %A Jackson, Chris %A Jang, Ik-Kyung %A Koenig, Wolfgang %A Lodder, Robert A %A March, Keith %A Demirovic, Jasenka %A Navab, Mohamad %A Priori, Silvia G %A Rekhter, Mark D %A Bahr, Raymond %A Grundy, Scott M %A Mehran, Roxana %A Colombo, Antonio %A Eric Boerwinkle %A Ballantyne, Christie %A Insull, William %A Schwartz, Robert S %A Vogel, Robert %A Serruys, Patrick W %A Hansson, Goran K %A Faxon, David P %A Kaul, Sanjay %A Drexler, Helmut %A Greenland, Philip %A Muller, James E %A Virmani, Renu %A Ridker, Paul M %A Zipes, Douglas P %A Shah, Prediman K %A Willerson, James T %K Acute Disease %K Arteriosclerosis %K Consensus %K Coronary Disease %K Death, Sudden, Cardiac %K Disease Progression %K Humans %K Models, Cardiovascular %K Risk Assessment %K Syndrome %K Terminology as Topic %XAtherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document focuses on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.
%B Circulation %V 108 %P 1664-72 %8 2003 Oct 07 %G eng %N 14 %1 https://www.ncbi.nlm.nih.gov/pubmed/14530185?dopt=Abstract %R 10.1161/01.CIR.0000087480.94275.97 %0 Journal Article %J Circulation %D 2003 %T From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II. %A Naghavi, Morteza %A Libby, Peter %A Falk, Erling %A Casscells, S Ward %A Litovsky, Silvio %A Rumberger, John %A Badimon, Juan Jose %A Stefanadis, Christodoulos %A Moreno, Pedro %A Pasterkamp, Gerard %A Fayad, Zahi %A Stone, Peter H %A Waxman, Sergio %A Raggi, Paolo %A Madjid, Mohammad %A Zarrabi, Alireza %A Burke, Allen %A Yuan, Chun %A Fitzgerald, Peter J %A Siscovick, David S %A de Korte, Chris L %A Aikawa, Masanori %A Airaksinen, K E Juhani %A Assmann, Gerd %A Becker, Christoph R %A Chesebro, James H %A Farb, Andrew %A Galis, Zorina S %A Jackson, Chris %A Jang, Ik-Kyung %A Koenig, Wolfgang %A Lodder, Robert A %A March, Keith %A Demirovic, Jasenka %A Navab, Mohamad %A Priori, Silvia G %A Rekhter, Mark D %A Bahr, Raymond %A Grundy, Scott M %A Mehran, Roxana %A Colombo, Antonio %A Eric Boerwinkle %A Ballantyne, Christie %A Insull, William %A Schwartz, Robert S %A Vogel, Robert %A Serruys, Patrick W %A Hansson, Goran K %A Faxon, David P %A Kaul, Sanjay %A Drexler, Helmut %A Greenland, Philip %A Muller, James E %A Virmani, Renu %A Ridker, Paul M %A Zipes, Douglas P %A Shah, Prediman K %A Willerson, James T %K Animals %K Biomarkers %K Coronary Artery Disease %K Death, Sudden, Cardiac %K Disease Susceptibility %K Female %K Humans %K Male %K Mass Screening %K Myocardial Infarction %K Myocardium %K Risk Assessment %K Severity of Illness Index %K Swine %K Thrombophilia %XAtherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document will focus on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.
%B Circulation %V 108 %P 1772-8 %8 2003 Oct 14 %G eng %N 15 %1 https://www.ncbi.nlm.nih.gov/pubmed/14557340?dopt=Abstract %R 10.1161/01.CIR.0000087481.55887.C9