%0 Journal Article %J Arterioscler Thromb Vasc Biol %D 2002 %T In the elderly, interleukin-6 plasma levels and the -174G>C polymorphism are associated with the development of cardiovascular disease. %A Jenny, Nancy S %A Tracy, Russell P %A Ogg, Malcolm S %A Luong, Le Ahn %A Kuller, Lewis H %A Arnold, Alice M %A Sharrett, A Richey %A Humphries, Steve E %K Age Factors %K Aged %K Biomarkers %K Cardiovascular Diseases %K Case-Control Studies %K Cytosine %K Female %K Follow-Up Studies %K Genetic Predisposition to Disease %K Genotype %K Guanine %K Health Surveys %K Humans %K Inflammation %K Interleukin-6 %K Linear Models %K Male %K Polymorphism, Genetic %K Predictive Value of Tests %K Promoter Regions, Genetic %X

OBJECTIVE: Interleukin (IL)-6-mediated inflammation is involved in cardiovascular disease (CVD). We assessed IL-6 levels and the -174G>C genotype in a case-control study of men and women (average age 73 years) within the Cardiovascular Health Study.

METHODS AND RESULTS: Cases included incident angina, myocardial infarction (MI), and stroke (5-year follow-up), prevalent MI, and MRI-detectable infarcts. A control group and a group free of subclinical CVD were used for comparison. The -174C allele was associated with higher C-reactive protein (11% higher, P=0.02), fibrinogen (3% higher, P=0.02), and IL-6 (5% higher; P=0.16). IL-6 was associated with increased atherosclerosis when the control group was compared with the group free of subclinical CVD. No further association with CVD events was found when case groups were compared with the control group. Compared with its absence, presence of the -174C allele was associated with risk of MRI infarcts (odds ratio 1.5).

CONCLUSIONS: IL-6 levels differentiated those with subclinical CVD from those without. Although the -174C allele was not associated with incident events, associations of the genotype with inflammation and MRI infarcts, combined with the plasma IL-6 results, suggest that IL-6 may chronically predispose an individual to develop atherosclerosis.

%B Arterioscler Thromb Vasc Biol %V 22 %P 2066-71 %8 2002 Dec 01 %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/12482836?dopt=Abstract %R 10.1161/01.atv.0000040224.49362.60 %0 Journal Article %J Hum Mol Genet %D 2011 %T A gene-centric association scan for Coagulation Factor VII levels in European and African Americans: the Candidate Gene Association Resource (CARe) Consortium. %A Taylor, Kira C %A Lange, Leslie A %A Zabaneh, Delilah %A Lange, Ethan %A Keating, Brendan J %A Tang, Weihong %A Smith, Nicholas L %A Delaney, Joseph A %A Kumari, Meena %A Hingorani, Aroon %A North, Kari E %A Kivimaki, Mika %A Tracy, Russell P %A O'Donnell, Christopher J %A Folsom, Aaron R %A Green, David %A Humphries, Steve E %A Reiner, Alexander P %K Adult %K African Americans %K Aged %K Cardiovascular Diseases %K European Continental Ancestry Group %K Factor VII %K Female %K Genetic Predisposition to Disease %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X

Polymorphisms in several distinct genomic regions, including the F7 gene, were recently associated with factor VII (FVII) levels in European Americans (EAs). The genetic determinants of FVII in African Americans (AAs) are unknown. We used a 50,000 single nucleotide polymorphism (SNP) gene-centric array having dense coverage of over 2,000 candidate genes for cardiovascular disease (CVD) pathways in a community-based sample of 16,324 EA and 3898 AA participants from the Candidate Gene Association Resource (CARe) consortium. Our aim was the discovery of new genomic loci and more detailed characterization of existing loci associated with FVII levels. In EAs, we identified three new loci associated with FVII, of which APOA5 on chromosome 11q23 and HNF4A on chromosome 20q12-13 were replicated in a sample of 4289 participants from the Whitehall II study. We confirmed four previously reported FVII-associated loci (GCKR, MS4A6A, F7 and PROCR) in CARe EA samples. In AAs, the F7 and PROCR regions were significantly associated with FVII. Several of the FVII-associated regions are known to be associated with lipids and other cardiovascular-related traits. At the F7 locus, there was evidence of at least five independently associated SNPs in EAs and three independent signals in AAs. Though the variance in FVII explained by the existing loci is substantial (20% in EA and 10% in AA), larger sample sizes and investigation of lower frequency variants may be required to identify additional FVII-associated loci in EAs and AAs and further clarify the relationship between FVII and other CVD risk factors.

%B Hum Mol Genet %V 20 %P 3525-34 %8 2011 Sep 01 %G eng %N 17 %1 http://www.ncbi.nlm.nih.gov/pubmed/21676895?dopt=Abstract %R 10.1093/hmg/ddr264 %0 Journal Article %J Nature %D 2011 %T Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. %A Ehret, Georg B %A Munroe, Patricia B %A Rice, Kenneth M %A Bochud, Murielle %A Johnson, Andrew D %A Chasman, Daniel I %A Smith, Albert V %A Tobin, Martin D %A Verwoert, Germaine C %A Hwang, Shih-Jen %A Pihur, Vasyl %A Vollenweider, Peter %A O'Reilly, Paul F %A Amin, Najaf %A Bragg-Gresham, Jennifer L %A Teumer, Alexander %A Glazer, Nicole L %A Launer, Lenore %A Zhao, Jing Hua %A Aulchenko, Yurii %A Heath, Simon %A Sõber, Siim %A Parsa, Afshin %A Luan, Jian'an %A Arora, Pankaj %A Dehghan, Abbas %A Zhang, Feng %A Lucas, Gavin %A Hicks, Andrew A %A Jackson, Anne U %A Peden, John F %A Tanaka, Toshiko %A Wild, Sarah H %A Rudan, Igor %A Igl, Wilmar %A Milaneschi, Yuri %A Parker, Alex N %A Fava, Cristiano %A Chambers, John C %A Fox, Ervin R %A Kumari, Meena %A Go, Min Jin %A van der Harst, Pim %A Kao, Wen Hong Linda %A Sjögren, Marketa %A Vinay, D G %A Alexander, Myriam %A Tabara, Yasuharu %A Shaw-Hawkins, Sue %A Whincup, Peter H %A Liu, Yongmei %A Shi, Gang %A Kuusisto, Johanna %A Tayo, Bamidele %A Seielstad, Mark %A Sim, Xueling %A Nguyen, Khanh-Dung Hoang %A Lehtimäki, Terho %A Matullo, Giuseppe %A Wu, Ying %A Gaunt, Tom R %A Onland-Moret, N Charlotte %A Cooper, Matthew N %A Platou, Carl G P %A Org, Elin %A Hardy, Rebecca %A Dahgam, Santosh %A Palmen, Jutta %A Vitart, Veronique %A Braund, Peter S %A Kuznetsova, Tatiana %A Uiterwaal, Cuno S P M %A Adeyemo, Adebowale %A Palmas, Walter %A Campbell, Harry %A Ludwig, Barbara %A Tomaszewski, Maciej %A Tzoulaki, Ioanna %A Palmer, Nicholette D %A Aspelund, Thor %A Garcia, Melissa %A Chang, Yen-Pei C %A O'Connell, Jeffrey R %A Steinle, Nanette I %A Grobbee, Diederick E %A Arking, Dan E %A Kardia, Sharon L %A Morrison, Alanna C %A Hernandez, Dena %A Najjar, Samer %A McArdle, Wendy L %A Hadley, David %A Brown, Morris J %A Connell, John M %A Hingorani, Aroon D %A Day, Ian N M %A Lawlor, Debbie A %A Beilby, John P %A Lawrence, Robert W %A Clarke, Robert %A Hopewell, Jemma C %A Ongen, Halit %A Dreisbach, Albert W %A Li, Yali %A Young, J Hunter %A Bis, Joshua C %A Kähönen, Mika %A Viikari, Jorma %A Adair, Linda S %A Lee, Nanette R %A Chen, Ming-Huei %A Olden, Matthias %A Pattaro, Cristian %A Bolton, Judith A Hoffman %A Köttgen, Anna %A Bergmann, Sven %A Mooser, Vincent %A Chaturvedi, Nish %A Frayling, Timothy M %A Islam, Muhammad %A Jafar, Tazeen H %A Erdmann, Jeanette %A Kulkarni, Smita R %A Bornstein, Stefan R %A Grässler, Jürgen %A Groop, Leif %A Voight, Benjamin F %A Kettunen, Johannes %A Howard, Philip %A Taylor, Andrew %A Guarrera, Simonetta %A Ricceri, Fulvio %A Emilsson, Valur %A Plump, Andrew %A Barroso, Inês %A Khaw, Kay-Tee %A Weder, Alan B %A Hunt, Steven C %A Sun, Yan V %A Bergman, Richard N %A Collins, Francis S %A Bonnycastle, Lori L %A Scott, Laura J %A Stringham, Heather M %A Peltonen, Leena %A Perola, Markus %A Vartiainen, Erkki %A Brand, Stefan-Martin %A Staessen, Jan A %A Wang, Thomas J %A Burton, Paul R %A Soler Artigas, Maria %A Dong, Yanbin %A Snieder, Harold %A Wang, Xiaoling %A Zhu, Haidong %A Lohman, Kurt K %A Rudock, Megan E %A Heckbert, Susan R %A Smith, Nicholas L %A Wiggins, Kerri L %A Doumatey, Ayo %A Shriner, Daniel %A Veldre, Gudrun %A Viigimaa, Margus %A Kinra, Sanjay %A Prabhakaran, Dorairaj %A Tripathy, Vikal %A Langefeld, Carl D %A Rosengren, Annika %A Thelle, Dag S %A Corsi, Anna Maria %A Singleton, Andrew %A Forrester, Terrence %A Hilton, Gina %A McKenzie, Colin A %A Salako, Tunde %A Iwai, Naoharu %A Kita, Yoshikuni %A Ogihara, Toshio %A Ohkubo, Takayoshi %A Okamura, Tomonori %A Ueshima, Hirotsugu %A Umemura, Satoshi %A Eyheramendy, Susana %A Meitinger, Thomas %A Wichmann, H-Erich %A Cho, Yoon Shin %A Kim, Hyung-Lae %A Lee, Jong-Young %A Scott, James %A Sehmi, Joban S %A Zhang, Weihua %A Hedblad, Bo %A Nilsson, Peter %A Smith, George Davey %A Wong, Andrew %A Narisu, Narisu %A Stančáková, Alena %A Raffel, Leslie J %A Yao, Jie %A Kathiresan, Sekar %A O'Donnell, Christopher J %A Schwartz, Stephen M %A Ikram, M Arfan %A Longstreth, W T %A Mosley, Thomas H %A Seshadri, Sudha %A Shrine, Nick R G %A Wain, Louise V %A Morken, Mario A %A Swift, Amy J %A Laitinen, Jaana %A Prokopenko, Inga %A Zitting, Paavo %A Cooper, Jackie A %A Humphries, Steve E %A Danesh, John %A Rasheed, Asif %A Goel, Anuj %A Hamsten, Anders %A Watkins, Hugh %A Bakker, Stephan J L %A van Gilst, Wiek H %A Janipalli, Charles S %A Mani, K Radha %A Yajnik, Chittaranjan S %A Hofman, Albert %A Mattace-Raso, Francesco U S %A Oostra, Ben A %A Demirkan, Ayse %A Isaacs, Aaron %A Rivadeneira, Fernando %A Lakatta, Edward G %A Orrù, Marco %A Scuteri, Angelo %A Ala-Korpela, Mika %A Kangas, Antti J %A Lyytikäinen, Leo-Pekka %A Soininen, Pasi %A Tukiainen, Taru %A Würtz, Peter %A Ong, Rick Twee-Hee %A Dörr, Marcus %A Kroemer, Heyo K %A Völker, Uwe %A Völzke, Henry %A Galan, Pilar %A Hercberg, Serge %A Lathrop, Mark %A Zelenika, Diana %A Deloukas, Panos %A Mangino, Massimo %A Spector, Tim D %A Zhai, Guangju %A Meschia, James F %A Nalls, Michael A %A Sharma, Pankaj %A Terzic, Janos %A Kumar, M V Kranthi %A Denniff, Matthew %A Zukowska-Szczechowska, Ewa %A Wagenknecht, Lynne E %A Fowkes, F Gerald R %A Charchar, Fadi J %A Schwarz, Peter E H %A Hayward, Caroline %A Guo, Xiuqing %A Rotimi, Charles %A Bots, Michiel L %A Brand, Eva %A Samani, Nilesh J %A Polasek, Ozren %A Talmud, Philippa J %A Nyberg, Fredrik %A Kuh, Diana %A Laan, Maris %A Hveem, Kristian %A Palmer, Lyle J %A van der Schouw, Yvonne T %A Casas, Juan P %A Mohlke, Karen L %A Vineis, Paolo %A Raitakari, Olli %A Ganesh, Santhi K %A Wong, Tien Y %A Tai, E Shyong %A Cooper, Richard S %A Laakso, Markku %A Rao, Dabeeru C %A Harris, Tamara B %A Morris, Richard W %A Dominiczak, Anna F %A Kivimaki, Mika %A Marmot, Michael G %A Miki, Tetsuro %A Saleheen, Danish %A Chandak, Giriraj R %A Coresh, Josef %A Navis, Gerjan %A Salomaa, Veikko %A Han, Bok-Ghee %A Zhu, Xiaofeng %A Kooner, Jaspal S %A Melander, Olle %A Ridker, Paul M %A Bandinelli, Stefania %A Gyllensten, Ulf B %A Wright, Alan F %A Wilson, James F %A Ferrucci, Luigi %A Farrall, Martin %A Tuomilehto, Jaakko %A Pramstaller, Peter P %A Elosua, Roberto %A Soranzo, Nicole %A Sijbrands, Eric J G %A Altshuler, David %A Loos, Ruth J F %A Shuldiner, Alan R %A Gieger, Christian %A Meneton, Pierre %A Uitterlinden, André G %A Wareham, Nicholas J %A Gudnason, Vilmundur %A Rotter, Jerome I %A Rettig, Rainer %A Uda, Manuela %A Strachan, David P %A Witteman, Jacqueline C M %A Hartikainen, Anna-Liisa %A Beckmann, Jacques S %A Boerwinkle, Eric %A Vasan, Ramachandran S %A Boehnke, Michael %A Larson, Martin G %A Jarvelin, Marjo-Riitta %A Psaty, Bruce M %A Abecasis, Goncalo R %A Chakravarti, Aravinda %A Elliott, Paul %A van Duijn, Cornelia M %A Newton-Cheh, Christopher %A Levy, Daniel %A Caulfield, Mark J %A Johnson, Toby %K Africa %K Asia %K Blood Pressure %K Cardiovascular Diseases %K Coronary Artery Disease %K Europe %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Hypertension %K Kidney Diseases %K Polymorphism, Single Nucleotide %K Stroke %X

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

%B Nature %V 478 %P 103-9 %8 2011 Sep 11 %G eng %N 7367 %1 http://www.ncbi.nlm.nih.gov/pubmed/21909115?dopt=Abstract %R 10.1038/nature10405 %0 Journal Article %J Nat Genet %D 2011 %T Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. %A Kilpeläinen, Tuomas O %A Zillikens, M Carola %A Stančáková, Alena %A Finucane, Francis M %A Ried, Janina S %A Langenberg, Claudia %A Zhang, Weihua %A Beckmann, Jacques S %A Luan, Jian'an %A Vandenput, Liesbeth %A Styrkarsdottir, Unnur %A Zhou, Yanhua %A Smith, Albert Vernon %A Zhao, Jing-Hua %A Amin, Najaf %A Vedantam, Sailaja %A Shin, So-Youn %A Haritunians, Talin %A Fu, Mao %A Feitosa, Mary F %A Kumari, Meena %A Halldorsson, Bjarni V %A Tikkanen, Emmi %A Mangino, Massimo %A Hayward, Caroline %A Song, Ci %A Arnold, Alice M %A Aulchenko, Yurii S %A Oostra, Ben A %A Campbell, Harry %A Cupples, L Adrienne %A Davis, Kathryn E %A Döring, Angela %A Eiriksdottir, Gudny %A Estrada, Karol %A Fernández-Real, José Manuel %A Garcia, Melissa %A Gieger, Christian %A Glazer, Nicole L %A Guiducci, Candace %A Hofman, Albert %A Humphries, Steve E %A Isomaa, Bo %A Jacobs, Leonie C %A Jula, Antti %A Karasik, David %A Karlsson, Magnus K %A Khaw, Kay-Tee %A Kim, Lauren J %A Kivimaki, Mika %A Klopp, Norman %A Kuhnel, Brigitte %A Kuusisto, Johanna %A Liu, Yongmei %A Ljunggren, Osten %A Lorentzon, Mattias %A Luben, Robert N %A McKnight, Barbara %A Mellström, Dan %A Mitchell, Braxton D %A Mooser, Vincent %A Moreno, José Maria %A Männistö, Satu %A O'Connell, Jeffery R %A Pascoe, Laura %A Peltonen, Leena %A Peral, Belén %A Perola, Markus %A Psaty, Bruce M %A Salomaa, Veikko %A Savage, David B %A Semple, Robert K %A Skaric-Juric, Tatjana %A Sigurdsson, Gunnar %A Song, Kijoung S %A Spector, Timothy D %A Syvänen, Ann-Christine %A Talmud, Philippa J %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Uitterlinden, André G %A van Duijn, Cornelia M %A Vidal-Puig, Antonio %A Wild, Sarah H %A Wright, Alan F %A Clegg, Deborah J %A Schadt, Eric %A Wilson, James F %A Rudan, Igor %A Ripatti, Samuli %A Borecki, Ingrid B %A Shuldiner, Alan R %A Ingelsson, Erik %A Jansson, John-Olov %A Kaplan, Robert C %A Gudnason, Vilmundur %A Harris, Tamara B %A Groop, Leif %A Kiel, Douglas P %A Rivadeneira, Fernando %A Walker, Mark %A Barroso, Inês %A Vollenweider, Peter %A Waeber, Gérard %A Chambers, John C %A Kooner, Jaspal S %A Soranzo, Nicole %A Hirschhorn, Joel N %A Stefansson, Kari %A Wichmann, H-Erich %A Ohlsson, Claes %A O'Rahilly, Stephen %A Wareham, Nicholas J %A Speliotes, Elizabeth K %A Fox, Caroline S %A Laakso, Markku %A Loos, Ruth J F %K Adiponectin %K Adiposity %K Alleles %K Body Fat Distribution %K Body Mass Index %K Body Weight %K Female %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Insulin Receptor Substrate Proteins %K Intracellular Signaling Peptides and Proteins %K Male %K Membrane Proteins %K Meta-Analysis as Topic %K Metabolome %K Obesity %K Polymorphism, Single Nucleotide %K Subcutaneous Fat %X

Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ∼2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.

%B Nat Genet %V 43 %P 753-60 %8 2011 Jun 26 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/21706003?dopt=Abstract %R 10.1038/ng.866 %0 Journal Article %J Nat Genet %D 2013 %T Common variants associated with plasma triglycerides and risk for coronary artery disease. %A Do, Ron %A Willer, Cristen J %A Schmidt, Ellen M %A Sengupta, Sebanti %A Gao, Chi %A Peloso, Gina M %A Gustafsson, Stefan %A Kanoni, Stavroula %A Ganna, Andrea %A Chen, Jin %A Buchkovich, Martin L %A Mora, Samia %A Beckmann, Jacques S %A Bragg-Gresham, Jennifer L %A Chang, Hsing-Yi %A Demirkan, Ayse %A Den Hertog, Heleen M %A Donnelly, Louise A %A Ehret, Georg B %A Esko, Tõnu %A Feitosa, Mary F %A Ferreira, Teresa %A Fischer, Krista %A Fontanillas, Pierre %A Fraser, Ross M %A Freitag, Daniel F %A Gurdasani, Deepti %A Heikkilä, Kauko %A Hyppönen, Elina %A Isaacs, Aaron %A Jackson, Anne U %A Johansson, Asa %A Johnson, Toby %A Kaakinen, Marika %A Kettunen, Johannes %A Kleber, Marcus E %A Li, Xiaohui %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A Magnusson, Patrik K E %A Mangino, Massimo %A Mihailov, Evelin %A Montasser, May E %A Müller-Nurasyid, Martina %A Nolte, Ilja M %A O'Connell, Jeffrey R %A Palmer, Cameron D %A Perola, Markus %A Petersen, Ann-Kristin %A Sanna, Serena %A Saxena, Richa %A Service, Susan K %A Shah, Sonia %A Shungin, Dmitry %A Sidore, Carlo %A Song, Ci %A Strawbridge, Rona J %A Surakka, Ida %A Tanaka, Toshiko %A Teslovich, Tanya M %A Thorleifsson, Gudmar %A van den Herik, Evita G %A Voight, Benjamin F %A Volcik, Kelly A %A Waite, Lindsay L %A Wong, Andrew %A Wu, Ying %A Zhang, Weihua %A Absher, Devin %A Asiki, Gershim %A Barroso, Inês %A Been, Latonya F %A Bolton, Jennifer L %A Bonnycastle, Lori L %A Brambilla, Paolo %A Burnett, Mary S %A Cesana, Giancarlo %A Dimitriou, Maria %A Doney, Alex S F %A Döring, Angela %A Elliott, Paul %A Epstein, Stephen E %A Eyjolfsson, Gudmundur Ingi %A Gigante, Bruna %A Goodarzi, Mark O %A Grallert, Harald %A Gravito, Martha L %A Groves, Christopher J %A Hallmans, Göran %A Hartikainen, Anna-Liisa %A Hayward, Caroline %A Hernandez, Dena %A Hicks, Andrew A %A Holm, Hilma %A Hung, Yi-Jen %A Illig, Thomas %A Jones, Michelle R %A Kaleebu, Pontiano %A Kastelein, John J P %A Khaw, Kay-Tee %A Kim, Eric %A Klopp, Norman %A Komulainen, Pirjo %A Kumari, Meena %A Langenberg, Claudia %A Lehtimäki, Terho %A Lin, Shih-Yi %A Lindström, Jaana %A Loos, Ruth J F %A Mach, François %A McArdle, Wendy L %A Meisinger, Christa %A Mitchell, Braxton D %A Müller, Gabrielle %A Nagaraja, Ramaiah %A Narisu, Narisu %A Nieminen, Tuomo V M %A Nsubuga, Rebecca N %A Olafsson, Isleifur %A Ong, Ken K %A Palotie, Aarno %A Papamarkou, Theodore %A Pomilla, Cristina %A Pouta, Anneli %A Rader, Daniel J %A Reilly, Muredach P %A Ridker, Paul M %A Rivadeneira, Fernando %A Rudan, Igor %A Ruokonen, Aimo %A Samani, Nilesh %A Scharnagl, Hubert %A Seeley, Janet %A Silander, Kaisa %A Stančáková, Alena %A Stirrups, Kathleen %A Swift, Amy J %A Tiret, Laurence %A Uitterlinden, André G %A van Pelt, L Joost %A Vedantam, Sailaja %A Wainwright, Nicholas %A Wijmenga, Cisca %A Wild, Sarah H %A Willemsen, Gonneke %A Wilsgaard, Tom %A Wilson, James F %A Young, Elizabeth H %A Zhao, Jing Hua %A Adair, Linda S %A Arveiler, Dominique %A Assimes, Themistocles L %A Bandinelli, Stefania %A Bennett, Franklyn %A Bochud, Murielle %A Boehm, Bernhard O %A Boomsma, Dorret I %A Borecki, Ingrid B %A Bornstein, Stefan R %A Bovet, Pascal %A Burnier, Michel %A Campbell, Harry %A Chakravarti, Aravinda %A Chambers, John C %A Chen, Yii-Der Ida %A Collins, Francis S %A Cooper, Richard S %A Danesh, John %A Dedoussis, George %A de Faire, Ulf %A Feranil, Alan B %A Ferrieres, Jean %A Ferrucci, Luigi %A Freimer, Nelson B %A Gieger, Christian %A Groop, Leif C %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Hamsten, Anders %A Harris, Tamara B %A Hingorani, Aroon %A Hirschhorn, Joel N %A Hofman, Albert %A Hovingh, G Kees %A Hsiung, Chao Agnes %A Humphries, Steve E %A Hunt, Steven C %A Hveem, Kristian %A Iribarren, Carlos %A Jarvelin, Marjo-Riitta %A Jula, Antti %A Kähönen, Mika %A Kaprio, Jaakko %A Kesäniemi, Antero %A Kivimaki, Mika %A Kooner, Jaspal S %A Koudstaal, Peter J %A Krauss, Ronald M %A Kuh, Diana %A Kuusisto, Johanna %A Kyvik, Kirsten O %A Laakso, Markku %A Lakka, Timo A %A Lind, Lars %A Lindgren, Cecilia M %A Martin, Nicholas G %A März, Winfried %A McCarthy, Mark I %A McKenzie, Colin A %A Meneton, Pierre %A Metspalu, Andres %A Moilanen, Leena %A Morris, Andrew D %A Munroe, Patricia B %A Njølstad, Inger %A Pedersen, Nancy L %A Power, Chris %A Pramstaller, Peter P %A Price, Jackie F %A Psaty, Bruce M %A Quertermous, Thomas %A Rauramaa, Rainer %A Saleheen, Danish %A Salomaa, Veikko %A Sanghera, Dharambir K %A Saramies, Jouko %A Schwarz, Peter E H %A Sheu, Wayne H-H %A Shuldiner, Alan R %A Siegbahn, Agneta %A Spector, Tim D %A Stefansson, Kari %A Strachan, David P %A Tayo, Bamidele O %A Tremoli, Elena %A Tuomilehto, Jaakko %A Uusitupa, Matti %A van Duijn, Cornelia M %A Vollenweider, Peter %A Wallentin, Lars %A Wareham, Nicholas J %A Whitfield, John B %A Wolffenbuttel, Bruce H R %A Altshuler, David %A Ordovas, Jose M %A Boerwinkle, Eric %A Palmer, Colin N A %A Thorsteinsdottir, Unnur %A Chasman, Daniel I %A Rotter, Jerome I %A Franks, Paul W %A Ripatti, Samuli %A Cupples, L Adrienne %A Sandhu, Manjinder S %A Rich, Stephen S %A Boehnke, Michael %A Deloukas, Panos %A Mohlke, Karen L %A Ingelsson, Erik %A Abecasis, Goncalo R %A Daly, Mark J %A Neale, Benjamin M %A Kathiresan, Sekar %K Biological Transport %K Cholesterol, HDL %K Cholesterol, LDL %K Coronary Artery Disease %K Humans %K Polymorphism, Single Nucleotide %K Risk Factors %K Triglycerides %X

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

%B Nat Genet %V 45 %P 1345-52 %8 2013 Nov %G eng %N 11 %R 10.1038/ng.2795 %0 Journal Article %J Nat Genet %D 2013 %T Discovery and refinement of loci associated with lipid levels. %A Willer, Cristen J %A Schmidt, Ellen M %A Sengupta, Sebanti %A Peloso, Gina M %A Gustafsson, Stefan %A Kanoni, Stavroula %A Ganna, Andrea %A Chen, Jin %A Buchkovich, Martin L %A Mora, Samia %A Beckmann, Jacques S %A Bragg-Gresham, Jennifer L %A Chang, Hsing-Yi %A Demirkan, Ayse %A Den Hertog, Heleen M %A Do, Ron %A Donnelly, Louise A %A Ehret, Georg B %A Esko, Tõnu %A Feitosa, Mary F %A Ferreira, Teresa %A Fischer, Krista %A Fontanillas, Pierre %A Fraser, Ross M %A Freitag, Daniel F %A Gurdasani, Deepti %A Heikkilä, Kauko %A Hyppönen, Elina %A Isaacs, Aaron %A Jackson, Anne U %A Johansson, Asa %A Johnson, Toby %A Kaakinen, Marika %A Kettunen, Johannes %A Kleber, Marcus E %A Li, Xiaohui %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A Magnusson, Patrik K E %A Mangino, Massimo %A Mihailov, Evelin %A Montasser, May E %A Müller-Nurasyid, Martina %A Nolte, Ilja M %A O'Connell, Jeffrey R %A Palmer, Cameron D %A Perola, Markus %A Petersen, Ann-Kristin %A Sanna, Serena %A Saxena, Richa %A Service, Susan K %A Shah, Sonia %A Shungin, Dmitry %A Sidore, Carlo %A Song, Ci %A Strawbridge, Rona J %A Surakka, Ida %A Tanaka, Toshiko %A Teslovich, Tanya M %A Thorleifsson, Gudmar %A van den Herik, Evita G %A Voight, Benjamin F %A Volcik, Kelly A %A Waite, Lindsay L %A Wong, Andrew %A Wu, Ying %A Zhang, Weihua %A Absher, Devin %A Asiki, Gershim %A Barroso, Inês %A Been, Latonya F %A Bolton, Jennifer L %A Bonnycastle, Lori L %A Brambilla, Paolo %A Burnett, Mary S %A Cesana, Giancarlo %A Dimitriou, Maria %A Doney, Alex S F %A Döring, Angela %A Elliott, Paul %A Epstein, Stephen E %A Ingi Eyjolfsson, Gudmundur %A Gigante, Bruna %A Goodarzi, Mark O %A Grallert, Harald %A Gravito, Martha L %A Groves, Christopher J %A Hallmans, Göran %A Hartikainen, Anna-Liisa %A Hayward, Caroline %A Hernandez, Dena %A Hicks, Andrew A %A Holm, Hilma %A Hung, Yi-Jen %A Illig, Thomas %A Jones, Michelle R %A Kaleebu, Pontiano %A Kastelein, John J P %A Khaw, Kay-Tee %A Kim, Eric %A Klopp, Norman %A Komulainen, Pirjo %A Kumari, Meena %A Langenberg, Claudia %A Lehtimäki, Terho %A Lin, Shih-Yi %A Lindström, Jaana %A Loos, Ruth J F %A Mach, François %A McArdle, Wendy L %A Meisinger, Christa %A Mitchell, Braxton D %A Müller, Gabrielle %A Nagaraja, Ramaiah %A Narisu, Narisu %A Nieminen, Tuomo V M %A Nsubuga, Rebecca N %A Olafsson, Isleifur %A Ong, Ken K %A Palotie, Aarno %A Papamarkou, Theodore %A Pomilla, Cristina %A Pouta, Anneli %A Rader, Daniel J %A Reilly, Muredach P %A Ridker, Paul M %A Rivadeneira, Fernando %A Rudan, Igor %A Ruokonen, Aimo %A Samani, Nilesh %A Scharnagl, Hubert %A Seeley, Janet %A Silander, Kaisa %A Stančáková, Alena %A Stirrups, Kathleen %A Swift, Amy J %A Tiret, Laurence %A Uitterlinden, André G %A van Pelt, L Joost %A Vedantam, Sailaja %A Wainwright, Nicholas %A Wijmenga, Cisca %A Wild, Sarah H %A Willemsen, Gonneke %A Wilsgaard, Tom %A Wilson, James F %A Young, Elizabeth H %A Zhao, Jing Hua %A Adair, Linda S %A Arveiler, Dominique %A Assimes, Themistocles L %A Bandinelli, Stefania %A Bennett, Franklyn %A Bochud, Murielle %A Boehm, Bernhard O %A Boomsma, Dorret I %A Borecki, Ingrid B %A Bornstein, Stefan R %A Bovet, Pascal %A Burnier, Michel %A Campbell, Harry %A Chakravarti, Aravinda %A Chambers, John C %A Chen, Yii-Der Ida %A Collins, Francis S %A Cooper, Richard S %A Danesh, John %A Dedoussis, George %A de Faire, Ulf %A Feranil, Alan B %A Ferrieres, Jean %A Ferrucci, Luigi %A Freimer, Nelson B %A Gieger, Christian %A Groop, Leif C %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Hamsten, Anders %A Harris, Tamara B %A Hingorani, Aroon %A Hirschhorn, Joel N %A Hofman, Albert %A Hovingh, G Kees %A Hsiung, Chao Agnes %A Humphries, Steve E %A Hunt, Steven C %A Hveem, Kristian %A Iribarren, Carlos %A Jarvelin, Marjo-Riitta %A Jula, Antti %A Kähönen, Mika %A Kaprio, Jaakko %A Kesäniemi, Antero %A Kivimaki, Mika %A Kooner, Jaspal S %A Koudstaal, Peter J %A Krauss, Ronald M %A Kuh, Diana %A Kuusisto, Johanna %A Kyvik, Kirsten O %A Laakso, Markku %A Lakka, Timo A %A Lind, Lars %A Lindgren, Cecilia M %A Martin, Nicholas G %A März, Winfried %A McCarthy, Mark I %A McKenzie, Colin A %A Meneton, Pierre %A Metspalu, Andres %A Moilanen, Leena %A Morris, Andrew D %A Munroe, Patricia B %A Njølstad, Inger %A Pedersen, Nancy L %A Power, Chris %A Pramstaller, Peter P %A Price, Jackie F %A Psaty, Bruce M %A Quertermous, Thomas %A Rauramaa, Rainer %A Saleheen, Danish %A Salomaa, Veikko %A Sanghera, Dharambir K %A Saramies, Jouko %A Schwarz, Peter E H %A Sheu, Wayne H-H %A Shuldiner, Alan R %A Siegbahn, Agneta %A Spector, Tim D %A Stefansson, Kari %A Strachan, David P %A Tayo, Bamidele O %A Tremoli, Elena %A Tuomilehto, Jaakko %A Uusitupa, Matti %A van Duijn, Cornelia M %A Vollenweider, Peter %A Wallentin, Lars %A Wareham, Nicholas J %A Whitfield, John B %A Wolffenbuttel, Bruce H R %A Ordovas, Jose M %A Boerwinkle, Eric %A Palmer, Colin N A %A Thorsteinsdottir, Unnur %A Chasman, Daniel I %A Rotter, Jerome I %A Franks, Paul W %A Ripatti, Samuli %A Cupples, L Adrienne %A Sandhu, Manjinder S %A Rich, Stephen S %A Boehnke, Michael %A Deloukas, Panos %A Kathiresan, Sekar %A Mohlke, Karen L %A Ingelsson, Erik %A Abecasis, Goncalo R %K African Continental Ancestry Group %K Asian Continental Ancestry Group %K Cholesterol, HDL %K Cholesterol, LDL %K Coronary Artery Disease %K European Continental Ancestry Group %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Lipids %K Triglycerides %X

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.

%B Nat Genet %V 45 %P 1274-1283 %8 2013 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/24097068?dopt=Abstract %R 10.1038/ng.2797 %0 Journal Article %J PLoS Genet %D 2013 %T Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits. %A Randall, Joshua C %A Winkler, Thomas W %A Kutalik, Zoltán %A Berndt, Sonja I %A Jackson, Anne U %A Monda, Keri L %A Kilpeläinen, Tuomas O %A Esko, Tõnu %A Mägi, Reedik %A Li, Shengxu %A Workalemahu, Tsegaselassie %A Feitosa, Mary F %A Croteau-Chonka, Damien C %A Day, Felix R %A Fall, Tove %A Ferreira, Teresa %A Gustafsson, Stefan %A Locke, Adam E %A Mathieson, Iain %A Scherag, Andre %A Vedantam, Sailaja %A Wood, Andrew R %A Liang, Liming %A Steinthorsdottir, Valgerdur %A Thorleifsson, Gudmar %A Dermitzakis, Emmanouil T %A Dimas, Antigone S %A Karpe, Fredrik %A Min, Josine L %A Nicholson, George %A Clegg, Deborah J %A Person, Thomas %A Krohn, Jon P %A Bauer, Sabrina %A Buechler, Christa %A Eisinger, Kristina %A Bonnefond, Amélie %A Froguel, Philippe %A Hottenga, Jouke-Jan %A Prokopenko, Inga %A Waite, Lindsay L %A Harris, Tamara B %A Smith, Albert Vernon %A Shuldiner, Alan R %A McArdle, Wendy L %A Caulfield, Mark J %A Munroe, Patricia B %A Grönberg, Henrik %A Chen, Yii-Der Ida %A Li, Guo %A Beckmann, Jacques S %A Johnson, Toby %A Thorsteinsdottir, Unnur %A Teder-Laving, Maris %A Khaw, Kay-Tee %A Wareham, Nicholas J %A Zhao, Jing Hua %A Amin, Najaf %A Oostra, Ben A %A Kraja, Aldi T %A Province, Michael A %A Cupples, L Adrienne %A Heard-Costa, Nancy L %A Kaprio, Jaakko %A Ripatti, Samuli %A Surakka, Ida %A Collins, Francis S %A Saramies, Jouko %A Tuomilehto, Jaakko %A Jula, Antti %A Salomaa, Veikko %A Erdmann, Jeanette %A Hengstenberg, Christian %A Loley, Christina %A Schunkert, Heribert %A Lamina, Claudia %A Wichmann, H Erich %A Albrecht, Eva %A Gieger, Christian %A Hicks, Andrew A %A Johansson, Asa %A Pramstaller, Peter P %A Kathiresan, Sekar %A Speliotes, Elizabeth K %A Penninx, Brenda %A Hartikainen, Anna-Liisa %A Jarvelin, Marjo-Riitta %A Gyllensten, Ulf %A Boomsma, Dorret I %A Campbell, Harry %A Wilson, James F %A Chanock, Stephen J %A Farrall, Martin %A Goel, Anuj %A Medina-Gómez, Carolina %A Rivadeneira, Fernando %A Estrada, Karol %A Uitterlinden, André G %A Hofman, Albert %A Zillikens, M Carola %A den Heijer, Martin %A Kiemeney, Lambertus A %A Maschio, Andrea %A Hall, Per %A Tyrer, Jonathan %A Teumer, Alexander %A Völzke, Henry %A Kovacs, Peter %A Tönjes, Anke %A Mangino, Massimo %A Spector, Tim D %A Hayward, Caroline %A Rudan, Igor %A Hall, Alistair S %A Samani, Nilesh J %A Attwood, Antony Paul %A Sambrook, Jennifer G %A Hung, Joseph %A Palmer, Lyle J %A Lokki, Marja-Liisa %A Sinisalo, Juha %A Boucher, Gabrielle %A Huikuri, Heikki %A Lorentzon, Mattias %A Ohlsson, Claes %A Eklund, Niina %A Eriksson, Johan G %A Barlassina, Cristina %A Rivolta, Carlo %A Nolte, Ilja M %A Snieder, Harold %A van der Klauw, Melanie M %A van Vliet-Ostaptchouk, Jana V %A Gejman, Pablo V %A Shi, Jianxin %A Jacobs, Kevin B %A Wang, Zhaoming %A Bakker, Stephan J L %A Mateo Leach, Irene %A Navis, Gerjan %A van der Harst, Pim %A Martin, Nicholas G %A Medland, Sarah E %A Montgomery, Grant W %A Yang, Jian %A Chasman, Daniel I %A Ridker, Paul M %A Rose, Lynda M %A Lehtimäki, Terho %A Raitakari, Olli %A Absher, Devin %A Iribarren, Carlos %A Basart, Hanneke %A Hovingh, Kees G %A Hyppönen, Elina %A Power, Chris %A Anderson, Denise %A Beilby, John P %A Hui, Jennie %A Jolley, Jennifer %A Sager, Hendrik %A Bornstein, Stefan R %A Schwarz, Peter E H %A Kristiansson, Kati %A Perola, Markus %A Lindström, Jaana %A Swift, Amy J %A Uusitupa, Matti %A Atalay, Mustafa %A Lakka, Timo A %A Rauramaa, Rainer %A Bolton, Jennifer L %A Fowkes, Gerry %A Fraser, Ross M %A Price, Jackie F %A Fischer, Krista %A Krjutå Kov, Kaarel %A Metspalu, Andres %A Mihailov, Evelin %A Langenberg, Claudia %A Luan, Jian'an %A Ong, Ken K %A Chines, Peter S %A Keinanen-Kiukaanniemi, Sirkka M %A Saaristo, Timo E %A Edkins, Sarah %A Franks, Paul W %A Hallmans, Göran %A Shungin, Dmitry %A Morris, Andrew David %A Palmer, Colin N A %A Erbel, Raimund %A Moebus, Susanne %A Nöthen, Markus M %A Pechlivanis, Sonali %A Hveem, Kristian %A Narisu, Narisu %A Hamsten, Anders %A Humphries, Steve E %A Strawbridge, Rona J %A Tremoli, Elena %A Grallert, Harald %A Thorand, Barbara %A Illig, Thomas %A Koenig, Wolfgang %A Müller-Nurasyid, Martina %A Peters, Annette %A Boehm, Bernhard O %A Kleber, Marcus E %A März, Winfried %A Winkelmann, Bernhard R %A Kuusisto, Johanna %A Laakso, Markku %A Arveiler, Dominique %A Cesana, Giancarlo %A Kuulasmaa, Kari %A Virtamo, Jarmo %A Yarnell, John W G %A Kuh, Diana %A Wong, Andrew %A Lind, Lars %A de Faire, Ulf %A Gigante, Bruna %A Magnusson, Patrik K E %A Pedersen, Nancy L %A Dedoussis, George %A Dimitriou, Maria %A Kolovou, Genovefa %A Kanoni, Stavroula %A Stirrups, Kathleen %A Bonnycastle, Lori L %A Njølstad, Inger %A Wilsgaard, Tom %A Ganna, Andrea %A Rehnberg, Emil %A Hingorani, Aroon %A Kivimaki, Mika %A Kumari, Meena %A Assimes, Themistocles L %A Barroso, Inês %A Boehnke, Michael %A Borecki, Ingrid B %A Deloukas, Panos %A Fox, Caroline S %A Frayling, Timothy %A Groop, Leif C %A Haritunians, Talin %A Hunter, David %A Ingelsson, Erik %A Kaplan, Robert %A Mohlke, Karen L %A O'Connell, Jeffrey R %A Schlessinger, David %A Strachan, David P %A Stefansson, Kari %A van Duijn, Cornelia M %A Abecasis, Goncalo R %A McCarthy, Mark I %A Hirschhorn, Joel N %A Qi, Lu %A Loos, Ruth J F %A Lindgren, Cecilia M %A North, Kari E %A Heid, Iris M %K Anthropometry %K Body Height %K Body Mass Index %K Body Weight %K Body Weights and Measures %K Female %K Genetic Loci %K Genome, Human %K Genome-Wide Association Study %K Humans %K Male %K Polymorphism, Single Nucleotide %K Sex Characteristics %K Waist Circumference %K Waist-Hip Ratio %X

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

%B PLoS Genet %V 9 %P e1003500 %8 2013 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23754948?dopt=Abstract %R 10.1371/journal.pgen.1003500 %0 Journal Article %J BMJ %D 2014 %T Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data. %A Holmes, Michael V %A Dale, Caroline E %A Zuccolo, Luisa %A Silverwood, Richard J %A Guo, Yiran %A Ye, Zheng %A Prieto-Merino, David %A Dehghan, Abbas %A Trompet, Stella %A Wong, Andrew %A Cavadino, Alana %A Drogan, Dagmar %A Padmanabhan, Sandosh %A Li, Shanshan %A Yesupriya, Ajay %A Leusink, Maarten %A Sundström, Johan %A Hubacek, Jaroslav A %A Pikhart, Hynek %A Swerdlow, Daniel I %A Panayiotou, Andrie G %A Borinskaya, Svetlana A %A Finan, Chris %A Shah, Sonia %A Kuchenbaecker, Karoline B %A Shah, Tina %A Engmann, Jorgen %A Folkersen, Lasse %A Eriksson, Per %A Ricceri, Fulvio %A Melander, Olle %A Sacerdote, Carlotta %A Gamble, Dale M %A Rayaprolu, Sruti %A Ross, Owen A %A McLachlan, Stela %A Vikhireva, Olga %A Sluijs, Ivonne %A Scott, Robert A %A Adamkova, Vera %A Flicker, Leon %A Bockxmeer, Frank M van %A Power, Christine %A Marques-Vidal, Pedro %A Meade, Tom %A Marmot, Michael G %A Ferro, Jose M %A Paulos-Pinheiro, Sofia %A Humphries, Steve E %A Talmud, Philippa J %A Mateo Leach, Irene %A Verweij, Niek %A Linneberg, Allan %A Skaaby, Tea %A Doevendans, Pieter A %A Cramer, Maarten J %A van der Harst, Pim %A Klungel, Olaf H %A Dowling, Nicole F %A Dominiczak, Anna F %A Kumari, Meena %A Nicolaides, Andrew N %A Weikert, Cornelia %A Boeing, Heiner %A Ebrahim, Shah %A Gaunt, Tom R %A Price, Jackie F %A Lannfelt, Lars %A Peasey, Anne %A Kubinova, Ruzena %A Pajak, Andrzej %A Malyutina, Sofia %A Voevoda, Mikhail I %A Tamosiunas, Abdonas %A Maitland-van der Zee, Anke H %A Norman, Paul E %A Hankey, Graeme J %A Bergmann, Manuela M %A Hofman, Albert %A Franco, Oscar H %A Cooper, Jackie %A Palmen, Jutta %A Spiering, Wilko %A de Jong, Pim A %A Kuh, Diana %A Hardy, Rebecca %A Uitterlinden, André G %A Ikram, M Arfan %A Ford, Ian %A Hyppönen, Elina %A Almeida, Osvaldo P %A Wareham, Nicholas J %A Khaw, Kay-Tee %A Hamsten, Anders %A Husemoen, Lise Lotte N %A Tjønneland, Anne %A Tolstrup, Janne S %A Rimm, Eric %A Beulens, Joline W J %A Verschuren, W M Monique %A Onland-Moret, N Charlotte %A Hofker, Marten H %A Wannamethee, S Goya %A Whincup, Peter H %A Morris, Richard %A Vicente, Astrid M %A Watkins, Hugh %A Farrall, Martin %A Jukema, J Wouter %A Meschia, James %A Cupples, L Adrienne %A Sharp, Stephen J %A Fornage, Myriam %A Kooperberg, Charles %A LaCroix, Andrea Z %A Dai, James Y %A Lanktree, Matthew B %A Siscovick, David S %A Jorgenson, Eric %A Spring, Bonnie %A Coresh, Josef %A Li, Yun R %A Buxbaum, Sarah G %A Schreiner, Pamela J %A Ellison, R Curtis %A Tsai, Michael Y %A Patel, Sanjay R %A Redline, Susan %A Johnson, Andrew D %A Hoogeveen, Ron C %A Hakonarson, Hakon %A Rotter, Jerome I %A Boerwinkle, Eric %A de Bakker, Paul I W %A Kivimaki, Mika %A Asselbergs, Folkert W %A Sattar, Naveed %A Lawlor, Debbie A %A Whittaker, John %A Davey Smith, George %A Mukamal, Kenneth %A Psaty, Bruce M %A Wilson, James G %A Lange, Leslie A %A Hamidovic, Ajna %A Hingorani, Aroon D %A Nordestgaard, Børge G %A Bobak, Martin %A Leon, David A %A Langenberg, Claudia %A Palmer, Tom M %A Reiner, Alex P %A Keating, Brendan J %A Dudbridge, Frank %A Casas, Juan P %K Adult %K Aged %K Alcohol Dehydrogenase %K Alcohol Drinking %K Biomarkers %K Coronary Disease %K Female %K Genetic Markers %K Genotype %K Humans %K Male %K Mendelian Randomization Analysis %K Middle Aged %K Models, Statistical %K Polymorphism, Single Nucleotide %K Stroke %X

OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease.

DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies.

PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers.

MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption.

RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)).

CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.

%B BMJ %V 349 %P g4164 %8 2014 Jul 10 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/25011450?dopt=Abstract %R 10.1136/bmj.g4164 %0 Journal Article %J Lancet %D 2015 %T HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. %A Swerdlow, Daniel I %A Preiss, David %A Kuchenbaecker, Karoline B %A Holmes, Michael V %A Engmann, Jorgen E L %A Shah, Tina %A Sofat, Reecha %A Stender, Stefan %A Johnson, Paul C D %A Scott, Robert A %A Leusink, Maarten %A Verweij, Niek %A Sharp, Stephen J %A Guo, Yiran %A Giambartolomei, Claudia %A Chung, Christina %A Peasey, Anne %A Amuzu, Antoinette %A Li, KaWah %A Palmen, Jutta %A Howard, Philip %A Cooper, Jackie A %A Drenos, Fotios %A Li, Yun R %A Lowe, Gordon %A Gallacher, John %A Stewart, Marlene C W %A Tzoulaki, Ioanna %A Buxbaum, Sarah G %A van der A, Daphne L %A Forouhi, Nita G %A Onland-Moret, N Charlotte %A van der Schouw, Yvonne T %A Schnabel, Renate B %A Hubacek, Jaroslav A %A Kubinova, Ruzena %A Baceviciene, Migle %A Tamosiunas, Abdonas %A Pajak, Andrzej %A Topor-Madry, Roman %A Stepaniak, Urszula %A Malyutina, Sofia %A Baldassarre, Damiano %A Sennblad, Bengt %A Tremoli, Elena %A de Faire, Ulf %A Veglia, Fabrizio %A Ford, Ian %A Jukema, J Wouter %A Westendorp, Rudi G J %A de Borst, Gert Jan %A de Jong, Pim A %A Algra, Ale %A Spiering, Wilko %A Maitland-van der Zee, Anke H %A Klungel, Olaf H %A de Boer, Anthonius %A Doevendans, Pieter A %A Eaton, Charles B %A Robinson, Jennifer G %A Duggan, David %A Kjekshus, John %A Downs, John R %A Gotto, Antonio M %A Keech, Anthony C %A Marchioli, Roberto %A Tognoni, Gianni %A Sever, Peter S %A Poulter, Neil R %A Waters, David D %A Pedersen, Terje R %A Amarenco, Pierre %A Nakamura, Haruo %A McMurray, John J V %A Lewsey, James D %A Chasman, Daniel I %A Ridker, Paul M %A Maggioni, Aldo P %A Tavazzi, Luigi %A Ray, Kausik K %A Seshasai, Sreenivasa Rao Kondapally %A Manson, JoAnn E %A Price, Jackie F %A Whincup, Peter H %A Morris, Richard W %A Lawlor, Debbie A %A Smith, George Davey %A Ben-Shlomo, Yoav %A Schreiner, Pamela J %A Fornage, Myriam %A Siscovick, David S %A Cushman, Mary %A Kumari, Meena %A Wareham, Nick J %A Verschuren, W M Monique %A Redline, Susan %A Patel, Sanjay R %A Whittaker, John C %A Hamsten, Anders %A Delaney, Joseph A %A Dale, Caroline %A Gaunt, Tom R %A Wong, Andrew %A Kuh, Diana %A Hardy, Rebecca %A Kathiresan, Sekar %A Castillo, Berta A %A van der Harst, Pim %A Brunner, Eric J %A Tybjaerg-Hansen, Anne %A Marmot, Michael G %A Krauss, Ronald M %A Tsai, Michael %A Coresh, Josef %A Hoogeveen, Ronald C %A Psaty, Bruce M %A Lange, Leslie A %A Hakonarson, Hakon %A Dudbridge, Frank %A Humphries, Steve E %A Talmud, Philippa J %A Kivimaki, Mika %A Timpson, Nicholas J %A Langenberg, Claudia %A Asselbergs, Folkert W %A Voevoda, Mikhail %A Bobak, Martin %A Pikhart, Hynek %A Wilson, James G %A Reiner, Alex P %A Keating, Brendan J %A Hingorani, Aroon D %A Sattar, Naveed %K Aged %K Body Mass Index %K Body Weight %K Cholesterol, HDL %K Cholesterol, LDL %K Diabetes Mellitus, Type 2 %K Female %K Genetic Testing %K Humans %K Hydroxymethylglutaryl CoA Reductases %K Hydroxymethylglutaryl-CoA Reductase Inhibitors %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Randomized Controlled Trials as Topic %K Risk Factors %X

BACKGROUND: Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.

METHODS: We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.

FINDINGS: Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials).

INTERPRETATION: The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.

FUNDING: The funding sources are cited at the end of the paper.

%B Lancet %V 385 %P 351-61 %8 2015 Jan 24 %G eng %N 9965 %1 http://www.ncbi.nlm.nih.gov/pubmed/25262344?dopt=Abstract %R 10.1016/S0140-6736(14)61183-1 %0 Journal Article %J Eur Heart J %D 2015 %T Mendelian randomization of blood lipids for coronary heart disease. %A Holmes, Michael V %A Asselbergs, Folkert W %A Palmer, Tom M %A Drenos, Fotios %A Lanktree, Matthew B %A Nelson, Christopher P %A Dale, Caroline E %A Padmanabhan, Sandosh %A Finan, Chris %A Swerdlow, Daniel I %A Tragante, Vinicius %A van Iperen, Erik P A %A Sivapalaratnam, Suthesh %A Shah, Sonia %A Elbers, Clara C %A Shah, Tina %A Engmann, Jorgen %A Giambartolomei, Claudia %A White, Jon %A Zabaneh, Delilah %A Sofat, Reecha %A McLachlan, Stela %A Doevendans, Pieter A %A Balmforth, Anthony J %A Hall, Alistair S %A North, Kari E %A Almoguera, Berta %A Hoogeveen, Ron C %A Cushman, Mary %A Fornage, Myriam %A Patel, Sanjay R %A Redline, Susan %A Siscovick, David S %A Tsai, Michael Y %A Karczewski, Konrad J %A Hofker, Marten H %A Verschuren, W Monique %A Bots, Michiel L %A van der Schouw, Yvonne T %A Melander, Olle %A Dominiczak, Anna F %A Morris, Richard %A Ben-Shlomo, Yoav %A Price, Jackie %A Kumari, Meena %A Baumert, Jens %A Peters, Annette %A Thorand, Barbara %A Koenig, Wolfgang %A Gaunt, Tom R %A Humphries, Steve E %A Clarke, Robert %A Watkins, Hugh %A Farrall, Martin %A Wilson, James G %A Rich, Stephen S %A de Bakker, Paul I W %A Lange, Leslie A %A Davey Smith, George %A Reiner, Alex P %A Talmud, Philippa J %A Kivimaki, Mika %A Lawlor, Debbie A %A Dudbridge, Frank %A Samani, Nilesh J %A Keating, Brendan J %A Hingorani, Aroon D %A Casas, Juan P %K Case-Control Studies %K Cholesterol, HDL %K Coronary Artery Disease %K Female %K Gene Frequency %K Genotype %K Genotyping Techniques %K Humans %K Male %K Mendelian Randomization Analysis %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk Assessment %K Triglycerides %X

AIMS: To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization.

METHODS AND RESULTS: We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75).

CONCLUSION: The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.

%B Eur Heart J %V 36 %P 539-50 %8 2015 Mar 01 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/24474739?dopt=Abstract %R 10.1093/eurheartj/eht571 %0 Journal Article %J Nat Commun %D 2018 %T GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes. %A Franceschini, Nora %A Giambartolomei, Claudia %A de Vries, Paul S %A Finan, Chris %A Bis, Joshua C %A Huntley, Rachael P %A Lovering, Ruth C %A Tajuddin, Salman M %A Winkler, Thomas W %A Graff, Misa %A Kavousi, Maryam %A Dale, Caroline %A Smith, Albert V %A Hofer, Edith %A van Leeuwen, Elisabeth M %A Nolte, Ilja M %A Lu, Lingyi %A Scholz, Markus %A Sargurupremraj, Muralidharan %A Pitkänen, Niina %A Franzén, Oscar %A Joshi, Peter K %A Noordam, Raymond %A Marioni, Riccardo E %A Hwang, Shih-Jen %A Musani, Solomon K %A Schminke, Ulf %A Palmas, Walter %A Isaacs, Aaron %A Correa, Adolfo %A Zonderman, Alan B %A Hofman, Albert %A Teumer, Alexander %A Cox, Amanda J %A Uitterlinden, André G %A Wong, Andrew %A Smit, Andries J %A Newman, Anne B %A Britton, Annie %A Ruusalepp, Arno %A Sennblad, Bengt %A Hedblad, Bo %A Pasaniuc, Bogdan %A Penninx, Brenda W %A Langefeld, Carl D %A Wassel, Christina L %A Tzourio, Christophe %A Fava, Cristiano %A Baldassarre, Damiano %A O'Leary, Daniel H %A Teupser, Daniel %A Kuh, Diana %A Tremoli, Elena %A Mannarino, Elmo %A Grossi, Enzo %A Boerwinkle, Eric %A Schadt, Eric E %A Ingelsson, Erik %A Veglia, Fabrizio %A Rivadeneira, Fernando %A Beutner, Frank %A Chauhan, Ganesh %A Heiss, Gerardo %A Snieder, Harold %A Campbell, Harry %A Völzke, Henry %A Markus, Hugh S %A Deary, Ian J %A Jukema, J Wouter %A de Graaf, Jacqueline %A Price, Jacqueline %A Pott, Janne %A Hopewell, Jemma C %A Liang, Jingjing %A Thiery, Joachim %A Engmann, Jorgen %A Gertow, Karl %A Rice, Kenneth %A Taylor, Kent D %A Dhana, Klodian %A Kiemeney, Lambertus A L M %A Lind, Lars %A Raffield, Laura M %A Launer, Lenore J %A Holdt, Lesca M %A Dörr, Marcus %A Dichgans, Martin %A Traylor, Matthew %A Sitzer, Matthias %A Kumari, Meena %A Kivimaki, Mika %A Nalls, Mike A %A Melander, Olle %A Raitakari, Olli %A Franco, Oscar H %A Rueda-Ochoa, Oscar L %A Roussos, Panos %A Whincup, Peter H %A Amouyel, Philippe %A Giral, Philippe %A Anugu, Pramod %A Wong, Quenna %A Malik, Rainer %A Rauramaa, Rainer %A Burkhardt, Ralph %A Hardy, Rebecca %A Schmidt, Reinhold %A de Mutsert, Renée %A Morris, Richard W %A Strawbridge, Rona J %A Wannamethee, S Goya %A Hägg, Sara %A Shah, Sonia %A McLachlan, Stela %A Trompet, Stella %A Seshadri, Sudha %A Kurl, Sudhir %A Heckbert, Susan R %A Ring, Susan %A Harris, Tamara B %A Lehtimäki, Terho %A Galesloot, Tessel E %A Shah, Tina %A de Faire, Ulf %A Plagnol, Vincent %A Rosamond, Wayne D %A Post, Wendy %A Zhu, Xiaofeng %A Zhang, Xiaoling %A Guo, Xiuqing %A Saba, Yasaman %A Dehghan, Abbas %A Seldenrijk, Adrie %A Morrison, Alanna C %A Hamsten, Anders %A Psaty, Bruce M %A van Duijn, Cornelia M %A Lawlor, Deborah A %A Mook-Kanamori, Dennis O %A Bowden, Donald W %A Schmidt, Helena %A Wilson, James F %A Wilson, James G %A Rotter, Jerome I %A Wardlaw, Joanna M %A Deanfield, John %A Halcox, Julian %A Lyytikäinen, Leo-Pekka %A Loeffler, Markus %A Evans, Michele K %A Debette, Stephanie %A Humphries, Steve E %A Völker, Uwe %A Gudnason, Vilmundur %A Hingorani, Aroon D %A Björkegren, Johan L M %A Casas, Juan P %A O'Donnell, Christopher J %K ADAMTS9 Protein %K Amino Acid Oxidoreductases %K Carotid Intima-Media Thickness %K Coronary Disease %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Lod Score %K Plaque, Atherosclerotic %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Risk Factors %X

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

%B Nat Commun %V 9 %P 5141 %8 2018 12 03 %G eng %N 1 %R 10.1038/s41467-018-07340-5