TY - JOUR T1 - Differential white blood cell count and type 2 diabetes: systematic review and meta-analysis of cross-sectional and prospective studies. JF - PLoS One Y1 - 2010 A1 - Gkrania-Klotsas, Effrossyni A1 - Ye, Zheng A1 - Cooper, Andrew J A1 - Sharp, Stephen J A1 - Luben, Robert A1 - Biggs, Mary L A1 - Chen, Liang-Kung A1 - Gokulakrishnan, Kuppan A1 - Hanefeld, Markolf A1 - Ingelsson, Erik A1 - Lai, Wen-An A1 - Lin, Shih-Yi A1 - Lind, Lars A1 - Lohsoonthorn, Vitool A1 - Mohan, Viswanathan A1 - Muscari, Antonio A1 - Nilsson, Goran A1 - Ohrvik, John A1 - Chao Qiang, Jiang A1 - Jenny, Nancy Swords A1 - Tamakoshi, Koji A1 - Temelkova-Kurktschiev, Theodora A1 - Wang, Ya-Yu A1 - Yajnik, Chittaranjan Sakerlal A1 - Zoli, Marco A1 - Khaw, Kay-Tee A1 - Forouhi, Nita G A1 - Wareham, Nicholas J A1 - Langenberg, Claudia KW - Adult KW - Aged KW - Cross-Sectional Studies KW - Diabetes Mellitus, Type 2 KW - Female KW - Humans KW - Leukocyte Count KW - Male KW - Middle Aged KW - Prospective Studies AB -

OBJECTIVE: Biological evidence suggests that inflammation might induce type 2 diabetes (T2D), and epidemiological studies have shown an association between higher white blood cell count (WBC) and T2D. However, the association has not been systematically investigated.

RESEARCH DESIGN AND METHODS: Studies were identified through computer-based and manual searches. Previously unreported studies were sought through correspondence. 20 studies were identified (8,647 T2D cases and 85,040 non-cases). Estimates of the association of WBC with T2D were combined using random effects meta-analysis; sources of heterogeneity as well as presence of publication bias were explored.

RESULTS: The combined relative risk (RR) comparing the top to bottom tertile of the WBC count was 1.61 (95% CI: 1.45; 1.79, p = 1.5*10(-18)). Substantial heterogeneity was present (I(2) = 83%). For granulocytes the RR was 1.38 (95% CI: 1.17; 1.64, p = 1.5*10(-4)), for lymphocytes 1.26 (95% CI: 1.02; 1.56, p = 0.029), and for monocytes 0.93 (95% CI: 0.68; 1.28, p = 0.67) comparing top to bottom tertile. In cross-sectional studies, RR was 1.74 (95% CI: 1.49; 2.02, p = 7.7*10(-13)), while in cohort studies it was 1.48 (95% CI: 1.22; 1.79, p = 7.7*10(-5)). We assessed the impact of confounding in EPIC-Norfolk study and found that the age and sex adjusted HR of 2.19 (95% CI: 1.74; 2.75) was attenuated to 1.82 (95% CI: 1.45; 2.29) after further accounting for smoking, T2D family history, physical activity, education, BMI and waist circumference.

CONCLUSIONS: A raised WBC is associated with higher risk of T2D. The presence of publication bias and failure to control for all potential confounders in all studies means the observed association is likely an overestimate.

VL - 5 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20976133?dopt=Abstract ER - TY - JOUR T1 - New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. JF - Nat Genet Y1 - 2010 A1 - Dupuis, Josée A1 - Langenberg, Claudia A1 - Prokopenko, Inga A1 - Saxena, Richa A1 - Soranzo, Nicole A1 - Jackson, Anne U A1 - Wheeler, Eleanor A1 - Glazer, Nicole L A1 - Bouatia-Naji, Nabila A1 - Gloyn, Anna L A1 - Lindgren, Cecilia M A1 - Mägi, Reedik A1 - Morris, Andrew P A1 - Randall, Joshua A1 - Johnson, Toby A1 - Elliott, Paul A1 - Rybin, Denis A1 - Thorleifsson, Gudmar A1 - Steinthorsdottir, Valgerdur A1 - Henneman, Peter A1 - Grallert, Harald A1 - Dehghan, Abbas A1 - Hottenga, Jouke Jan A1 - Franklin, Christopher S A1 - Navarro, Pau A1 - Song, Kijoung A1 - Goel, Anuj A1 - Perry, John R B A1 - Egan, Josephine M A1 - Lajunen, Taina A1 - Grarup, Niels A1 - Sparsø, Thomas A1 - Doney, Alex A1 - Voight, Benjamin F A1 - Stringham, Heather M A1 - Li, Man A1 - Kanoni, Stavroula A1 - Shrader, Peter A1 - Cavalcanti-Proença, Christine A1 - Kumari, Meena A1 - Qi, Lu A1 - Timpson, Nicholas J A1 - Gieger, Christian A1 - Zabena, Carina A1 - Rocheleau, Ghislain A1 - Ingelsson, Erik A1 - An, Ping A1 - O'Connell, Jeffrey A1 - Luan, Jian'an A1 - Elliott, Amanda A1 - McCarroll, Steven A A1 - Payne, Felicity A1 - Roccasecca, Rosa Maria A1 - Pattou, François A1 - Sethupathy, Praveen A1 - Ardlie, Kristin A1 - Ariyurek, Yavuz A1 - Balkau, Beverley A1 - Barter, Philip A1 - Beilby, John P A1 - Ben-Shlomo, Yoav A1 - Benediktsson, Rafn A1 - Bennett, Amanda J A1 - Bergmann, Sven A1 - Bochud, Murielle A1 - Boerwinkle, Eric A1 - Bonnefond, Amélie A1 - Bonnycastle, Lori L A1 - Borch-Johnsen, Knut A1 - Böttcher, Yvonne A1 - Brunner, Eric A1 - Bumpstead, Suzannah J A1 - Charpentier, Guillaume A1 - Chen, Yii-Der Ida A1 - Chines, Peter A1 - Clarke, Robert A1 - Coin, Lachlan J M A1 - Cooper, Matthew N A1 - Cornelis, Marilyn A1 - Crawford, Gabe A1 - Crisponi, Laura A1 - Day, Ian N M A1 - de Geus, Eco J C A1 - Delplanque, Jerome A1 - Dina, Christian A1 - Erdos, Michael R A1 - Fedson, Annette C A1 - Fischer-Rosinsky, Antje A1 - Forouhi, Nita G A1 - Fox, Caroline S A1 - Frants, Rune A1 - Franzosi, Maria Grazia A1 - Galan, Pilar A1 - Goodarzi, Mark O A1 - Graessler, Jürgen A1 - Groves, Christopher J A1 - Grundy, Scott A1 - Gwilliam, Rhian A1 - Gyllensten, Ulf A1 - Hadjadj, Samy A1 - Hallmans, Göran A1 - Hammond, Naomi A1 - Han, Xijing A1 - Hartikainen, Anna-Liisa A1 - Hassanali, Neelam A1 - Hayward, Caroline A1 - Heath, Simon C A1 - Hercberg, Serge A1 - Herder, Christian A1 - Hicks, Andrew A A1 - Hillman, David R A1 - Hingorani, Aroon D A1 - Hofman, Albert A1 - Hui, Jennie A1 - Hung, Joe A1 - Isomaa, Bo A1 - Johnson, Paul R V A1 - Jørgensen, Torben A1 - Jula, Antti A1 - Kaakinen, Marika A1 - Kaprio, Jaakko A1 - Kesaniemi, Y Antero A1 - Kivimaki, Mika A1 - Knight, Beatrice A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Kyvik, Kirsten Ohm A1 - Lathrop, G Mark A1 - Lawlor, Debbie A A1 - Le Bacquer, Olivier A1 - Lecoeur, Cécile A1 - Li, Yun A1 - Lyssenko, Valeriya A1 - Mahley, Robert A1 - Mangino, Massimo A1 - Manning, Alisa K A1 - Martínez-Larrad, María Teresa A1 - McAteer, Jarred B A1 - McCulloch, Laura J A1 - McPherson, Ruth A1 - Meisinger, Christa A1 - Melzer, David A1 - Meyre, David A1 - Mitchell, Braxton D A1 - Morken, Mario A A1 - Mukherjee, Sutapa A1 - Naitza, Silvia A1 - Narisu, Narisu A1 - Neville, Matthew J A1 - Oostra, Ben A A1 - Orrù, Marco A1 - Pakyz, Ruth A1 - Palmer, Colin N A A1 - Paolisso, Giuseppe A1 - Pattaro, Cristian A1 - Pearson, Daniel A1 - Peden, John F A1 - Pedersen, Nancy L A1 - Perola, Markus A1 - Pfeiffer, Andreas F H A1 - Pichler, Irene A1 - Polasek, Ozren A1 - Posthuma, Danielle A1 - Potter, Simon C A1 - Pouta, Anneli A1 - Province, Michael A A1 - Psaty, Bruce M A1 - Rathmann, Wolfgang A1 - Rayner, Nigel W A1 - Rice, Kenneth A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Roden, Michael A1 - Rolandsson, Olov A1 - Sandbaek, Annelli A1 - Sandhu, Manjinder A1 - Sanna, Serena A1 - Sayer, Avan Aihie A1 - Scheet, Paul A1 - Scott, Laura J A1 - Seedorf, Udo A1 - Sharp, Stephen J A1 - Shields, Beverley A1 - Sigurethsson, Gunnar A1 - Sijbrands, Eric J G A1 - Silveira, Angela A1 - Simpson, Laila A1 - Singleton, Andrew A1 - Smith, Nicholas L A1 - Sovio, Ulla A1 - Swift, Amy A1 - Syddall, Holly A1 - Syvänen, Ann-Christine A1 - Tanaka, Toshiko A1 - Thorand, Barbara A1 - Tichet, Jean A1 - Tönjes, Anke A1 - Tuomi, Tiinamaija A1 - Uitterlinden, André G A1 - van Dijk, Ko Willems A1 - van Hoek, Mandy A1 - Varma, Dhiraj A1 - Visvikis-Siest, Sophie A1 - Vitart, Veronique A1 - Vogelzangs, Nicole A1 - Waeber, Gérard A1 - Wagner, Peter J A1 - Walley, Andrew A1 - Walters, G Bragi A1 - Ward, Kim L A1 - Watkins, Hugh A1 - Weedon, Michael N A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Witteman, Jaqueline C M A1 - Yarnell, John W G A1 - Zeggini, Eleftheria A1 - Zelenika, Diana A1 - Zethelius, Björn A1 - Zhai, Guangju A1 - Zhao, Jing Hua A1 - Zillikens, M Carola A1 - Borecki, Ingrid B A1 - Loos, Ruth J F A1 - Meneton, Pierre A1 - Magnusson, Patrik K E A1 - Nathan, David M A1 - Williams, Gordon H A1 - Hattersley, Andrew T A1 - Silander, Kaisa A1 - Salomaa, Veikko A1 - Smith, George Davey A1 - Bornstein, Stefan R A1 - Schwarz, Peter A1 - Spranger, Joachim A1 - Karpe, Fredrik A1 - Shuldiner, Alan R A1 - Cooper, Cyrus A1 - Dedoussis, George V A1 - Serrano-Ríos, Manuel A1 - Morris, Andrew D A1 - Lind, Lars A1 - Palmer, Lyle J A1 - Hu, Frank B A1 - Franks, Paul W A1 - Ebrahim, Shah A1 - Marmot, Michael A1 - Kao, W H Linda A1 - Pankow, James S A1 - Sampson, Michael J A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Hansen, Torben A1 - Pedersen, Oluf A1 - Pramstaller, Peter Paul A1 - Wichmann, H Erich A1 - Illig, Thomas A1 - Rudan, Igor A1 - Wright, Alan F A1 - Stumvoll, Michael A1 - Campbell, Harry A1 - Wilson, James F A1 - Bergman, Richard N A1 - Buchanan, Thomas A A1 - Collins, Francis S A1 - Mohlke, Karen L A1 - Tuomilehto, Jaakko A1 - Valle, Timo T A1 - Altshuler, David A1 - Rotter, Jerome I A1 - Siscovick, David S A1 - Penninx, Brenda W J H A1 - Boomsma, Dorret I A1 - Deloukas, Panos A1 - Spector, Timothy D A1 - Frayling, Timothy M A1 - Ferrucci, Luigi A1 - Kong, Augustine A1 - Thorsteinsdottir, Unnur A1 - Stefansson, Kari A1 - van Duijn, Cornelia M A1 - Aulchenko, Yurii S A1 - Cao, Antonio A1 - Scuteri, Angelo A1 - Schlessinger, David A1 - Uda, Manuela A1 - Ruokonen, Aimo A1 - Jarvelin, Marjo-Riitta A1 - Waterworth, Dawn M A1 - Vollenweider, Peter A1 - Peltonen, Leena A1 - Mooser, Vincent A1 - Abecasis, Goncalo R A1 - Wareham, Nicholas J A1 - Sladek, Robert A1 - Froguel, Philippe A1 - Watanabe, Richard M A1 - Meigs, James B A1 - Groop, Leif A1 - Boehnke, Michael A1 - McCarthy, Mark I A1 - Florez, Jose C A1 - Barroso, Inês KW - Adolescent KW - Adult KW - Alleles KW - Blood Glucose KW - Child KW - Databases, Genetic KW - Diabetes Mellitus, Type 2 KW - DNA Copy Number Variations KW - Fasting KW - Gene Expression Regulation KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Homeostasis KW - Humans KW - Meta-Analysis as Topic KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Quantitative Trait, Heritable KW - Reproducibility of Results AB -

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

VL - 42 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20081858?dopt=Abstract ER - TY - JOUR T1 - Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals. JF - PLoS Genet Y1 - 2012 A1 - Dastani, Zari A1 - Hivert, Marie-France A1 - Timpson, Nicholas A1 - Perry, John R B A1 - Yuan, Xin A1 - Scott, Robert A A1 - Henneman, Peter A1 - Heid, Iris M A1 - Kizer, Jorge R A1 - Lyytikäinen, Leo-Pekka A1 - Fuchsberger, Christian A1 - Tanaka, Toshiko A1 - Morris, Andrew P A1 - Small, Kerrin A1 - Isaacs, Aaron A1 - Beekman, Marian A1 - Coassin, Stefan A1 - Lohman, Kurt A1 - Qi, Lu A1 - Kanoni, Stavroula A1 - Pankow, James S A1 - Uh, Hae-Won A1 - Wu, Ying A1 - Bidulescu, Aurelian A1 - Rasmussen-Torvik, Laura J A1 - Greenwood, Celia M T A1 - Ladouceur, Martin A1 - Grimsby, Jonna A1 - Manning, Alisa K A1 - Liu, Ching-Ti A1 - Kooner, Jaspal A1 - Mooser, Vincent E A1 - Vollenweider, Peter A1 - Kapur, Karen A A1 - Chambers, John A1 - Wareham, Nicholas J A1 - Langenberg, Claudia A1 - Frants, Rune A1 - Willems-Vandijk, Ko A1 - Oostra, Ben A A1 - Willems, Sara M A1 - Lamina, Claudia A1 - Winkler, Thomas W A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Brody, Jennifer A1 - Chen, Ida A1 - Viikari, Jorma A1 - Kähönen, Mika A1 - Pramstaller, Peter P A1 - Evans, David M A1 - St Pourcain, Beate A1 - Sattar, Naveed A1 - Wood, Andrew R A1 - Bandinelli, Stefania A1 - Carlson, Olga D A1 - Egan, Josephine M A1 - Böhringer, Stefan A1 - van Heemst, Diana A1 - Kedenko, Lyudmyla A1 - Kristiansson, Kati A1 - Nuotio, Marja-Liisa A1 - Loo, Britt-Marie A1 - Harris, Tamara A1 - Garcia, Melissa A1 - Kanaya, Alka A1 - Haun, Margot A1 - Klopp, Norman A1 - Wichmann, H-Erich A1 - Deloukas, Panos A1 - Katsareli, Efi A1 - Couper, David J A1 - Duncan, Bruce B A1 - Kloppenburg, Margreet A1 - Adair, Linda S A1 - Borja, Judith B A1 - Wilson, James G A1 - Musani, Solomon A1 - Guo, Xiuqing A1 - Johnson, Toby A1 - Semple, Robert A1 - Teslovich, Tanya M A1 - Allison, Matthew A A1 - Redline, Susan A1 - Buxbaum, Sarah G A1 - Mohlke, Karen L A1 - Meulenbelt, Ingrid A1 - Ballantyne, Christie M A1 - Dedoussis, George V A1 - Hu, Frank B A1 - Liu, Yongmei A1 - Paulweber, Bernhard A1 - Spector, Timothy D A1 - Slagboom, P Eline A1 - Ferrucci, Luigi A1 - Jula, Antti A1 - Perola, Markus A1 - Raitakari, Olli A1 - Florez, Jose C A1 - Salomaa, Veikko A1 - Eriksson, Johan G A1 - Frayling, Timothy M A1 - Hicks, Andrew A A1 - Lehtimäki, Terho A1 - Smith, George Davey A1 - Siscovick, David S A1 - Kronenberg, Florian A1 - van Duijn, Cornelia A1 - Loos, Ruth J F A1 - Waterworth, Dawn M A1 - Meigs, James B A1 - Dupuis, Josée A1 - Richards, J Brent A1 - Voight, Benjamin F A1 - Scott, Laura J A1 - Steinthorsdottir, Valgerdur A1 - Dina, Christian A1 - Welch, Ryan P A1 - Zeggini, Eleftheria A1 - Huth, Cornelia A1 - Aulchenko, Yurii S A1 - Thorleifsson, Gudmar A1 - McCulloch, Laura J A1 - Ferreira, Teresa A1 - Grallert, Harald A1 - Amin, Najaf A1 - Wu, Guanming A1 - Willer, Cristen J A1 - Raychaudhuri, Soumya A1 - McCarroll, Steve A A1 - Hofmann, Oliver M A1 - Segrè, Ayellet V A1 - van Hoek, Mandy A1 - Navarro, Pau A1 - Ardlie, Kristin A1 - Balkau, Beverley A1 - Benediktsson, Rafn A1 - Bennett, Amanda J A1 - Blagieva, Roza A1 - Boerwinkle, Eric A1 - Bonnycastle, Lori L A1 - Boström, Kristina Bengtsson A1 - Bravenboer, Bert A1 - Bumpstead, Suzannah A1 - Burtt, Noel P A1 - Charpentier, Guillaume A1 - Chines, Peter S A1 - Cornelis, Marilyn A1 - Crawford, Gabe A1 - Doney, Alex S F A1 - Elliott, Katherine S A1 - Elliott, Amanda L A1 - Erdos, Michael R A1 - Fox, Caroline S A1 - Franklin, Christopher S A1 - Ganser, Martha A1 - Gieger, Christian A1 - Grarup, Niels A1 - Green, Todd A1 - Griffin, Simon A1 - Groves, Christopher J A1 - Guiducci, Candace A1 - Hadjadj, Samy A1 - Hassanali, Neelam A1 - Herder, Christian A1 - Isomaa, Bo A1 - Jackson, Anne U A1 - Johnson, Paul R V A1 - Jørgensen, Torben A1 - Kao, Wen H L A1 - Kong, Augustine A1 - Kraft, Peter A1 - Kuusisto, Johanna A1 - Lauritzen, Torsten A1 - Li, Man A1 - Lieverse, Aloysius A1 - Lindgren, Cecilia M A1 - Lyssenko, Valeriya A1 - Marre, Michel A1 - Meitinger, Thomas A1 - Midthjell, Kristian A1 - Morken, Mario A A1 - Narisu, Narisu A1 - Nilsson, Peter A1 - Owen, Katharine R A1 - Payne, Felicity A1 - Petersen, Ann-Kristin A1 - Platou, Carl A1 - Proença, Christine A1 - Prokopenko, Inga A1 - Rathmann, Wolfgang A1 - Rayner, N William A1 - Robertson, Neil R A1 - Rocheleau, Ghislain A1 - Roden, Michael A1 - Sampson, Michael J A1 - Saxena, Richa A1 - Shields, Beverley M A1 - Shrader, Peter A1 - Sigurdsson, Gunnar A1 - Sparsø, Thomas A1 - Strassburger, Klaus A1 - Stringham, Heather M A1 - Sun, Qi A1 - Swift, Amy J A1 - Thorand, Barbara A1 - Tichet, Jean A1 - Tuomi, Tiinamaija A1 - van Dam, Rob M A1 - van Haeften, Timon W A1 - van Herpt, Thijs A1 - van Vliet-Ostaptchouk, Jana V A1 - Walters, G Bragi A1 - Weedon, Michael N A1 - Wijmenga, Cisca A1 - Witteman, Jacqueline A1 - Bergman, Richard N A1 - Cauchi, Stephane A1 - Collins, Francis S A1 - Gloyn, Anna L A1 - Gyllensten, Ulf A1 - Hansen, Torben A1 - Hide, Winston A A1 - Hitman, Graham A A1 - Hofman, Albert A1 - Hunter, David J A1 - Hveem, Kristian A1 - Laakso, Markku A1 - Morris, Andrew D A1 - Palmer, Colin N A A1 - Rudan, Igor A1 - Sijbrands, Eric A1 - Stein, Lincoln D A1 - Tuomilehto, Jaakko A1 - Uitterlinden, Andre A1 - Walker, Mark A1 - Watanabe, Richard M A1 - Abecasis, Goncalo R A1 - Boehm, Bernhard O A1 - Campbell, Harry A1 - Daly, Mark J A1 - Hattersley, Andrew T A1 - Pedersen, Oluf A1 - Barroso, Inês A1 - Groop, Leif A1 - Sladek, Rob A1 - Thorsteinsdottir, Unnur A1 - Wilson, James F A1 - Illig, Thomas A1 - Froguel, Philippe A1 - van Duijn, Cornelia M A1 - Stefansson, Kari A1 - Altshuler, David A1 - Boehnke, Michael A1 - McCarthy, Mark I A1 - Soranzo, Nicole A1 - Wheeler, Eleanor A1 - Glazer, Nicole L A1 - Bouatia-Naji, Nabila A1 - Mägi, Reedik A1 - Randall, Joshua A1 - Elliott, Paul A1 - Rybin, Denis A1 - Dehghan, Abbas A1 - Hottenga, Jouke Jan A1 - Song, Kijoung A1 - Goel, Anuj A1 - Lajunen, Taina A1 - Doney, Alex A1 - Cavalcanti-Proença, Christine A1 - Kumari, Meena A1 - Timpson, Nicholas J A1 - Zabena, Carina A1 - Ingelsson, Erik A1 - An, Ping A1 - O'Connell, Jeffrey A1 - Luan, Jian'an A1 - Elliott, Amanda A1 - McCarroll, Steven A A1 - Roccasecca, Rosa Maria A1 - Pattou, François A1 - Sethupathy, Praveen A1 - Ariyurek, Yavuz A1 - Barter, Philip A1 - Beilby, John P A1 - Ben-Shlomo, Yoav A1 - Bergmann, Sven A1 - Bochud, Murielle A1 - Bonnefond, Amélie A1 - Borch-Johnsen, Knut A1 - Böttcher, Yvonne A1 - Brunner, Eric A1 - Bumpstead, Suzannah J A1 - Chen, Yii-Der Ida A1 - Chines, Peter A1 - Clarke, Robert A1 - Coin, Lachlan J M A1 - Cooper, Matthew N A1 - Crisponi, Laura A1 - Day, Ian N M A1 - de Geus, Eco J C A1 - Delplanque, Jerome A1 - Fedson, Annette C A1 - Fischer-Rosinsky, Antje A1 - Forouhi, Nita G A1 - Franzosi, Maria Grazia A1 - Galan, Pilar A1 - Goodarzi, Mark O A1 - Graessler, Jürgen A1 - Grundy, Scott A1 - Gwilliam, Rhian A1 - Hallmans, Göran A1 - Hammond, Naomi A1 - Han, Xijing A1 - Hartikainen, Anna-Liisa A1 - Hayward, Caroline A1 - Heath, Simon C A1 - Hercberg, Serge A1 - Hillman, David R A1 - Hingorani, Aroon D A1 - Hui, Jennie A1 - Hung, Joe A1 - Kaakinen, Marika A1 - Kaprio, Jaakko A1 - Kesaniemi, Y Antero A1 - Kivimaki, Mika A1 - Knight, Beatrice A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Kyvik, Kirsten Ohm A1 - Lathrop, G Mark A1 - Lawlor, Debbie A A1 - Le Bacquer, Olivier A1 - Lecoeur, Cécile A1 - Li, Yun A1 - Mahley, Robert A1 - Mangino, Massimo A1 - Martínez-Larrad, María Teresa A1 - McAteer, Jarred B A1 - McPherson, Ruth A1 - Meisinger, Christa A1 - Melzer, David A1 - Meyre, David A1 - Mitchell, Braxton D A1 - Mukherjee, Sutapa A1 - Naitza, Silvia A1 - Neville, Matthew J A1 - Orrù, Marco A1 - Pakyz, Ruth A1 - Paolisso, Giuseppe A1 - Pattaro, Cristian A1 - Pearson, Daniel A1 - Peden, John F A1 - Pedersen, Nancy L A1 - Pfeiffer, Andreas F H A1 - Pichler, Irene A1 - Polasek, Ozren A1 - Posthuma, Danielle A1 - Potter, Simon C A1 - Pouta, Anneli A1 - Province, Michael A A1 - Rayner, Nigel W A1 - Rice, Kenneth A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Rolandsson, Olov A1 - Sandbaek, Annelli A1 - Sandhu, Manjinder A1 - Sanna, Serena A1 - Sayer, Avan Aihie A1 - Scheet, Paul A1 - Seedorf, Udo A1 - Sharp, Stephen J A1 - Shields, Beverley A1 - Sigurðsson, Gunnar A1 - Sijbrands, Eric J G A1 - Silveira, Angela A1 - Simpson, Laila A1 - Singleton, Andrew A1 - Smith, Nicholas L A1 - Sovio, Ulla A1 - Swift, Amy A1 - Syddall, Holly A1 - Syvänen, Ann-Christine A1 - Tönjes, Anke A1 - Uitterlinden, André G A1 - van Dijk, Ko Willems A1 - Varma, Dhiraj A1 - Visvikis-Siest, Sophie A1 - Vitart, Veronique A1 - Vogelzangs, Nicole A1 - Waeber, Gérard A1 - Wagner, Peter J A1 - Walley, Andrew A1 - Ward, Kim L A1 - Watkins, Hugh A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Witteman, Jaqueline C M A1 - Yarnell, John W G A1 - Zelenika, Diana A1 - Zethelius, Björn A1 - Zhai, Guangju A1 - Zhao, Jing Hua A1 - Zillikens, M Carola A1 - Borecki, Ingrid B A1 - Meneton, Pierre A1 - Magnusson, Patrik K E A1 - Nathan, David M A1 - Williams, Gordon H A1 - Silander, Kaisa A1 - Bornstein, Stefan R A1 - Schwarz, Peter A1 - Spranger, Joachim A1 - Karpe, Fredrik A1 - Shuldiner, Alan R A1 - Cooper, Cyrus A1 - Serrano-Ríos, Manuel A1 - Lind, Lars A1 - Palmer, Lyle J A1 - Hu, Frank B A1 - Franks, Paul W A1 - Ebrahim, Shah A1 - Marmot, Michael A1 - Kao, W H Linda A1 - Pramstaller, Peter Paul A1 - Wright, Alan F A1 - Stumvoll, Michael A1 - Hamsten, Anders A1 - Buchanan, Thomas A A1 - Valle, Timo T A1 - Rotter, Jerome I A1 - Penninx, Brenda W J H A1 - Boomsma, Dorret I A1 - Cao, Antonio A1 - Scuteri, Angelo A1 - Schlessinger, David A1 - Uda, Manuela A1 - Ruokonen, Aimo A1 - Jarvelin, Marjo-Riitta A1 - Peltonen, Leena A1 - Mooser, Vincent A1 - Sladek, Robert A1 - Musunuru, Kiran A1 - Smith, Albert V A1 - Edmondson, Andrew C A1 - Stylianou, Ioannis M A1 - Koseki, Masahiro A1 - Pirruccello, James P A1 - Chasman, Daniel I A1 - Johansen, Christopher T A1 - Fouchier, Sigrid W A1 - Peloso, Gina M A1 - Barbalic, Maja A1 - Ricketts, Sally L A1 - Bis, Joshua C A1 - Feitosa, Mary F A1 - Orho-Melander, Marju A1 - Melander, Olle A1 - Li, Xiaohui A1 - Li, Mingyao A1 - Cho, Yoon Shin A1 - Go, Min Jin A1 - Kim, Young Jin A1 - Lee, Jong-Young A1 - Park, Taesung A1 - Kim, Kyunga A1 - Sim, Xueling A1 - Ong, Rick Twee-Hee A1 - Croteau-Chonka, Damien C A1 - Lange, Leslie A A1 - Smith, Joshua D A1 - Ziegler, Andreas A1 - Zhang, Weihua A1 - Zee, Robert Y L A1 - Whitfield, John B A1 - Thompson, John R A1 - Surakka, Ida A1 - Spector, Tim D A1 - Smit, Johannes H A1 - Sinisalo, Juha A1 - Scott, James A1 - Saharinen, Juha A1 - Sabatti, Chiara A1 - Rose, Lynda M A1 - Roberts, Robert A1 - Rieder, Mark A1 - Parker, Alex N A1 - Paré, Guillaume A1 - O'Donnell, Christopher J A1 - Nieminen, Markku S A1 - Nickerson, Deborah A A1 - Montgomery, Grant W A1 - McArdle, Wendy A1 - Masson, David A1 - Martin, Nicholas G A1 - Marroni, Fabio A1 - Lucas, Gavin A1 - Luben, Robert A1 - Lokki, Marja-Liisa A1 - Lettre, Guillaume A1 - Launer, Lenore J A1 - Lakatta, Edward G A1 - Laaksonen, Reijo A1 - Kyvik, Kirsten O A1 - König, Inke R A1 - Khaw, Kay-Tee A1 - Kaplan, Lee M A1 - Johansson, Asa A1 - Janssens, A Cecile J W A1 - Igl, Wilmar A1 - Hovingh, G Kees A1 - Hengstenberg, Christian A1 - Havulinna, Aki S A1 - Hastie, Nicholas D A1 - Harris, Tamara B A1 - Haritunians, Talin A1 - Hall, Alistair S A1 - Groop, Leif C A1 - Gonzalez, Elena A1 - Freimer, Nelson B A1 - Erdmann, Jeanette A1 - Ejebe, Kenechi G A1 - Döring, Angela A1 - Dominiczak, Anna F A1 - Demissie, Serkalem A1 - Deloukas, Panagiotis A1 - de Faire, Ulf A1 - Crawford, Gabriel A1 - Chen, Yii-der I A1 - Caulfield, Mark J A1 - Boekholdt, S Matthijs A1 - Assimes, Themistocles L A1 - Quertermous, Thomas A1 - Seielstad, Mark A1 - Wong, Tien Y A1 - Tai, E-Shyong A1 - Feranil, Alan B A1 - Kuzawa, Christopher W A1 - Taylor, Herman A A1 - Gabriel, Stacey B A1 - Holm, Hilma A1 - Gudnason, Vilmundur A1 - Krauss, Ronald M A1 - Ordovas, Jose M A1 - Munroe, Patricia B A1 - Kooner, Jaspal S A1 - Tall, Alan R A1 - Hegele, Robert A A1 - Kastelein, John J P A1 - Schadt, Eric E A1 - Strachan, David P A1 - Reilly, Muredach P A1 - Samani, Nilesh J A1 - Schunkert, Heribert A1 - Cupples, L Adrienne A1 - Sandhu, Manjinder S A1 - Ridker, Paul M A1 - Rader, Daniel J A1 - Kathiresan, Sekar KW - Adiponectin KW - African Americans KW - Asian Continental Ancestry Group KW - Cholesterol, HDL KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Female KW - Gene Expression KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glucose Tolerance Test KW - Humans KW - Insulin Resistance KW - Male KW - Metabolic Networks and Pathways KW - Polymorphism, Single Nucleotide KW - Waist-Hip Ratio AB -

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

VL - 8 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22479202?dopt=Abstract ER - TY - JOUR T1 - Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data. JF - BMJ Y1 - 2014 A1 - Holmes, Michael V A1 - Dale, Caroline E A1 - Zuccolo, Luisa A1 - Silverwood, Richard J A1 - Guo, Yiran A1 - Ye, Zheng A1 - Prieto-Merino, David A1 - Dehghan, Abbas A1 - Trompet, Stella A1 - Wong, Andrew A1 - Cavadino, Alana A1 - Drogan, Dagmar A1 - Padmanabhan, Sandosh A1 - Li, Shanshan A1 - Yesupriya, Ajay A1 - Leusink, Maarten A1 - Sundström, Johan A1 - Hubacek, Jaroslav A A1 - Pikhart, Hynek A1 - Swerdlow, Daniel I A1 - Panayiotou, Andrie G A1 - Borinskaya, Svetlana A A1 - Finan, Chris A1 - Shah, Sonia A1 - Kuchenbaecker, Karoline B A1 - Shah, Tina A1 - Engmann, Jorgen A1 - Folkersen, Lasse A1 - Eriksson, Per A1 - Ricceri, Fulvio A1 - Melander, Olle A1 - Sacerdote, Carlotta A1 - Gamble, Dale M A1 - Rayaprolu, Sruti A1 - Ross, Owen A A1 - McLachlan, Stela A1 - Vikhireva, Olga A1 - Sluijs, Ivonne A1 - Scott, Robert A A1 - Adamkova, Vera A1 - Flicker, Leon A1 - Bockxmeer, Frank M van A1 - Power, Christine A1 - Marques-Vidal, Pedro A1 - Meade, Tom A1 - Marmot, Michael G A1 - Ferro, Jose M A1 - Paulos-Pinheiro, Sofia A1 - Humphries, Steve E A1 - Talmud, Philippa J A1 - Mateo Leach, Irene A1 - Verweij, Niek A1 - Linneberg, Allan A1 - Skaaby, Tea A1 - Doevendans, Pieter A A1 - Cramer, Maarten J A1 - van der Harst, Pim A1 - Klungel, Olaf H A1 - Dowling, Nicole F A1 - Dominiczak, Anna F A1 - Kumari, Meena A1 - Nicolaides, Andrew N A1 - Weikert, Cornelia A1 - Boeing, Heiner A1 - Ebrahim, Shah A1 - Gaunt, Tom R A1 - Price, Jackie F A1 - Lannfelt, Lars A1 - Peasey, Anne A1 - Kubinova, Ruzena A1 - Pajak, Andrzej A1 - Malyutina, Sofia A1 - Voevoda, Mikhail I A1 - Tamosiunas, Abdonas A1 - Maitland-van der Zee, Anke H A1 - Norman, Paul E A1 - Hankey, Graeme J A1 - Bergmann, Manuela M A1 - Hofman, Albert A1 - Franco, Oscar H A1 - Cooper, Jackie A1 - Palmen, Jutta A1 - Spiering, Wilko A1 - de Jong, Pim A A1 - Kuh, Diana A1 - Hardy, Rebecca A1 - Uitterlinden, André G A1 - Ikram, M Arfan A1 - Ford, Ian A1 - Hyppönen, Elina A1 - Almeida, Osvaldo P A1 - Wareham, Nicholas J A1 - Khaw, Kay-Tee A1 - Hamsten, Anders A1 - Husemoen, Lise Lotte N A1 - Tjønneland, Anne A1 - Tolstrup, Janne S A1 - Rimm, Eric A1 - Beulens, Joline W J A1 - Verschuren, W M Monique A1 - Onland-Moret, N Charlotte A1 - Hofker, Marten H A1 - Wannamethee, S Goya A1 - Whincup, Peter H A1 - Morris, Richard A1 - Vicente, Astrid M A1 - Watkins, Hugh A1 - Farrall, Martin A1 - Jukema, J Wouter A1 - Meschia, James A1 - Cupples, L Adrienne A1 - Sharp, Stephen J A1 - Fornage, Myriam A1 - Kooperberg, Charles A1 - LaCroix, Andrea Z A1 - Dai, James Y A1 - Lanktree, Matthew B A1 - Siscovick, David S A1 - Jorgenson, Eric A1 - Spring, Bonnie A1 - Coresh, Josef A1 - Li, Yun R A1 - Buxbaum, Sarah G A1 - Schreiner, Pamela J A1 - Ellison, R Curtis A1 - Tsai, Michael Y A1 - Patel, Sanjay R A1 - Redline, Susan A1 - Johnson, Andrew D A1 - Hoogeveen, Ron C A1 - Hakonarson, Hakon A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - de Bakker, Paul I W A1 - Kivimaki, Mika A1 - Asselbergs, Folkert W A1 - Sattar, Naveed A1 - Lawlor, Debbie A A1 - Whittaker, John A1 - Davey Smith, George A1 - Mukamal, Kenneth A1 - Psaty, Bruce M A1 - Wilson, James G A1 - Lange, Leslie A A1 - Hamidovic, Ajna A1 - Hingorani, Aroon D A1 - Nordestgaard, Børge G A1 - Bobak, Martin A1 - Leon, David A A1 - Langenberg, Claudia A1 - Palmer, Tom M A1 - Reiner, Alex P A1 - Keating, Brendan J A1 - Dudbridge, Frank A1 - Casas, Juan P KW - Adult KW - Aged KW - Alcohol Dehydrogenase KW - Alcohol Drinking KW - Biomarkers KW - Coronary Disease KW - Female KW - Genetic Markers KW - Genotype KW - Humans KW - Male KW - Mendelian Randomization Analysis KW - Middle Aged KW - Models, Statistical KW - Polymorphism, Single Nucleotide KW - Stroke AB -

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.

VL - 349 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25011450?dopt=Abstract ER - TY - JOUR T1 - HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. JF - Lancet Y1 - 2015 A1 - Swerdlow, Daniel I A1 - Preiss, David A1 - Kuchenbaecker, Karoline B A1 - Holmes, Michael V A1 - Engmann, Jorgen E L A1 - Shah, Tina A1 - Sofat, Reecha A1 - Stender, Stefan A1 - Johnson, Paul C D A1 - Scott, Robert A A1 - Leusink, Maarten A1 - Verweij, Niek A1 - Sharp, Stephen J A1 - Guo, Yiran A1 - Giambartolomei, Claudia A1 - Chung, Christina A1 - Peasey, Anne A1 - Amuzu, Antoinette A1 - Li, KaWah A1 - Palmen, Jutta A1 - Howard, Philip A1 - Cooper, Jackie A A1 - Drenos, Fotios A1 - Li, Yun R A1 - Lowe, Gordon A1 - Gallacher, John A1 - Stewart, Marlene C W A1 - Tzoulaki, Ioanna A1 - Buxbaum, Sarah G A1 - van der A, Daphne L A1 - Forouhi, Nita G A1 - Onland-Moret, N Charlotte A1 - van der Schouw, Yvonne T A1 - Schnabel, Renate B A1 - Hubacek, Jaroslav A A1 - Kubinova, Ruzena A1 - Baceviciene, Migle A1 - Tamosiunas, Abdonas A1 - Pajak, Andrzej A1 - Topor-Madry, Roman A1 - Stepaniak, Urszula A1 - Malyutina, Sofia A1 - Baldassarre, Damiano A1 - Sennblad, Bengt A1 - Tremoli, Elena A1 - de Faire, Ulf A1 - Veglia, Fabrizio A1 - Ford, Ian A1 - Jukema, J Wouter A1 - Westendorp, Rudi G J A1 - de Borst, Gert Jan A1 - de Jong, Pim A A1 - Algra, Ale A1 - Spiering, Wilko A1 - Maitland-van der Zee, Anke H A1 - Klungel, Olaf H A1 - de Boer, Anthonius A1 - Doevendans, Pieter A A1 - Eaton, Charles B A1 - Robinson, Jennifer G A1 - Duggan, David A1 - Kjekshus, John A1 - Downs, John R A1 - Gotto, Antonio M A1 - Keech, Anthony C A1 - Marchioli, Roberto A1 - Tognoni, Gianni A1 - Sever, Peter S A1 - Poulter, Neil R A1 - Waters, David D A1 - Pedersen, Terje R A1 - Amarenco, Pierre A1 - Nakamura, Haruo A1 - McMurray, John J V A1 - Lewsey, James D A1 - Chasman, Daniel I A1 - Ridker, Paul M A1 - Maggioni, Aldo P A1 - Tavazzi, Luigi A1 - Ray, Kausik K A1 - Seshasai, Sreenivasa Rao Kondapally A1 - Manson, JoAnn E A1 - Price, Jackie F A1 - Whincup, Peter H A1 - Morris, Richard W A1 - Lawlor, Debbie A A1 - Smith, George Davey A1 - Ben-Shlomo, Yoav A1 - Schreiner, Pamela J A1 - Fornage, Myriam A1 - Siscovick, David S A1 - Cushman, Mary A1 - Kumari, Meena A1 - Wareham, Nick J A1 - Verschuren, W M Monique A1 - Redline, Susan A1 - Patel, Sanjay R A1 - Whittaker, John C A1 - Hamsten, Anders A1 - Delaney, Joseph A A1 - Dale, Caroline A1 - Gaunt, Tom R A1 - Wong, Andrew A1 - Kuh, Diana A1 - Hardy, Rebecca A1 - Kathiresan, Sekar A1 - Castillo, Berta A A1 - van der Harst, Pim A1 - Brunner, Eric J A1 - Tybjaerg-Hansen, Anne A1 - Marmot, Michael G A1 - Krauss, Ronald M A1 - Tsai, Michael A1 - Coresh, Josef A1 - Hoogeveen, Ronald C A1 - Psaty, Bruce M A1 - Lange, Leslie A A1 - Hakonarson, Hakon A1 - Dudbridge, Frank A1 - Humphries, Steve E A1 - Talmud, Philippa J A1 - Kivimaki, Mika A1 - Timpson, Nicholas J A1 - Langenberg, Claudia A1 - Asselbergs, Folkert W A1 - Voevoda, Mikhail A1 - Bobak, Martin A1 - Pikhart, Hynek A1 - Wilson, James G A1 - Reiner, Alex P A1 - Keating, Brendan J A1 - Hingorani, Aroon D A1 - Sattar, Naveed KW - Aged KW - Body Mass Index KW - Body Weight KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Diabetes Mellitus, Type 2 KW - Female KW - Genetic Testing KW - Humans KW - Hydroxymethylglutaryl CoA Reductases KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Randomized Controlled Trials as Topic KW - Risk Factors AB -

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.

VL - 385 IS - 9965 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25262344?dopt=Abstract ER - TY - JOUR T1 - Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis. JF - PLoS Med Y1 - 2017 A1 - Wheeler, Eleanor A1 - Leong, Aaron A1 - Liu, Ching-Ti A1 - Hivert, Marie-France A1 - Strawbridge, Rona J A1 - Podmore, Clara A1 - Li, Man A1 - Yao, Jie A1 - Sim, Xueling A1 - Hong, Jaeyoung A1 - Chu, Audrey Y A1 - Zhang, Weihua A1 - Wang, Xu A1 - Chen, Peng A1 - Maruthur, Nisa M A1 - Porneala, Bianca C A1 - Sharp, Stephen J A1 - Jia, Yucheng A1 - Kabagambe, Edmond K A1 - Chang, Li-Ching A1 - Chen, Wei-Min A1 - Elks, Cathy E A1 - Evans, Daniel S A1 - Fan, Qiao A1 - Giulianini, Franco A1 - Go, Min Jin A1 - Hottenga, Jouke-Jan A1 - Hu, Yao A1 - Jackson, Anne U A1 - Kanoni, Stavroula A1 - Kim, Young Jin A1 - Kleber, Marcus E A1 - Ladenvall, Claes A1 - Lecoeur, Cécile A1 - Lim, Sing-Hui A1 - Lu, Yingchang A1 - Mahajan, Anubha A1 - Marzi, Carola A1 - Nalls, Mike A A1 - Navarro, Pau A1 - Nolte, Ilja M A1 - Rose, Lynda M A1 - Rybin, Denis V A1 - Sanna, Serena A1 - Shi, Yuan A1 - Stram, Daniel O A1 - Takeuchi, Fumihiko A1 - Tan, Shu Pei A1 - van der Most, Peter J A1 - van Vliet-Ostaptchouk, Jana V A1 - Wong, Andrew A1 - Yengo, Loic A1 - Zhao, Wanting A1 - Goel, Anuj A1 - Martinez Larrad, Maria Teresa A1 - Radke, Dörte A1 - Salo, Perttu A1 - Tanaka, Toshiko A1 - van Iperen, Erik P A A1 - Abecasis, Goncalo A1 - Afaq, Saima A1 - Alizadeh, Behrooz Z A1 - Bertoni, Alain G A1 - Bonnefond, Amélie A1 - Böttcher, Yvonne A1 - Bottinger, Erwin P A1 - Campbell, Harry A1 - Carlson, Olga D A1 - Chen, Chien-Hsiun A1 - Cho, Yoon Shin A1 - Garvey, W Timothy A1 - Gieger, Christian A1 - Goodarzi, Mark O A1 - Grallert, Harald A1 - Hamsten, Anders A1 - Hartman, Catharina A A1 - Herder, Christian A1 - Hsiung, Chao Agnes A1 - Huang, Jie A1 - Igase, Michiya A1 - Isono, Masato A1 - Katsuya, Tomohiro A1 - Khor, Chiea-Chuen A1 - Kiess, Wieland A1 - Kohara, Katsuhiko A1 - Kovacs, Peter A1 - Lee, Juyoung A1 - Lee, Wen-Jane A1 - Lehne, Benjamin A1 - Li, Huaixing A1 - Liu, Jianjun A1 - Lobbens, Stephane A1 - Luan, Jian'an A1 - Lyssenko, Valeriya A1 - Meitinger, Thomas A1 - Miki, Tetsuro A1 - Miljkovic, Iva A1 - Moon, Sanghoon A1 - Mulas, Antonella A1 - Müller, Gabriele A1 - Müller-Nurasyid, Martina A1 - Nagaraja, Ramaiah A1 - Nauck, Matthias A1 - Pankow, James S A1 - Polasek, Ozren A1 - Prokopenko, Inga A1 - Ramos, Paula S A1 - Rasmussen-Torvik, Laura A1 - Rathmann, Wolfgang A1 - Rich, Stephen S A1 - Robertson, Neil R A1 - Roden, Michael A1 - Roussel, Ronan A1 - Rudan, Igor A1 - Scott, Robert A A1 - Scott, William R A1 - Sennblad, Bengt A1 - Siscovick, David S A1 - Strauch, Konstantin A1 - Sun, Liang A1 - Swertz, Morris A1 - Tajuddin, Salman M A1 - Taylor, Kent D A1 - Teo, Yik-Ying A1 - Tham, Yih Chung A1 - Tönjes, Anke A1 - Wareham, Nicholas J A1 - Willemsen, Gonneke A1 - Wilsgaard, Tom A1 - Hingorani, Aroon D A1 - Egan, Josephine A1 - Ferrucci, Luigi A1 - Hovingh, G Kees A1 - Jula, Antti A1 - Kivimaki, Mika A1 - Kumari, Meena A1 - Njølstad, Inger A1 - Palmer, Colin N A A1 - Serrano Ríos, Manuel A1 - Stumvoll, Michael A1 - Watkins, Hugh A1 - Aung, Tin A1 - Blüher, Matthias A1 - Boehnke, Michael A1 - Boomsma, Dorret I A1 - Bornstein, Stefan R A1 - Chambers, John C A1 - Chasman, Daniel I A1 - Chen, Yii-Der Ida A1 - Chen, Yduan-Tsong A1 - Cheng, Ching-Yu A1 - Cucca, Francesco A1 - de Geus, Eco J C A1 - Deloukas, Panos A1 - Evans, Michele K A1 - Fornage, Myriam A1 - Friedlander, Yechiel A1 - Froguel, Philippe A1 - Groop, Leif A1 - Gross, Myron D A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Heng, Chew-Kiat A1 - Ingelsson, Erik A1 - Kato, Norihiro A1 - Kim, Bong-Jo A1 - Koh, Woon-Puay A1 - Kooner, Jaspal S A1 - Körner, Antje A1 - Kuh, Diana A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lin, Xu A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Magnusson, Patrik K E A1 - März, Winfried A1 - McCarthy, Mark I A1 - Oldehinkel, Albertine J A1 - Ong, Ken K A1 - Pedersen, Nancy L A1 - Pereira, Mark A A1 - Peters, Annette A1 - Ridker, Paul M A1 - Sabanayagam, Charumathi A1 - Sale, Michele A1 - Saleheen, Danish A1 - Saltevo, Juha A1 - Schwarz, Peter Eh A1 - Sheu, Wayne H H A1 - Snieder, Harold A1 - Spector, Timothy D A1 - Tabara, Yasuharu A1 - Tuomilehto, Jaakko A1 - van Dam, Rob M A1 - Wilson, James G A1 - Wilson, James F A1 - Wolffenbuttel, Bruce H R A1 - Wong, Tien Yin A1 - Wu, Jer-Yuarn A1 - Yuan, Jian-Min A1 - Zonderman, Alan B A1 - Soranzo, Nicole A1 - Guo, Xiuqing A1 - Roberts, David J A1 - Florez, Jose C A1 - Sladek, Robert A1 - Dupuis, Josée A1 - Morris, Andrew P A1 - Tai, E-Shyong A1 - Selvin, Elizabeth A1 - Rotter, Jerome I A1 - Langenberg, Claudia A1 - Barroso, Inês A1 - Meigs, James B KW - Diabetes Mellitus, Type 2 KW - Genetic Variation KW - Genome-Wide Association Study KW - Glycated Hemoglobin A KW - Humans KW - Phenotype KW - Risk AB -

BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.

METHODS & FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.

CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

VL - 14 IS - 9 ER -