@article {1308, title = {Total zinc intake may modify the glucose-raising effect of a zinc transporter (SLC30A8) variant: a 14-cohort meta-analysis.}, journal = {Diabetes}, volume = {60}, year = {2011}, month = {2011 Sep}, pages = {2407-16}, abstract = {

OBJECTIVE: Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for β-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants.

RESEARCH DESIGN AND METHODS: We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes.

RESULTS: We observed a significant association of total zinc intake with lower fasting glucose levels (β-coefficient {\textpm} SE per 1 mg/day of zinc intake: -0.0012 {\textpm} 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (β-coefficient {\textpm} SE per A allele for 1 mg/day of greater total zinc intake: -0.0017 {\textpm} 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant.

CONCLUSIONS: Our results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels.

}, keywords = {Blood Glucose, Cation Transport Proteins, Cohort Studies, Humans, Polymorphism, Single Nucleotide, Zinc, Zinc Transporter 8}, issn = {1939-327X}, doi = {10.2337/db11-0176}, author = {Kanoni, Stavroula and Nettleton, Jennifer A and Hivert, Marie-France and Ye, Zheng and van Rooij, Frank J A and Shungin, Dmitry and Sonestedt, Emily and Ngwa, Julius S and Wojczynski, Mary K and Lemaitre, Rozenn N and Gustafsson, Stefan and Anderson, Jennifer S and Tanaka, Toshiko and Hindy, George and Saylor, Georgia and Renstrom, Frida and Bennett, Amanda J and van Duijn, Cornelia M and Florez, Jose C and Fox, Caroline S and Hofman, Albert and Hoogeveen, Ron C and Houston, Denise K and Hu, Frank B and Jacques, Paul F and Johansson, Ingegerd and Lind, Lars and Liu, Yongmei and McKeown, Nicola and Ordovas, Jose and Pankow, James S and Sijbrands, Eric J G and Syv{\"a}nen, Ann-Christine and Uitterlinden, Andr{\'e} G and Yannakoulia, Mary and Zillikens, M Carola and Wareham, Nick J and Prokopenko, Inga and Bandinelli, Stefania and Forouhi, Nita G and Cupples, L Adrienne and Loos, Ruth J and Hallmans, G{\"o}ran and Dupuis, Jos{\'e}e and Langenberg, Claudia and Ferrucci, Luigi and Kritchevsky, Stephen B and McCarthy, Mark I and Ingelsson, Erik and Borecki, Ingrid B and Witteman, Jacqueline C M and Orho-Melander, Marju and Siscovick, David S and Meigs, James B and Franks, Paul W and Dedoussis, George V} } @article {8016, title = {Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.}, journal = {Nat Genet}, volume = {44}, year = {2012}, month = {2012 Apr 15}, pages = {491-501}, abstract = {

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 {\texttimes} 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 {\texttimes} 10(-4), Bonferroni corrected), of which six reached P < 5 {\texttimes} 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

}, keywords = {Bone Density, Computational Biology, European Continental Ancestry Group, Extracellular Matrix Proteins, Female, Femur Neck, Fractures, Bone, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Glycoproteins, Humans, Intercellular Signaling Peptides and Proteins, Low Density Lipoprotein Receptor-Related Protein-5, Lumbar Vertebrae, Male, Mitochondrial Membrane Transport Proteins, Osteoporosis, Phosphoproteins, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Spectrin}, issn = {1546-1718}, doi = {10.1038/ng.2249}, author = {Estrada, Karol and Styrkarsdottir, Unnur and Evangelou, Evangelos and Hsu, Yi-Hsiang and Duncan, Emma L and Ntzani, Evangelia E and Oei, Ling and Albagha, Omar M E and Amin, Najaf and Kemp, John P and Koller, Daniel L and Li, Guo and Liu, Ching-Ti and Minster, Ryan L and Moayyeri, Alireza and Vandenput, Liesbeth and Willner, Dana and Xiao, Su-Mei and Yerges-Armstrong, Laura M and Zheng, Hou-Feng and Alonso, Nerea and Eriksson, Joel and Kammerer, Candace M and Kaptoge, Stephen K and Leo, Paul J and Thorleifsson, Gudmar and Wilson, Scott G and Wilson, James F and Aalto, Ville and Alen, Markku and Aragaki, Aaron K and Aspelund, Thor and Center, Jacqueline R and Dailiana, Zoe and Duggan, David J and Garcia, Melissa and Garc{\'\i}a-Giralt, Natalia and Giroux, Sylvie and Hallmans, G{\"o}ran and Hocking, Lynne J and Husted, Lise Bjerre and Jameson, Karen A and Khusainova, Rita and Kim, Ghi Su and Kooperberg, Charles and Koromila, Theodora and Kruk, Marcin and Laaksonen, Marika and LaCroix, Andrea Z and Lee, Seung Hun and Leung, Ping C and Lewis, Joshua R and Masi, Laura and Mencej-Bedrac, Simona and Nguyen, Tuan V and Nogues, Xavier and Patel, Millan S and Prezelj, Janez and Rose, Lynda M and Scollen, Serena and Siggeirsdottir, Kristin and Smith, Albert V and Svensson, Olle and Trompet, Stella and Trummer, Olivia and van Schoor, Natasja M and Woo, Jean and Zhu, Kun and Balcells, Susana and Brandi, Maria Luisa and Buckley, Brendan M and Cheng, Sulin and Christiansen, Claus and Cooper, Cyrus and Dedoussis, George and Ford, Ian and Frost, Morten and Goltzman, David and Gonz{\'a}lez-Mac{\'\i}as, Jes{\'u}s and K{\"a}h{\"o}nen, Mika and Karlsson, Magnus and Khusnutdinova, Elza and Koh, Jung-Min and Kollia, Panagoula and Langdahl, Bente Lomholt and Leslie, William D and Lips, Paul and Ljunggren, Osten and Lorenc, Roman S and Marc, Janja and Mellstr{\"o}m, Dan and Obermayer-Pietsch, Barbara and Olmos, Jos{\'e} M and Pettersson-Kymmer, Ulrika and Reid, David M and Riancho, Jos{\'e} A and Ridker, Paul M and Rousseau, Fran{\c c}ois and Slagboom, P Eline and Tang, Nelson L S and Urreizti, Roser and Van Hul, Wim and Viikari, Jorma and Zarrabeitia, Mar{\'\i}a T and Aulchenko, Yurii S and Castano-Betancourt, Martha and Grundberg, Elin and Herrera, Lizbeth and Ingvarsson, Thorvaldur and Johannsdottir, Hrefna and Kwan, Tony and Li, Rui and Luben, Robert and Medina-G{\'o}mez, Carolina and Palsson, Stefan Th and Reppe, Sjur and Rotter, Jerome I and Sigurdsson, Gunnar and van Meurs, Joyce B J and Verlaan, Dominique and Williams, Frances M K and Wood, Andrew R and Zhou, Yanhua and Gautvik, Kaare M and Pastinen, Tomi and Raychaudhuri, Soumya and Cauley, Jane A and Chasman, Daniel I and Clark, Graeme R and Cummings, Steven R and Danoy, Patrick and Dennison, Elaine M and Eastell, Richard and Eisman, John A and Gudnason, Vilmundur and Hofman, Albert and Jackson, Rebecca D and Jones, Graeme and Jukema, J Wouter and Khaw, Kay-Tee and Lehtim{\"a}ki, Terho and Liu, Yongmei and Lorentzon, Mattias and McCloskey, Eugene and Mitchell, Braxton D and Nandakumar, Kannabiran and Nicholson, Geoffrey C and Oostra, Ben A and Peacock, Munro and Pols, Huibert A P and Prince, Richard L and Raitakari, Olli and Reid, Ian R and Robbins, John and Sambrook, Philip N and Sham, Pak Chung and Shuldiner, Alan R and Tylavsky, Frances A and van Duijn, Cornelia M and Wareham, Nick J and Cupples, L Adrienne and Econs, Michael J and Evans, David M and Harris, Tamara B and Kung, Annie Wai Chee and Psaty, Bruce M and Reeve, Jonathan and Spector, Timothy D and Streeten, Elizabeth A and Zillikens, M Carola and Thorsteinsdottir, Unnur and Ohlsson, Claes and Karasik, David and Richards, J Brent and Brown, Matthew A and Stefansson, Kari and Uitterlinden, Andr{\'e} G and Ralston, Stuart H and Ioannidis, John P A and Kiel, Douglas P and Rivadeneira, Fernando} } @article {6863, title = {HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.}, journal = {Lancet}, volume = {385}, year = {2015}, month = {2015 Jan 24}, pages = {351-61}, abstract = {

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{\textperiodcentered}06 mmol/L (95\% CI 0{\textperiodcentered}05-0{\textperiodcentered}07) lower LDL cholesterol and higher body weight (0{\textperiodcentered}30 kg, 0{\textperiodcentered}18-0{\textperiodcentered}43), waist circumference (0{\textperiodcentered}32 cm, 0{\textperiodcentered}16-0{\textperiodcentered}47), plasma insulin concentration (1{\textperiodcentered}62\%, 0{\textperiodcentered}53-2{\textperiodcentered}72), and plasma glucose concentration (0{\textperiodcentered}23\%, 0{\textperiodcentered}02-0{\textperiodcentered}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{\textperiodcentered}02, 95\% CI 1{\textperiodcentered}00-1{\textperiodcentered}05); the rs12916-T allele association was consistent (1{\textperiodcentered}06, 1{\textperiodcentered}03-1{\textperiodcentered}09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0{\textperiodcentered}92 mmol/L (95\% CI 0{\textperiodcentered}18-1{\textperiodcentered}67) at 1-year of follow-up, increased bodyweight by 0{\textperiodcentered}24 kg (95\% CI 0{\textperiodcentered}10-0{\textperiodcentered}38 in all trials; 0{\textperiodcentered}33 kg, 95\% CI 0{\textperiodcentered}24-0{\textperiodcentered}42 in placebo or standard care controlled trials and -0{\textperiodcentered}15 kg, 95\% CI -0{\textperiodcentered}39 to 0{\textperiodcentered}08 in intensive-dose vs moderate-dose trials) at a mean of 4{\textperiodcentered}2 years (range 1{\textperiodcentered}9-6{\textperiodcentered}7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1{\textperiodcentered}12, 95\% CI 1{\textperiodcentered}06-1{\textperiodcentered}18 in all trials; 1{\textperiodcentered}11, 95\% CI 1{\textperiodcentered}03-1{\textperiodcentered}20 in placebo or standard care controlled trials and 1{\textperiodcentered}12, 95\% CI 1{\textperiodcentered}04-1{\textperiodcentered}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.

}, keywords = {Aged, Body Mass Index, Body Weight, Cholesterol, HDL, Cholesterol, LDL, Diabetes Mellitus, Type 2, Female, Genetic Testing, Humans, Hydroxymethylglutaryl CoA Reductases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Male, Middle Aged, Polymorphism, Single Nucleotide, Randomized Controlled Trials as Topic, Risk Factors}, issn = {1474-547X}, doi = {10.1016/S0140-6736(14)61183-1}, author = {Swerdlow, Daniel I and Preiss, David and Kuchenbaecker, Karoline B and Holmes, Michael V and Engmann, Jorgen E L and Shah, Tina and Sofat, Reecha and Stender, Stefan and Johnson, Paul C D and Scott, Robert A and Leusink, Maarten and Verweij, Niek and Sharp, Stephen J and Guo, Yiran and Giambartolomei, Claudia and Chung, Christina and Peasey, Anne and Amuzu, Antoinette and Li, KaWah and Palmen, Jutta and Howard, Philip and Cooper, Jackie A and Drenos, Fotios and Li, Yun R and Lowe, Gordon and Gallacher, John and Stewart, Marlene C W and Tzoulaki, Ioanna and Buxbaum, Sarah G and van der A, Daphne L and Forouhi, Nita G and Onland-Moret, N Charlotte and van der Schouw, Yvonne T and Schnabel, Renate B and Hubacek, Jaroslav A and Kubinova, Ruzena and Baceviciene, Migle and Tamosiunas, Abdonas and Pajak, Andrzej and Topor-Madry, Roman and Stepaniak, Urszula and Malyutina, Sofia and Baldassarre, Damiano and Sennblad, Bengt and Tremoli, Elena and de Faire, Ulf and Veglia, Fabrizio and Ford, Ian and Jukema, J Wouter and Westendorp, Rudi G J and de Borst, Gert Jan and de Jong, Pim A and Algra, Ale and Spiering, Wilko and Maitland-van der Zee, Anke H and Klungel, Olaf H and de Boer, Anthonius and Doevendans, Pieter A and Eaton, Charles B and Robinson, Jennifer G and Duggan, David and Kjekshus, John and Downs, John R and Gotto, Antonio M and Keech, Anthony C and Marchioli, Roberto and Tognoni, Gianni and Sever, Peter S and Poulter, Neil R and Waters, David D and Pedersen, Terje R and Amarenco, Pierre and Nakamura, Haruo and McMurray, John J V and Lewsey, James D and Chasman, Daniel I and Ridker, Paul M and Maggioni, Aldo P and Tavazzi, Luigi and Ray, Kausik K and Seshasai, Sreenivasa Rao Kondapally and Manson, JoAnn E and Price, Jackie F and Whincup, Peter H and Morris, Richard W and Lawlor, Debbie A and Smith, George Davey and Ben-Shlomo, Yoav and Schreiner, Pamela J and Fornage, Myriam and Siscovick, David S and Cushman, Mary and Kumari, Meena and Wareham, Nick J and Verschuren, W M Monique and Redline, Susan and Patel, Sanjay R and Whittaker, John C and Hamsten, Anders and Delaney, Joseph A and Dale, Caroline and Gaunt, Tom R and Wong, Andrew and Kuh, Diana and Hardy, Rebecca and Kathiresan, Sekar and Castillo, Berta A and van der Harst, Pim and Brunner, Eric J and Tybjaerg-Hansen, Anne and Marmot, Michael G and Krauss, Ronald M and Tsai, Michael and Coresh, Josef and Hoogeveen, Ronald C and Psaty, Bruce M and Lange, Leslie A and Hakonarson, Hakon and Dudbridge, Frank and Humphries, Steve E and Talmud, Philippa J and Kivimaki, Mika and Timpson, Nicholas J and Langenberg, Claudia and Asselbergs, Folkert W and Voevoda, Mikhail and Bobak, Martin and Pikhart, Hynek and Wilson, James G and Reiner, Alex P and Keating, Brendan J and Hingorani, Aroon D and Sattar, Naveed} } @article {6936, title = {A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration.}, journal = {Hum Mol Genet}, volume = {25}, year = {2016}, month = {2016 Jan 15}, pages = {358-70}, abstract = {

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including \~{}120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3\% of the variance in plasma fibrinogen concentration.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddv454}, author = {de Vries, Paul S and Chasman, Daniel I and Sabater-Lleal, Maria and Chen, Ming-Huei and Huffman, Jennifer E and Steri, Maristella and Tang, Weihong and Teumer, Alexander and Marioni, Riccardo E and Grossmann, Vera and Hottenga, Jouke J and Trompet, Stella and M{\"u}ller-Nurasyid, Martina and Zhao, Jing Hua and Brody, Jennifer A and Kleber, Marcus E and Guo, Xiuqing and Wang, Jie Jin and Auer, Paul L and Attia, John R and Yanek, Lisa R and Ahluwalia, Tarunveer S and Lahti, Jari and Venturini, Cristina and Tanaka, Toshiko and Bielak, Lawrence F and Joshi, Peter K and Rocanin-Arjo, Ares and Kolcic, Ivana and Navarro, Pau and Rose, Lynda M and Oldmeadow, Christopher and Riess, Helene and Mazur, Johanna and Basu, Saonli and Goel, Anuj and Yang, Qiong and Ghanbari, Mohsen and Willemsen, Gonneke and Rumley, Ann and Fiorillo, Edoardo and de Craen, Anton J M and Grotevendt, Anne and Scott, Robert and Taylor, Kent D and Delgado, Graciela E and Yao, Jie and Kifley, Annette and Kooperberg, Charles and Qayyum, Rehan and Lopez, Lorna M and Berentzen, Tina L and R{\"a}ikk{\"o}nen, Katri and Mangino, Massimo and Bandinelli, Stefania and Peyser, Patricia A and Wild, Sarah and Tr{\'e}gou{\"e}t, David-Alexandre and Wright, Alan F and Marten, Jonathan and Zemunik, Tatijana and Morrison, Alanna C and Sennblad, Bengt and Tofler, Geoffrey and de Maat, Moniek P M and de Geus, Eco J C and Lowe, Gordon D and Zoledziewska, Magdalena and Sattar, Naveed and Binder, Harald and V{\"o}lker, Uwe and Waldenberger, Melanie and Khaw, Kay-Tee and McKnight, Barbara and Huang, Jie and Jenny, Nancy S and Holliday, Elizabeth G and Qi, Lihong and Mcevoy, Mark G and Becker, Diane M and Starr, John M and Sarin, Antti-Pekka and Hysi, Pirro G and Hernandez, Dena G and Jhun, Min A and Campbell, Harry and Hamsten, Anders and Rivadeneira, Fernando and McArdle, Wendy L and Slagboom, P Eline and Zeller, Tanja and Koenig, Wolfgang and Psaty, Bruce M and Haritunians, Talin and Liu, Jingmin and Palotie, Aarno and Uitterlinden, Andr{\'e} G and Stott, David J and Hofman, Albert and Franco, Oscar H and Polasek, Ozren and Rudan, Igor and Morange, Pierre-Emmanuel and Wilson, James F and Kardia, Sharon L R and Ferrucci, Luigi and Spector, Tim D and Eriksson, Johan G and Hansen, Torben and Deary, Ian J and Becker, Lewis C and Scott, Rodney J and Mitchell, Paul and M{\"a}rz, Winfried and Wareham, Nick J and Peters, Annette and Greinacher, Andreas and Wild, Philipp S and Jukema, J Wouter and Boomsma, Dorret I and Hayward, Caroline and Cucca, Francesco and Tracy, Russell and Watkins, Hugh and Reiner, Alex P and Folsom, Aaron R and Ridker, Paul M and O{\textquoteright}Donnell, Christopher J and Smith, Nicholas L and Strachan, David P and Dehghan, Abbas} } @article {7573, title = {Exome-wide association study of plasma lipids in >300,000 individuals.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Dec}, pages = {1758-1766}, abstract = {

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

}, keywords = {Coronary Artery Disease, Diabetes Mellitus, Type 2, Exome, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Genotype, Humans, Lipids, Macular Degeneration, Phenotype, Risk Factors}, issn = {1546-1718}, doi = {10.1038/ng.3977}, author = {Liu, Dajiang J and Peloso, Gina M and Yu, Haojie and Butterworth, Adam S and Wang, Xiao and Mahajan, Anubha and Saleheen, Danish and Emdin, Connor and Alam, Dewan and Alves, Alexessander Couto and Amouyel, Philippe and Di Angelantonio, Emanuele and Arveiler, Dominique and Assimes, Themistocles L and Auer, Paul L and Baber, Usman and Ballantyne, Christie M and Bang, Lia E and Benn, Marianne and Bis, Joshua C and Boehnke, Michael and Boerwinkle, Eric and Bork-Jensen, Jette and Bottinger, Erwin P and Brandslund, Ivan and Brown, Morris and Busonero, Fabio and Caulfield, Mark J and Chambers, John C and Chasman, Daniel I and Chen, Y Eugene and Chen, Yii-Der Ida and Chowdhury, Rajiv and Christensen, Cramer and Chu, Audrey Y and Connell, John M and Cucca, Francesco and Cupples, L Adrienne and Damrauer, Scott M and Davies, Gail and Deary, Ian J and Dedoussis, George and Denny, Joshua C and Dominiczak, Anna and Dub{\'e}, Marie-Pierre and Ebeling, Tapani and Eiriksdottir, Gudny and Esko, T{\~o}nu and Farmaki, Aliki-Eleni and Feitosa, Mary F and Ferrario, Marco and Ferrieres, Jean and Ford, Ian and Fornage, Myriam and Franks, Paul W and Frayling, Timothy M and Frikke-Schmidt, Ruth and Fritsche, Lars G and Frossard, Philippe and Fuster, Valentin and Ganesh, Santhi K and Gao, Wei and Garcia, Melissa E and Gieger, Christian and Giulianini, Franco and Goodarzi, Mark O and Grallert, Harald and Grarup, Niels and Groop, Leif and Grove, Megan L and Gudnason, Vilmundur and Hansen, Torben and Harris, Tamara B and Hayward, Caroline and Hirschhorn, Joel N and Holmen, Oddgeir L and Huffman, Jennifer and Huo, Yong and Hveem, Kristian and Jabeen, Sehrish and Jackson, Anne U and Jakobsdottir, Johanna and Jarvelin, Marjo-Riitta and Jensen, Gorm B and J{\o}rgensen, Marit E and Jukema, J Wouter and Justesen, Johanne M and Kamstrup, Pia R and Kanoni, Stavroula and Karpe, Fredrik and Kee, Frank and Khera, Amit V and Klarin, Derek and Koistinen, Heikki A and Kooner, Jaspal S and Kooperberg, Charles and Kuulasmaa, Kari and Kuusisto, Johanna and Laakso, Markku and Lakka, Timo and Langenberg, Claudia and Langsted, Anne and Launer, Lenore J and Lauritzen, Torsten and Liewald, David C M and Lin, Li An and Linneberg, Allan and Loos, Ruth J F and Lu, Yingchang and Lu, Xiangfeng and M{\"a}gi, Reedik and M{\"a}larstig, Anders and Manichaikul, Ani and Manning, Alisa K and M{\"a}ntyselk{\"a}, Pekka and Marouli, Eirini and Masca, Nicholas G D and Maschio, Andrea and Meigs, James B and Melander, Olle and Metspalu, Andres and Morris, Andrew P and Morrison, Alanna C and Mulas, Antonella and M{\"u}ller-Nurasyid, Martina and Munroe, Patricia B and Neville, Matt J and Nielsen, Jonas B and Nielsen, Sune F and Nordestgaard, B{\o}rge G and Ordovas, Jose M and Mehran, Roxana and O{\textquoteright}Donnell, Christoper J and Orho-Melander, Marju and Molony, Cliona M and Muntendam, Pieter and Padmanabhan, Sandosh and Palmer, Colin N A and Pasko, Dorota and Patel, Aniruddh P and Pedersen, Oluf and Perola, Markus and Peters, Annette and Pisinger, Charlotta and Pistis, Giorgio and Polasek, Ozren and Poulter, Neil and Psaty, Bruce M and Rader, Daniel J and Rasheed, Asif and Rauramaa, Rainer and Reilly, Dermot F and Reiner, Alex P and Renstrom, Frida and Rich, Stephen S and Ridker, Paul M and Rioux, John D and Robertson, Neil R and Roden, Dan M and Rotter, Jerome I and Rudan, Igor and Salomaa, Veikko and Samani, Nilesh J and Sanna, Serena and Sattar, Naveed and Schmidt, Ellen M and Scott, Robert A and Sever, Peter and Sevilla, Raquel S and Shaffer, Christian M and Sim, Xueling and Sivapalaratnam, Suthesh and Small, Kerrin S and Smith, Albert V and Smith, Blair H and Somayajula, Sangeetha and Southam, Lorraine and Spector, Timothy D and Speliotes, Elizabeth K and Starr, John M and Stirrups, Kathleen E and Stitziel, Nathan and Strauch, Konstantin and Stringham, Heather M and Surendran, Praveen and Tada, Hayato and Tall, Alan R and Tang, Hua and Tardif, Jean-Claude and Taylor, Kent D and Trompet, Stella and Tsao, Philip S and Tuomilehto, Jaakko and Tybjaerg-Hansen, Anne and van Zuydam, Natalie R and Varbo, Anette and Varga, Tibor V and Virtamo, Jarmo and Waldenberger, Melanie and Wang, Nan and Wareham, Nick J and Warren, Helen R and Weeke, Peter E and Weinstock, Joshua and Wessel, Jennifer and Wilson, James G and Wilson, Peter W F and Xu, Ming and Yaghootkar, Hanieh and Young, Robin and Zeggini, Eleftheria and Zhang, He and Zheng, Neil S and Zhang, Weihua and Zhang, Yan and Zhou, Wei and Zhou, Yanhua and Zoledziewska, Magdalena and Howson, Joanna M M and Danesh, John and McCarthy, Mark I and Cowan, Chad A and Abecasis, Goncalo and Deloukas, Panos and Musunuru, Kiran and Willer, Cristen J and Kathiresan, Sekar} } @article {7688, title = {Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness.}, journal = {Nat Commun}, volume = {8}, year = {2017}, month = {2017 Jul 12}, pages = {16015}, abstract = {

Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 {\texttimes} 10) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.

}, issn = {2041-1723}, doi = {10.1038/ncomms16015}, author = {Willems, Sara M and Wright, Daniel J and Day, Felix R and Trajanoska, Katerina and Joshi, Peter K and Morris, John A and Matteini, Amy M and Garton, Fleur C and Grarup, Niels and Oskolkov, Nikolay and Thalamuthu, Anbupalam and Mangino, Massimo and Liu, Jun and Demirkan, Ayse and Lek, Monkol and Xu, Liwen and Wang, Guan and Oldmeadow, Christopher and Gaulton, Kyle J and Lotta, Luca A and Miyamoto-Mikami, Eri and Rivas, Manuel A and White, Tom and Loh, Po-Ru and Aadahl, Mette and Amin, Najaf and Attia, John R and Austin, Krista and Benyamin, Beben and Brage, S{\o}ren and Cheng, Yu-Ching and Ci{\k e}szczyk, Pawe{\l} and Derave, Wim and Eriksson, Karl-Fredrik and Eynon, Nir and Linneberg, Allan and Lucia, Alejandro and Massidda, Myosotis and Mitchell, Braxton D and Miyachi, Motohiko and Murakami, Haruka and Padmanabhan, Sandosh and Pandey, Ashutosh and Papadimitriou, Ioannis and Rajpal, Deepak K and Sale, Craig and Schnurr, Theresia M and Sessa, Francesco and Shrine, Nick and Tobin, Martin D and Varley, Ian and Wain, Louise V and Wray, Naomi R and Lindgren, Cecilia M and MacArthur, Daniel G and Waterworth, Dawn M and McCarthy, Mark I and Pedersen, Oluf and Khaw, Kay-Tee and Kiel, Douglas P and Pitsiladis, Yannis and Fuku, Noriyuki and Franks, Paul W and North, Kathryn N and van Duijn, Cornelia M and Mather, Karen A and Hansen, Torben and Hansson, Ola and Spector, Tim and Murabito, Joanne M and Richards, J Brent and Rivadeneira, Fernando and Langenberg, Claudia and Perry, John R B and Wareham, Nick J and Scott, Robert A} } @article {8041, title = {Fatty acid biomarkers of dairy fat consumption and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies.}, journal = {PLoS Med}, volume = {15}, year = {2018}, month = {2018 10}, pages = {e1002670}, abstract = {

BACKGROUND: We aimed to investigate prospective associations of circulating or adipose tissue odd-chain fatty acids 15:0 and 17:0 and trans-palmitoleic acid, t16:1n-7, as potential biomarkers of dairy fat intake, with incident type 2 diabetes (T2D).

METHODS AND FINDINGS: Sixteen prospective cohorts from 12 countries (7 from the United States, 7 from Europe, 1 from Australia, 1 from Taiwan) performed new harmonised individual-level analysis for the prospective associations according to a standardised plan. In total, 63,682 participants with a broad range of baseline ages and BMIs and 15,180 incident cases of T2D over the average of 9 years of follow-up were evaluated. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Prespecified interactions by age, sex, BMI, and race/ethnicity were explored in each cohort and were meta-analysed. Potential heterogeneity by cohort-specific characteristics (regions, lipid compartments used for fatty acid assays) was assessed with metaregression. After adjustment for potential confounders, including measures of adiposity (BMI, waist circumference) and lipogenesis (levels of palmitate, triglycerides), higher levels of 15:0, 17:0, and t16:1n-7 were associated with lower incidence of T2D. In the most adjusted model, the hazard ratio (95\% CI) for incident T2D per cohort-specific 10th to 90th percentile range of 15:0 was 0.80 (0.73-0.87); of 17:0, 0.65 (0.59-0.72); of t16:1n7, 0.82 (0.70-0.96); and of their sum, 0.71 (0.63-0.79). In exploratory analyses, similar associations for 15:0, 17:0, and the sum of all three fatty acids were present in both genders but stronger in women than in men (pinteraction < 0.001). Whereas studying associations with biomarkers has several advantages, as limitations, the biomarkers do not distinguish between different food sources of dairy fat (e.g., cheese, yogurt, milk), and residual confounding by unmeasured or imprecisely measured confounders may exist.

CONCLUSIONS: In a large meta-analysis that pooled the findings from 16 prospective cohort studies, higher levels of 15:0, 17:0, and t16:1n-7 were associated with a lower risk of T2D.

}, keywords = {Aged, Australia, Biomarkers, Dairy Products, Diabetes Mellitus, Type 2, Dietary Fats, Europe, Fatty Acids, Fatty Acids, Monounsaturated, Female, Humans, Incidence, Male, Middle Aged, Prospective Studies, Sex Factors, Taiwan, United States}, issn = {1549-1676}, doi = {10.1371/journal.pmed.1002670}, author = {Imamura, Fumiaki and Fretts, Amanda and Marklund, Matti and Ardisson Korat, Andres V and Yang, Wei-Sin and Lankinen, Maria and Qureshi, Waqas and Helmer, Catherine and Chen, Tzu-An and Wong, Kerry and Bassett, Julie K and Murphy, Rachel and Tintle, Nathan and Yu, Chaoyu Ian and Brouwer, Ingeborg A and Chien, Kuo-Liong and Frazier-Wood, Alexis C and Del Gobbo, Liana C and Djouss{\'e}, Luc and Geleijnse, Johanna M and Giles, Graham G and de Goede, Janette and Gudnason, Vilmundur and Harris, William S and Hodge, Allison and Hu, Frank and Koulman, Albert and Laakso, Markku and Lind, Lars and Lin, Hung-Ju and McKnight, Barbara and Rajaobelina, Kalina and Riserus, Ulf and Robinson, Jennifer G and Samieri, Cecilia and Siscovick, David S and Soedamah-Muthu, Sabita S and Sotoodehnia, Nona and Sun, Qi and Tsai, Michael Y and Uusitupa, Matti and Wagenknecht, Lynne E and Wareham, Nick J and Wu, Jason HY and Micha, Renata and Forouhi, Nita G and Lemaitre, Rozenn N and Mozaffarian, Dariush} } @article {7558, title = {Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Jan}, pages = {42-53}, abstract = {

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

}, issn = {1546-1718}, doi = {10.1038/s41588-017-0014-7}, author = {Demenais, Florence and Margaritte-Jeannin, Patricia and Barnes, Kathleen C and Cookson, William O C and Altm{\"u}ller, Janine and Ang, Wei and Barr, R Graham and Beaty, Terri H and Becker, Allan B and Beilby, John and Bisgaard, Hans and Bjornsdottir, Unnur Steina and Bleecker, Eugene and B{\o}nnelykke, Klaus and Boomsma, Dorret I and Bouzigon, Emmanuelle and Brightling, Christopher E and Brossard, Myriam and Brusselle, Guy G and Burchard, Esteban and Burkart, Kristin M and Bush, Andrew and Chan-Yeung, Moira and Chung, Kian Fan and Couto Alves, Alexessander and Curtin, John A and Custovic, Adnan and Daley, Denise and de Jongste, Johan C and Del-Rio-Navarro, Blanca E and Donohue, Kathleen M and Duijts, Liesbeth and Eng, Celeste and Eriksson, Johan G and Farrall, Martin and Fedorova, Yuliya and Feenstra, Bjarke and Ferreira, Manuel A and Freidin, Maxim B and Gajdos, Zofia and Gauderman, Jim and Gehring, Ulrike and Geller, Frank and Genuneit, Jon and Gharib, Sina A and Gilliland, Frank and Granell, Raquel and Graves, Penelope E and Gudbjartsson, Daniel F and Haahtela, Tari and Heckbert, Susan R and Heederik, Dick and Heinrich, Joachim and Heli{\"o}vaara, Markku and Henderson, John and Himes, Blanca E and Hirose, Hiroshi and Hirschhorn, Joel N and Hofman, Albert and Holt, Patrick and Hottenga, Jouke and Hudson, Thomas J and Hui, Jennie and Imboden, Medea and Ivanov, Vladimir and Jaddoe, Vincent W V and James, Alan and Janson, Christer and Jarvelin, Marjo-Riitta and Jarvis, Deborah and Jones, Graham and Jonsdottir, Ingileif and Jousilahti, Pekka and Kabesch, Michael and K{\"a}h{\"o}nen, Mika and Kantor, David B and Karunas, Alexandra S and Khusnutdinova, Elza and Koppelman, Gerard H and Kozyrskyj, Anita L and Kreiner, Eskil and Kubo, Michiaki and Kumar, Rajesh and Kumar, Ashish and Kuokkanen, Mikko and Lahousse, Lies and Laitinen, Tarja and Laprise, Catherine and Lathrop, Mark and Lau, Susanne and Lee, Young-Ae and Lehtim{\"a}ki, Terho and Letort, S{\'e}bastien and Levin, Albert M and Li, Guo and Liang, Liming and Loehr, Laura R and London, Stephanie J and Loth, Daan W and Manichaikul, Ani and Marenholz, Ingo and Martinez, Fernando J and Matheson, Melanie C and Mathias, Rasika A and Matsumoto, Kenji and Mbarek, Hamdi and McArdle, Wendy L and Melbye, Mads and Mel{\'e}n, Erik and Meyers, Deborah and Michel, Sven and Mohamdi, Hamida and Musk, Arthur W and Myers, Rachel A and Nieuwenhuis, Maartje A E and Noguchi, Emiko and O{\textquoteright}Connor, George T and Ogorodova, Ludmila M and Palmer, Cameron D and Palotie, Aarno and Park, Julie E and Pennell, Craig E and Pershagen, G{\"o}ran and Polonikov, Alexey and Postma, Dirkje S and Probst-Hensch, Nicole and Puzyrev, Valery P and Raby, Benjamin A and Raitakari, Olli T and Ramasamy, Adaikalavan and Rich, Stephen S and Robertson, Colin F and Romieu, Isabelle and Salam, Muhammad T and Salomaa, Veikko and Schl{\"u}nssen, Vivi and Scott, Robert and Selivanova, Polina A and Sigsgaard, Torben and Simpson, Angela and Siroux, Val{\'e}rie and Smith, Lewis J and Solodilova, Maria and Standl, Marie and Stefansson, Kari and Strachan, David P and Stricker, Bruno H and Takahashi, Atsushi and Thompson, Philip J and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tiesler, Carla M T and Torgerson, Dara G and Tsunoda, Tatsuhiko and Uitterlinden, Andr{\'e} G and van der Valk, Ralf J P and Vaysse, Amaury and Vedantam, Sailaja and von Berg, Andrea and von Mutius, Erika and Vonk, Judith M and Waage, Johannes and Wareham, Nick J and Weiss, Scott T and White, Wendy B and Wickman, Magnus and Widen, Elisabeth and Willemsen, Gonneke and Williams, L Keoki and Wouters, Inge M and Yang, James J and Zhao, Jing Hua and Moffatt, Miriam F and Ober, Carole and Nicolae, Dan L} } @article {8830, title = {Sugar-Sweetened Beverage Consumption May Modify Associations Between Genetic Variants in the CHREBP (Carbohydrate Responsive Element Binding Protein) Locus and HDL-C (High-Density Lipoprotein Cholesterol) and Triglyceride Concentrations.}, journal = {Circ Genom Precis Med}, volume = {14}, year = {2021}, month = {2021 Aug}, pages = {e003288}, abstract = {

BACKGROUND: ChREBP (carbohydrate responsive element binding protein) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the locus have separately been linked to HDL-C (high-density lipoprotein cholesterol) and triglyceride concentrations. We hypothesized that SSB consumption would modify the association between genetic variants in the locus and dyslipidemia.

METHODS: Data from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (N=63 599) and the UK Biobank (N=59 220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and triglyceride concentrations using linear regression models. A total of 1606 single nucleotide polymorphisms within or near were considered. SSB consumption was estimated from validated questionnaires, and participants were grouped by their estimated intake.

RESULTS: In a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers (β, 2.12 [95\% CI, 1.16-3.07] mg/dL per allele; <0.0001), but not significantly among the lowest SSB consumers (=0.81; <0.0001). Similar results were observed for 2 additional variants (rs35709627 and rs71556736). For triglyceride, rs55673514 was positively associated with triglyceride concentrations only among the highest SSB consumers (β, 0.06 [95\% CI, 0.02-0.09] ln-mg/dL per allele, =0.001) but not the lowest SSB consumers (=0.84; =0.0005).

CONCLUSIONS: Our results identified genetic variants in the locus that may protect against SSB-associated reductions in HDL-C and other variants that may exacerbate SSB-associated increases in triglyceride concentrations. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00005133, NCT00005121, NCT00005487, and NCT00000479.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.120.003288}, author = {Haslam, Danielle E and Peloso, Gina M and Guirette, Melanie and Imamura, Fumiaki and Bartz, Traci M and Pitsillides, Achilleas N and Wang, Carol A and Li-Gao, Ruifang and Westra, Jason M and Pitk{\"a}nen, Niina and Young, Kristin L and Graff, Mariaelisa and Wood, Alexis C and Braun, Kim V E and Luan, Jian{\textquoteright}an and K{\"a}h{\"o}nen, Mika and Kiefte-de Jong, Jessica C and Ghanbari, Mohsen and Tintle, Nathan and Lemaitre, Rozenn N and Mook-Kanamori, Dennis O and North, Kari and Helminen, Mika and Mossavar-Rahmani, Yasmin and Snetselaar, Linda and Martin, Lisa W and Viikari, Jorma S and Oddy, Wendy H and Pennell, Craig E and Rosendall, Frits R and Ikram, M Arfan and Uitterlinden, Andr{\'e} G and Psaty, Bruce M and Mozaffarian, Dariush and Rotter, Jerome I and Taylor, Kent D and Lehtim{\"a}ki, Terho and Raitakari, Olli T and Livingston, Kara A and Voortman, Trudy and Forouhi, Nita G and Wareham, Nick J and de Mutsert, Ren{\'e}e and Rich, Steven S and Manson, JoAnn E and Mora, Samia and Ridker, Paul M and Merino, Jordi and Meigs, James B and Dashti, Hassan S and Chasman, Daniel I and Lichtenstein, Alice H and Smith, Caren E and Dupuis, Jos{\'e}e and Herman, Mark A and McKeown, Nicola M} }