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1. Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Author

Tobias Hermle, Holger Kirsten, Karsten B. Sieber, Aiko P. J. de Vries, Su Chi Lim, Peter Kovacs, Charumathi Sabanayagam, Carl D. Langefeld, Bernhard K. Krämer, Kent D. Taylor, Janine F. Felix, Belen Ponte, Markus Loeffler, Mary F. Feitosa, Kai-Uwe Eckardt, Jianjun Liu, Katalin Dittrich, Charlene A. Wong, Uwe Völker, Adriana M. Hung, Thomas Meitinger, Anubha Mahajan, Anselm Hoppmann, Erik Ingelsson, Martin H. de Borst, Oscar H. Franco, Niek Verweij, Kai-Uwe Saum, Vilmundur Gudnason, Bram P. Prins, Carsten A. Böger, Terho Lehtimäki, Andrew A. Hicks, Todd L. Edwards, Olivier Devuyst, Peter P. Pramstaller, Katrin Horn, Leslie A. Lange, Johanne Tremblay, Jin-Fang Chai, Sahar Ghasemi, Kjell Nikus, Tanja Poulain, Massimiliano Cocca, Anna Köttgen, Eric Boerwinkle, Barry I. Freedman, Miao-Ling Chee, Man Li, Stephan J. L. Bakker, Tamara B. Harris, Albert V. Smith, Ton J. Rabelink, Dennis O. Mook-Kanamori, Iris M. Heid, Jasmin Divers, Chaolong Wang, Kathleen A. Ryan, Pavel Hamet, Silke Szymczak, Shih-Jen Hwang, Hauke Thomsen, Rainer Rettig, Ayush Giri, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Cristian Pattaro, Andrej Teren, Valencia Hui Xian Foo, Myriam Rheinberger, Audrey Y. Chu, Barbara McMullen, Franziska Grundner-Culemann, Masayuki Yasuda, Murielle Bochud, Martin Gögele, Anke Tönjes, Jeannette Lee, Adrienne Tin, Kevin Ho, Konstantin Strauch, Josef Coresh, Renée de Mutsert, Sandra Freitag-Wolf, Gardar Sveinbjornsson, Yizhe Xu, Katalin Susztak, Tien Yin Wong, Mary L. Biggs, Isleifur Olafsson, Qiong Yang, Antje Körner, Chengxiang Qiu, E-Shyong Tai, Martina Müller-Nurasyid, Ben Schöttker, Jeffrey O' Connell, Mengmeng Chen, Daniel F. Gudbjartsson, Dermot F. Reilly, Vincent W. V. Jaddoe, Damia Noce, Pim van der Harst, Sanaz Sedaghat, Chiea Chuen Khor, Adam S. Butterworth, Mathias Gorski, Robert J. Carroll, James G. Wilson, Johan Ärnlöv, Christa Meisinger, Kenneth Rice, Bettina Jung, Christian M. Shaffer, Unnur Thorsteinsdottir, Matthias Nauck, Shreeram Akilesh, Mika Kähönen, Johanna Jakobsdottir, Melanie Waldenberger, Ralph Burkhardt, Daniela Baptista, John Danesh, Benjamin B. Sun, Karlhans Endlich, Holly Kramer, Frauke Degenhardt, Wolfgang Lieb, Kari Stefansson, Joachim Thiery, Lars Lind, Nicholette D. Palmer, Sarah A. Pendergrass, Suzanne Vogelezang, Peter J. van der Most, Afshin Parsa, Markus Scholz, Florian Kronenberg, Joseph C. Maranville, Laura M. Raffield, Hermann Brenner, Wieland Kiess, Anna I. Podgornaia, Yuan Shi, Tanguy Corre, Miao-Li Chee, Deborah Mascalzoni, Bamidele O. Tayo, Navya Shilpa Josyula, Ching-Yu Cheng, Lea Gerstner, Nisha Bansal, Jerome I. Rotter, Alexander Teumer, Vilmantas Giedraitis, Raymond Noordam, Ron T. Gansevoort, Lihua Wang, Andrew P. Morris, Bruce M. Psaty, Boting Ning, Zhi Yu, Christian Fuchsberger, Matthias Wuttke, Heiko Runz, Annette Peters, Yih Chung Tham, James P. Cook, Yong Li, Chris H. L. Thio, Hilma Holm, Alessandro De Grandi, Jonathan Marten, André G. Uitterlinden, Andre Franke, Nicholas Y. Q. Tan, Otis D. Wilson, Georg Ehret, Cecilia M. Lindgren, Josyf C. Mychaleckyj, Wolfgang Koenig, Harold Snieder, Michael Stumvoll, Kozeta Miliku, M. Arfan Ikram, Teresa Nutile, Læknadeild (HÍ), Faculty of Medicine (UI), School of Health Sciences (UI), Heilbrigðisvísindasvið (HÍ), Háskóli Íslands, University of Iceland, Teumer, Alexander [0000-0002-8309-094X], Li, Yong [0000-0003-2651-8791], Wuttke, Matthias [0000-0003-3420-5082], Giri, Ayush [0000-0002-7786-4670], Qiu, Chengxiang [0000-0002-6346-8669], Kirsten, Holger [0000-0002-3126-7950], Tin, Adrienne [0000-0002-4207-5866], Feitosa, Mary F. [0000-0002-0933-2410], Chai, Jin-Fang [0000-0003-3770-1137], Cocca, Massimiliano [0000-0002-1127-7596], Gorski, Mathias [0000-0002-9103-5860], Horn, Katrin [0000-0002-5307-6936], Li, Man [0000-0002-3839-0281], Marten, Jonathan [0000-0001-6916-2014], van der Most, Peter J. [0000-0001-8450-3518], Burkhardt, Ralph [0000-0003-1924-1202], Coresh, Josef [0000-0002-4598-0669], de Borst, Martin H. [0000-0002-4127-8733], Ehret, Georg [0000-0002-5730-0675], Endlich, Karlhans [0000-0001-6052-6061], Felix, Janine F. [0000-0002-9801-5774], Franke, Andre [0000-0003-1530-5811], Freedman, Barry I. [0000-0003-0275-5530], Freitag-Wolf, Sandra [0000-0002-1069-7740], Giedraitis, Vilmantas [0000-0003-3423-2021], Grundner-Culemann, Franziska [0000-0001-9649-281X], Gudnason, Vilmundur [0000-0001-5696-0084], Hicks, Andrew A. [0000-0001-6320-0411], Ikram, M. Arfan [0000-0003-0372-8585], Ingelsson, Erik [0000-0003-2256-6972], Jaddoe, Vincent W. V. [0000-0003-2939-0041], Josyula, Navya Shilpa [0000-0003-2782-8812], Khor, Chiea-Chuen [0000-0002-1128-4729], Koenig, Wolfgang [0000-0002-2064-9603], Kovacs, Peter [0000-0002-0290-5423], Kronenberg, Florian [0000-0003-2229-1120], Lindgren, Cecilia M. [0000-0002-4903-9374], Liu, Jianjun [0000-0002-3255-3019], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], Mahajan, Anubha [0000-0001-5585-3420], Mascalzoni, Deborah [0000-0003-4156-1464], Miliku, Kozeta [0000-0002-9614-7191], Müller-Nurasyid, Martina [0000-0003-3793-5910], Mychaleckyj, Josyf C. [0000-0003-2595-0005], Palmer, Nicholette D. [0000-0001-8883-2511], Poulain, Tanja [0000-0003-3825-5829], Raffield, Laura M. [0000-0002-7892-193X], Rice, Kenneth M. [0000-0002-3071-7278], Rivadeneira, Fernando [0000-0001-9435-9441], Sabanayagam, Charumathi [0000-0002-4042-4719], Smith, Albert V. [0000-0003-1942-5845], Sun, Benjamin B. [0000-0001-6347-2281], Szymczak, Silke [0000-0002-8897-9035], Taylor, Kent D. [0000-0002-2756-4370], Thio, Chris H. L. [0000-0003-2623-7172], Uitterlinden, André G. [0000-0002-7276-3387], van der Harst, Pim [0000-0002-2713-686X], Verweij, Niek [0000-0002-4303-7685], Völker, Uwe [0000-0002-5689-3448], Wang, Chaolong [0000-0003-3945-1012], Yang, Qiong [0000-0002-3658-1375], Devuyst, Olivier [0000-0003-3744-4767], Edwards, Todd L. [0000-0003-4318-6119], Ho, Kevin [0000-0002-3054-8697], Morris, Andrew P. [0000-0002-6805-6014], Pendergrass, Sarah A. [0000-0002-0565-6522], Rotter, Jerome I. [0000-0001-7191-1723], Stefansson, Kari [0000-0003-1676-864X], Susztak, Katalin [0000-0002-1005-3726], Scholz, Markus [0000-0002-4059-1779], Butterworth, Adam S. [0000-0002-6915-9015], Hung, Adriana M. [0000-0002-3203-1608], Pattaro, Cristian [0000-0002-4119-0109], Köttgen, Anna [0000-0002-4671-3714], Apollo - University of Cambridge Repository, Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Epidemiology, Erasmus MC other, Pediatrics, Internal Medicine, Feitosa, Mary F [0000-0002-0933-2410], van der Most, Peter J [0000-0001-8450-3518], de Borst, Martin H [0000-0002-4127-8733], Felix, Janine F [0000-0002-9801-5774], Freedman, Barry I [0000-0003-0275-5530], Hicks, Andrew A [0000-0001-6320-0411], Ikram, M Arfan [0000-0003-0372-8585], Jaddoe, Vincent WV [0000-0003-2939-0041], Lindgren, Cecilia M [0000-0002-4903-9374], Mychaleckyj, Josyf C [0000-0003-2595-0005], Palmer, Nicholette D [0000-0001-8883-2511], Raffield, Laura M [0000-0002-7892-193X], Rice, Kenneth M [0000-0002-3071-7278], Smith, Albert V [0000-0003-1942-5845], Sun, Benjamin B [0000-0001-6347-2281], Taylor, Kent D [0000-0002-2756-4370], Thio, Chris HL [0000-0003-2623-7172], Uitterlinden, André G [0000-0002-7276-3387], Edwards, Todd L [0000-0003-4318-6119], Morris, Andrew P [0000-0002-6805-6014], Pendergrass, Sarah A [0000-0002-0565-6522], Rotter, Jerome I [0000-0001-7191-1723], Butterworth, Adam S [0000-0002-6915-9015], and Hung, Adriana M [0000-0002-3203-1608]

Subjects
0301 basic medicine, Drosophila melanogaster/genetics, Diabetes Mellitus/genetics, LD SCORE REGRESSION, 030232 urology & nephrology, 45/43, General Physics and Astronomy, Genome-wide association study, BLOOD-PRESSURE, Bioinformatics, GLOMERULAR-FILTRATION-RATE, Genome-wide association studies, Diabetes mellitus genetics, 0302 clinical medicine, Creatinine/urine, Risk Factors, Genome-wide, Phenomics, lcsh:Science, ddc:616, Regulation of gene expression, RISK, Gene knockdown, Kidney diseases, Multidisciplinary, HERITABILITY, Albuminuria/genetics, article, Chromosome Mapping, Kidney disease, ddc, 3. Good health, Drosophila melanogaster, Creatinine, Nýrnasjúkdómar, 692/4022/1585, Slit diaphragm, Medical genetics, medicine.symptom, Erfðarannsóknir, Medical Genetics, medicine.medical_specialty, Science, 631/208/205/2138, 610 Medicine & health, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Meta-Analysis as Topic, 360 Social problems & social services, Diabetes Mellitus, medicine, Animals, Humans, Albuminuria, Genetic Predisposition to Disease, ddc:610, EXCRETION RATE, CARDIOVASCULAR EVENTS, Genetic association, Medicinsk genetik, TRANS-EQTLS, KIDNEY-DISEASE, General Chemistry, 030104 developmental biology, Gene Expression Regulation, Genetic Loci, COLLABORATIVE METAANALYSIS, lcsh:Q, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein)., Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria., Competing interests: Karsten B. Sieber is full-time employee of GlaxoSmithKline. Gardar Sveinbjornsson, Daniel F. Gudbjartsson, Hilma Holm, Unnur Thorsteinsdottir and Kari Stefansson are full-time employees of deCODE genetics, Amgen Inc. John Danesh is member of the Novartis Cardiovascular and Metabolic Advisory Board, received grant support from Novartis. Oscar H. Franco works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA. Wolfgang Koenig received modest consultation fees for advisory board meetings from Amgen, DalCor, Kowa, Novartis, Pfizer and Sanofi, and modest personal fees for lectures from Amgen, AstraZeneca, Novartis, Pfizer and Sanofi. Anna I. Podgornaia and Dermot F. Reilly are employees of Merck Sharp Dohme Corp., Whitehouse Station, NJ, USA. Kevin Ho disclosed a research and financial relationship with Sanofi-Genzyme. Bruce M. Psaty serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Markus Scholz: Consultancy of and grant support from Merck Serono not related to this project. Adam S. Butterworth received grants from MSD, Pfizer, Novartis, Biogen and Bioverativ and personal fees from Novartis. Anna Köttgen received grant support from Gruenenthal not related to this project. The other authors declare no competing interests.

Published
2019
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2. Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation

Author

Yolande F. M. Ramos, Tom Fiers, Jari Lahti, Tarunveer S. Ahluwalia, Elisa Kasbohm, Silvia Naitza, Hou-Feng Zheng, Charlotte Cerqueira, Ingrid Meulenbelt, Betina H. Thuesen, Ernst Rietzschel, Anne R. Cappola, John P. Walsh, Alessandro De Grandi, Johan G. Eriksson, Suzanne J. Brown, Jiaojiao Jing, Deborah Mascalzoni, Nicole Soranzo, Daniel Taliun, Margreet Kloppenburg, Purdey J Campbell, Kai-Uwe Eckardt, Yong Li, Mauro Pala, Marco Medici, Florian Kronenberg, Caterina Barbieri, Francesco Cucca, Allan Linneberg, Anna Köttgen, Bruce M. Psaty, Eric Boerwinkle, Ian J. Deary, Jennie Hui, Joris Deelen, Matthijs Moed, Astrid Petersmann, Graziano Ceresini, Michela Marina, Iris Postmus, Alice M. Arnold, Michiaki Kubo, J. Brent Richards, Marc De Buyzere, Henriette E. Meyer zu Schwabedissen, Eleonora Porcu, Christian Fuchsberger, Celia Di Munno, Dan E. Arking, David J. Stott, Toshiko Tanaka, Sofie Bekaert, Andrew A. Hicks, W. Edward Visser, Wouter den Hollander, Martin Gögele, Cinzia Sala, Peter P. Pramstaller, Georg Homuth, Yukinori Okada, Arne Astrup, Arif B. Ekici, Ulla T. Schultheiss, Richard A. Jensen, Christa Meisinger, Romana T. Netea-Maier, Rafael T. Mikolajczyk, Theo J. Visser, Marian Beekman, Michela Traglia, David C. Liewald, Koichi Matsuda, Thorkild I. A. Sørensen, Ilja M. Nolte, André G. Uitterlinden, David Schlessinger, Luigi Ferrrucci, Shuo Li, Alexander Teumer, Daniel Tiller, Sarah E. Harris, J. Wouter Jukema, Rajesh Rawal, Tim De Meyer, Kadri Haljas, Greet Roef, Yoichiro Kamatani, Karin Halina Greiser, Jean-Marc Kaufman, Serena Sanna, Bruce H. R. Wolffenbuttel, Scott Wilson, Daniela Toniolo, Ee Mun Lim, Stefan Groeneweg, Caroline S. Fox, Torben Hansen, Masato Akiyama, Christian Gieger, Layal Chaker, Tim D. Spector, Ian Ford, Martin den Heijer, P. Eline Slagboom, Elizabeth Selvin, Lambertus A. Kiemeney, Emil V. R. Appel, Niels Grarup, Diana van Heemst, Youri Taes, Robin P. Peeters, Henry Völzke, Cristian Pattaro, Daniel Medenwald, John M. Starr, Qiong Yang, Jerome I. Rotter, M. Arfan Ikram, Edoardo Fiorillo, Till Ittermann, Oluf Pedersen, Eero Kajantie, John Beilby, Tessel E. Galesloot, Fernando Rivadeneira, Paul Redmond, Bruno Lapauw, Lifelines Cohort Study, Alizadeh, B.Z., Boezen, H.M., Franke, L., van der Harst, P., Navis, G., Rots, M., Snieder, H., Swertz, M.A., Wijmenga, C., Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Clinicum, University of Helsinki, Department of Psychology and Logopedics, Doctoral Programme in Cognition, Learning, Instruction and Communication, Medicum, Lastentautien yksikkö, Children's Hospital, HUS Children and Adolescents, Developmental Psychology Research Group, Internal medicine, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Movement Sciences - Rehabilitation & Development, Amsterdam Movement Sciences - Restoration and Development, APH - Aging & Later Life, Epidemiology, Internal Medicine, Teumer, Alexander [0000-0002-8309-094X], Ahluwalia, Tarunveer S [0000-0002-7464-3354], Appel, Emil Vincent R [0000-0001-7704-6611], Astrup, Arne [0000-0001-8968-8996], Beekman, Marian [0000-0003-0585-6206], Beilby, John P [0000-0002-4915-2254], Ekici, Arif B [0000-0001-6099-7066], Grarup, Niels [0000-0001-5526-1070], Hansen, Torben [0000-0001-8748-3831], Hicks, Andrew A [0000-0001-6320-0411], Ikram, M Arfan [0000-0003-0372-8585], Jukema, J Wouter [0000-0002-3246-8359], Kamatani, Yoichiro [0000-0001-8748-5597], Kronenberg, Florian [0000-0003-2229-1120], Lahti, Jari [0000-0002-4310-5297], Li, Shuo [0000-0003-2331-2448], Liewald, David CM [0000-0002-0544-7368], Linneberg, Allan [0000-0002-0994-0184], Mascalzoni, Deborah [0000-0003-4156-1464], Meulenbelt, Ingrid [0000-0001-7786-7081], Netea-Maier, Romana T [0000-0002-9603-0460], Nolte, Ilja M [0000-0001-5047-4077], Okada, Yukinori [0000-0002-0311-8472], Ramos, Yolande FM [0000-0003-1459-413X], Richards, J Brent [0000-0002-3746-9086], Soranzo, Nicole [0000-0003-1095-3852], Yang, Qiong [0000-0002-3658-1375], Köttgen, Anna [0000-0002-4671-3714], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Genetic variants, endocrine system diseases, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Thyroid Gland, Thyrotropin, Metabolyzing hormone (AADAT), General Physics and Astronomy, EFFICIENT, Genome-wide association study, Thyroid hormone transporter (SLC17A4), Disease, VARIANTS, Bioinformatics, Hyperthyroidism, DISEASE, 0302 clinical medicine, SUBCLINICAL HYPOTHYROIDISM, Risk Factors, Genome-wide analysis, Chlorocebus aethiops, Faculty of Science, Medicine, lcsh:Science, POPULATION, RISK, education.field_of_study, Multidisciplinary, HERITABILITY, Thyroid disease, Thyroid, Thyroid dysfunction, ASSOCIATION, 3. Good health, medicine.anatomical_structure, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], COS Cells, Thyroid function, Sodium-Phosphate Cotransporter Proteins, Type I, Thyroid Hormones, endocrine system, PARTICIPANT DATA-ANALYSIS, Science, Population, 030209 endocrinology & metabolism, Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], Polymorphism, Single Nucleotide, White People, Article, General Biochemistry, Genetics and Molecular Biology, MONOCARBOXYLATE TRANSPORTER-8, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Hypothyroidism, Animals, Humans, ddc:610, education, METAANALYSIS, Genetic association, 2-Aminoadipate Transaminase, IDENTIFICATION, business.industry, Biology and Life Sciences, Biological Transport, General Chemistry, REFERENCE RANGE, medicine.disease, R1, 2-Aminoadipate Transaminase/genetics, 2-Aminoadipate Transaminase/metabolism, Cercopithecus aethiops, European Continental Ancestry Group, Gene Expression Regulation/genetics, Genome-Wide Association Study, Hyperthyroidism/genetics, Hyperthyroidism/physiopathology, Hypothyroidism/genetics, Hypothyroidism/physiopathology, Sodium-Phosphate Cotransporter Proteins, Type I/genetics, Sodium-Phosphate Cotransporter Proteins, Type I/metabolism, Thyroid Gland/metabolism, Thyroid Gland/physiopathology, Thyroid Hormones/genetics, Thyroid Hormones/metabolism, Thyrotropin/metabolism, 030104 developmental biology, Gene Expression Regulation, ATRIAL-FIBRILLATION, lcsh:Q, 3111 Biomedicine, business, Thyroid hormone regulation, Hormone
Abstract

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets., Thyroid dysfunction is a common public health problem and associated with cardiovascular co-morbidities. Here, the authors carry out genome-wide meta-analysis for thyroid hormone (TH) levels, hyper- and hypothyroidism and identify SLC17A4 as a TH transporter and AADAT as a TH metabolizing enzyme.

Published
2018

3. Lipoprotein(a) and incident type-2 diabetes: results from the prospective Bruneck study and a meta-analysis of published literature

Author

Paige, Ellie, Masconi, Katya L, Tsimikas, Sotirios, Kronenberg, Florian, Santer, Peter, Weger, Siegfried, Willeit, Johann, Kiechl, Stefan, Willeit, Peter, Paige, Ellie [0000-0003-0855-9872], Masconi, Katya L [0000-0002-9822-1105], Kronenberg, Florian [0000-0003-2229-1120], Willeit, Johann [0000-0003-4083-0466], Willeit, Peter [0000-0002-1866-7159], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Incidence, Endocrinology, Diabetes and Metabolism, Diabetes, Middle Aged, Meta-analysis, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Italy, Risk Factors, Population Surveillance, Humans, Female, Prospective Studies, Prospective study, Cardiology and Cardiovascular Medicine, Lipoprotein(a), Aged, Follow-Up Studies
Abstract

AIMS: We aimed to (1) assess the association between lipoprotein(a) [Lp(a)] concentration and incident type-2 diabetes in the Bruneck study, a prospective population-based study, and (2) combine findings with evidence from published studies in a literature-based meta-analysis. METHODS: We used Cox proportional hazards models to calculate hazard ratios (HR) for incident type-2 diabetes over 20 years of follow-up in 815 participants of the Bruneck study according to their long-term average Lp(a) concentration. For the meta-analysis, we searched Medline, Embase and Web of Science for relevant prospective cohort studies published up to October 2016. RESULTS: In the Bruneck study, there was a 12% higher risk of type-2 diabetes for a one standard deviation lower concentration of log Lp(a) (HR = 1.12 [95% CI 0.95-1.32]; P = 0.171), after adjustment for age, sex, alcohol consumption, body mass index, smoking status, socioeconomic status, physical activity, systolic blood pressure, HDL cholesterol, log high-sensitivity C-reactive protein and waist-hip ratio. In a meta-analysis involving four prospective cohorts with a total of 74,575 participants and 4514 incident events, the risk of type-2 diabetes was higher in the lowest two quintiles of Lp(a) concentrations (weighted mean Lp(a) = 3.3 and 7.0 mg/dL, respectively) compared to the highest quintile (62.9 mg/dL), with the highest risk of type-2 diabetes seen in quintile 1 (HR = 1.28 [1.14-1.43]; P < 0.001). CONCLUSIONS: The current available evidence from prospective studies suggests that there is an inverse association between Lp(a) concentration and risk of type-2 diabetes, with a higher risk of type-2 diabetes at low Lp(a) concentrations (approximately

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