Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene - eScholarship

Downloaded from http://www.jci.org on March 23, 2015. http://dx.doi.org/10.1172/JCI74692 Research article The Journal of Clinical Investigation Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene Joshua W. Knowles, 1 Weijia Xie, 2 Zhongyang Zhang, 3 Indumathi Chennemsetty, 1 Themistocles L. Assimes, 1 Jussi Paananen, 4 Ola Hansson, 5 James Pankow, 6 Mark O. Goodarzi, 7 Ivan Carcamo-Orive, 1 Andrew P. Morris, 8,9 Yii-Der I. Chen, 10 Ville-Petteri Makinen, 11 Andrea Ganna, 12 Anubha Mahajan, 9 Xiuqing Guo, 10 Fahim Abbasi, 1 Danielle M. Greenawalt, 13 Pek Lum, 13 Cliona Molony, 13 Lars Lind, 14 Cecilia Lindgren, 9 Leslie J. Raffel, 15 Philip S. Tsao, 1 The RISC (Relationship between Insulin Sensitivity and Cardiovascular Disease) consortium, 16 The EUGENE2 (European Network on Functional Genomics of Type 2 Diabetes) study, 16 The GUARDIAN (Genetics UndeRlying DIAbetes in HispaNics) consortium, 16 The SAPPHIRe (Stanford Asian and Pacific Program for Hypertension and Insulin Resistance) study, 16 Eric E. Schadt, 3 Jerome I. Rotter, 10 Alan Sinaiko, 17 Gerald Reaven, 1 Xia Yang, 11 Chao A. Hsiung, 18 Leif Groop, 5 Heather J. Cordell, 19 Markku Laakso, 4 Ke Hao, 3 Erik Ingelsson, 9,12 Timothy M. Frayling, 2 Michael N. Weedon, 2 Mark Walker, 20 and Thomas Quertermous 1 Stanford University, Division of Cardiovascular Medicine and Stanford Cardiovascular Institute, Falk Cardiovascular Research Center, Stanford, California, USA. 2 Institute of Biomedical and Clinical Science, University of Exeter Medical School, University of Exeter, Exeter, United Kingdom. 3 Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. 4 Department of Medicine, University of Eastern Finland, Kuopio, Finland. 5 Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, Clinical Research Centre, Skane University Hospital, Malmo, Sweden. 6 Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, USA. 7 Division of Endocrinology, Diabetes & Metabolism, Cedars-Sinai Medical Center, Los Angeles, California, USA. 8 Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom. 9 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. 10 Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA. 11 Department of Integrative Biology and Physiology, UCLA, Los Angeles, California, USA. 12 Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. 13 Merck Research Labs, Boston, Massachusetts, USA. 14 Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden. Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. 16 The RISC consortium, The EUGENE2 study, The GUARDIAN consortium, and The SAPPHIRe study are detailed in the supplemental material. 17 Department of Pediatrics, University of Minnesota, Amplatz Children’s Hospital, Minneapolis, Minnesota, USA. 18 Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan. 19 Institute for Genetic Medicine and 20 Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom. Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 “A” allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoprotere- nol-stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity. Authorship note: Joshua W. Knowles, Weijia Xie, Zhongyang Zhang, Indumathi Chennemsetty, Ke Hao, Erik Ingelsson, Timothy M. Frayling, Michael N. Weedon, Mark Walker, and Thomas Quertermous contributed equally to this work. Conflict of interest: Danielle M. Greenawalt is currently an employee and has income from AstraZeneca. Cliona Molony is an employee and has income from Merck. Pek Lum was an employee at Merck at the time that some of the work herein was performed and is now an employee at Capella Biosciences. Submitted: December 16, 2013; Accepted: February 5, 2015. Reference information: J Clin Invest. doi:10.1172/JCI74692. Introduction Insulin resistance (IR) is present in the vast majority of patients who eventually develop type 2 diabetes and seems to be a nec- essary, but not sufficient, abnormality leading to hyperglycemia in these individuals. Insulin-resistant persons who continue to secrete enough insulin to prevent gross decompensation of glu- cose homeostasis are still at increased risk to develop cardiovascu- lar disease. It is estimated that 25% to 33% of the US population is jci.org