iScience (Nov 2021)
Type 2 diabetes sex-specific effects associated with E167K coding variant in TM6SF2
- Yanbo Fan,
- Brooke N. Wolford,
- Haocheng Lu,
- Wenying Liang,
- Jinjian Sun,
- Wei Zhou,
- Oren Rom,
- Anubha Mahajan,
- Ida Surakka,
- Sarah E. Graham,
- Zhipeng Liu,
- Hyunbae Kim,
- Shweta Ramdas,
- Lars G. Fritsche,
- Jonas B. Nielsen,
- Maiken Elvestad Gabrielsen,
- Kristian Hveem,
- Dongshan Yang,
- Jun Song,
- Minerva T. Garcia-Barrio,
- Jifeng Zhang,
- Wanqing Liu,
- Kezhong Zhang,
- Cristen J. Willer,
- Y. Eugene Chen
Affiliations
- Yanbo Fan
- Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, NCRC Bldg 26, Rm 361S, 2800 Plymouth Road, Ann Arbor, MI 48109, USA; Department of Cancer Biology, University of Cincinnati College of Medicine, Vontz Center, 3125 Eden Avenue, Cincinnati, OH45267, USA; Corresponding author
- Brooke N. Wolford
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI48109, USA
- Haocheng Lu
- Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, NCRC Bldg 26, Rm 361S, 2800 Plymouth Road, Ann Arbor, MI 48109, USA
- Wenying Liang
- Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, NCRC Bldg 26, Rm 361S, 2800 Plymouth Road, Ann Arbor, MI 48109, USA
- Jinjian Sun
- Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, NCRC Bldg 26, Rm 361S, 2800 Plymouth Road, Ann Arbor, MI 48109, USA
- Wei Zhou
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI48109, USA
- Oren Rom
- Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, NCRC Bldg 26, Rm 361S, 2800 Plymouth Road, Ann Arbor, MI 48109, USA; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA71103, USA
- Anubha Mahajan
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
- Ida Surakka
- Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, NCRC Bldg 26, Rm 361S, 2800 Plymouth Road, Ann Arbor, MI 48109, USA
- Sarah E. Graham
- Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, NCRC Bldg 26, Rm 361S, 2800 Plymouth Road, Ann Arbor, MI 48109, USA
- Zhipeng Liu
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN, USA
- Hyunbae Kim
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI48201, USA
- Shweta Ramdas
- Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA
- Lars G. Fritsche
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA
- Jonas B. Nielsen
- Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, NCRC Bldg 26, Rm 361S, 2800 Plymouth Road, Ann Arbor, MI 48109, USA
- Maiken Elvestad Gabrielsen
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, NTNU, Trondheim, Norway
- Kristian Hveem
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, NTNU, Trondheim, Norway
- Dongshan Yang
- Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, NCRC Bldg 26, Rm 361S, 2800 Plymouth Road, Ann Arbor, MI 48109, USA
- Jun Song
- Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, NCRC Bldg 26, Rm 361S, 2800 Plymouth Road, Ann Arbor, MI 48109, USA
- Minerva T. Garcia-Barrio
- Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, NCRC Bldg 26, Rm 361S, 2800 Plymouth Road, Ann Arbor, MI 48109, USA
- Jifeng Zhang
- Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, NCRC Bldg 26, Rm 361S, 2800 Plymouth Road, Ann Arbor, MI 48109, USA
- Wanqing Liu
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA
- Kezhong Zhang
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI48201, USA
- Cristen J. Willer
- Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, NCRC Bldg 26, Rm 361S, 2800 Plymouth Road, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA; Corresponding author
- Y. Eugene Chen
- Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, NCRC Bldg 26, Rm 361S, 2800 Plymouth Road, Ann Arbor, MI 48109, USA; Corresponding author
- Journal volume & issue
-
Vol. 24,
no. 11
p. 103196
Abstract
Summary: The rs58542926C >T (E167K) variant of the transmembrane 6 superfamily member 2 gene (TM6SF2) is associated with increased risks for nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). Nevertheless, the role of the TM6SF2 rs58542926 variant in glucose metabolism is poorly understood. We performed a sex-stratified analysis of the association between the rs58542926C >T variant and T2D in multiple cohorts. The E167K variant was significantly associated with T2D, especially in males. Using an E167K knockin (KI) mouse model, we found that male but not the female KI mice exhibited impaired glucose tolerance. As an ER membrane protein, TM6SF2 was found to interact with inositol-requiring enzyme 1 α (IRE1α), a primary ER stress sensor. The male Tm6sf2 KI mice exhibited impaired IRE1α signaling in the liver. In conclusion, the E167K variant of TM6SF2 is associated with glucose intolerance primarily in males, both in humans and mice.
