Year: 2021
Type: article
Study design: Observational Study
Abstract: 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.
Source: iScience
Authors: 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
Institutions: University of Michigan, Michigan Medicine, University of Cincinnati, Louisiana State University Health Sciences Center Shreveport, Centre for Human Genetics, University of Oxford, Purdue University West Lafayette, Wayne State University, University of Pennsylvania, Norwegian University of Science and Technology, Eugene Applebaum College of Pharmacy and Health Sciences
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,000
Awards: Using genetic variation to study biology of blood lipids & coronary heart disease, KLF14 and Cardiovascular Disease, Mechanisms of glycine-based therapy for atherosclerosis, A novel CREBH-derived hepatokine regulates triglyceride metabolism, Fatty Acid Desaturase 1 (FADS1) Variants and Non-alcoholic Fatty Liver Disease, Using Genetics to Inform Mechanism of Cardiovascular Disease, G6219713290, G643570424, Kruppel-like factor 11 (KLF11) and atherosclerosis, Transcription Factor-EB and Postischemic Angiogenesis, The Role of TM6SF2 in Cardiovascular Disease, G8257453039, G8604391010, University of Michigan Training Program in Genomic Science, Michigan Diabetes Research Center (MDRC), Using genetics to discover mechanisms of abdominal aortic aneurysm, The role of TFEB in aortic aneurysms
OpenAlex ID: W3204567638