SMIM1 absence is associated with reduced energy expenditure and excess weight

Luca Stefanucci, Camous Moslemi, Ana R. Tomé, Samuel Virtue, Guillaume Bidault, Nicholas S. Gleadall, Laura P.E. Watson, Jing E. Kwa, Frances Burden, Samantha Farrow, Karina Banasik, Jakob Bay, Jens Kjærgaard Boldsen, Thorsten Brodersen, Søren Brunak, Kristoffer Burgdorf, Mona Ameri Chalmer, Maria Didriksen, Khoa Manh Dinh, Joseph DowsettChristian Erikstrup, Bjarke Feenstra, Frank Geller, Daniel Gudbjartsson, Thomas Folkmann Hansen, Lotte Hindhede, Henrik Hjalgrim, Rikke Louise Jacobsen, Gregor Jemec, Bitten Aagaard Jensen, Katrine Kaspersen, Bertram Dalskov Kjerulff, Lisette Kogelman, Margit Anita Hørup Larsen, Ioannis Louloudis, Agnete Lundgaard, Susan, Christina Mikkelsen, Ioanna Nissen, Mette Nyegaard, Sisse Rye Ostrowski, Ole Birger Pedersen, Alexander Pil Henriksen, Palle Duun Rohde, Klaus Rostgaard, Michael Schwinn, Kari Stefansson, Hreinn Stefánsson, Erik Sørensen, Unnur þorsteinsdóttir, Lise Wegner Thørner, Mie Topholm Bruun, Henrik Ullum, Thomas Werge, David Westergaard, Ji Chen, Cassandra N. Spracklen, Gaëlle Marenne, Arushi Varshney, Laura J. Corbin, Jian'an Luan, Sara M. Willems, Ying Wu, Xiaoshuai Zhang, Momoko Horikoshi, Thibaud S. Boutin, Reedik Mägi, Johannes Waage, Ruifang Li-Gao, Kei Hang Katie Chan, Jie Yao, Mila D. Anasanti, Audrey Y. Chu, Annique Claringbould, Jani Heikkinen, Jaeyoung Hong, Jouke Jan Hottenga, Shaofeng Huo, Marika A. Kaakinen, Tin Louie, Winfried März, Hortensia Moreno-Macias, Anne Ndungu, Sarah C. Nelson, Ilja M. Nolte, Kari E. North, Chelsea K. Raulerson, Debashree Ray, Rebecca Rohde, Denis Rybin, Claudia Schurmann, Xueling Sim, Loz Southam, Isobel D. Stewart, Carol A. Wang, Yujie Wang, Peitao Wu, Weihua Zhang, Tarunveer S. Ahluwalia, Emil V.R. Appel, Lawrence F. Bielak, Jennifer A. Brody, Noël P. Burtt, Claudia P. Cabrera, Brian E. Cade, Jin Fang Chai, Xiaoran Chai, Li Ching Chang, Chien Hsiun Chen, Brian H. Chen, Kumaraswamy Naidu Chitrala, Yen Feng Chiu, Hugoline G. de Haan, Graciela E. Delgado, Ayse Demirkan, Qing Duan, Jorgen Engmann, Segun A. Fatumo, Javier Gayán, Franco Giulianini, Jung Ho Gong, Stefan Gustafsson, Yang Hai, Fernando P. Hartwig, Jing He, Yoriko Heianza, Tao Huang, Alicia Huerta-Chagoya, Mi Yeong Hwang, Richard A. Jensen, Takahisa Kawaguchi, Katherine A. Kentistou, Young Jin Kim, Marcus E. Kleber, Ishminder K. Kooner, Shuiqing Lai, Leslie A. Lange, Carl D. Langefeld, Marie Lauzon, Man Li, Symen Ligthart, Jun Liu, Marie Loh, Jirong Long, Valeriya Lyssenko, Massimo Mangino, Carola Marzi, May E. Montasser, Abhishek Nag, Masahiro Nakatochi, Damia Noce, Raymond Noordam, Giorgio Pistis, Michael Preuss, Laura Raffield, Laura J. Rasmussen-Torvik, Stephen S. Rich, Neil R. Robertson, Rico Rueedi, Kathleen Ryan, Serena Sanna, Richa Saxena, Katharina E. Schraut, Bengt Sennblad, Kazuya Setoh, Albert V. Smith, Lorraine Southam, Thomas Sparsø, Rona J. Strawbridge, Fumihiko Takeuchi, Jingyi Tan, Stella Trompet, Erik van den Akker, Peter J. van der Most, Niek Verweij, Mandy Vogel, Heming Wang, Chaolong Wang, Nan Wang, Helen R. Warren, Wanqing Wen, Tom Wilsgaard, Andrew Wong, Andrew R. Wood, Tian Xie, Mohammad Hadi Zafarmand, Jing Hua Zhao, Wei Zhao, Najaf Amin, Zorayr Arzumanyan, Arne Astrup, Stephan J.L. Bakker, Damiano Baldassarre, Marian Beekman, Richard N. Bergman, Alain Bertoni, Matthias Blüher, Lori L. Bonnycastle, Stefan R. Bornstein, Donald W. Bowden, Qiuyin Cai, Archie Campbell, Harry Campbell, Yi Cheng Chang, Eco J.C. de Geus, Abbas Dehghan, Shufa Du, Gudny Eiriksdottir, Aliki Eleni Farmaki, Mattias Frånberg, Christian Fuchsberger, Yutang Gao, Anette P. Gjesing, Anuj Goel, Sohee Han, Catharina A. Hartman, Christian Herder, Andrew A. Hicks, Chang Hsun Hsieh, Willa A. Hsueh, Sahoko Ichihara, Michiya Igase, M. Arfan Ikram, W. Craig Johnson, Marit E. Jørgensen, Peter K. Joshi, Rita R. Kalyani, Fouad R. Kandeel, Tomohiro Katsuya, Chiea Chuen Khor, Wieland Kiess, Ivana Kolcic, Teemu Kuulasmaa, Johanna Kuusisto, Kristi Läll, Kelvin Lam, Deborah A. Lawlor, Nanette R. Lee, Rozenn N. Lemaitre, Honglan Li, Shih Yi Lin, Jaana Lindström, Allan Linneberg, Jianjun Liu, Carlos Lorenzo, Tatsuaki Matsubara, Fumihiko Matsuda, Geltrude Mingrone, Simon Mooijaart, Sanghoon Moon, Toru Nabika, Girish N. Nadkarni, Jerry L. Nadler, Mari Nelis, Matt J. Neville, Jill M. Norris, Yasumasa Ohyagi, Annette Peters, Patricia A. Peyser, Ozren Polasek, Qibin Qi, Dennis Raven, Dermot F. Reilly, Alex Reiner, Fernando Rivideneira, Kathryn Roll, Igor Rudan, Charumathi Sabanayagam, Kevin Sandow, Naveed Sattar, Annette Schürmann, Jinxiu Shi, Heather M. Stringham, Kent D. Taylor, Tanya M. Teslovich, Betina Thuesen, Paul R.H.J. Timmers, Elena Tremoli, Michael Y. Tsai, Andre Uitterlinden, Rob M. van Dam, Diana van Heemst, Astrid van Hylckama Vlieg, Jana V. Van Vliet-Ostaptchouk, Jagadish Vangipurapu, Henrik Vestergaard, Tao Wang, Ko Willems van Dijk, Tatijana Zemunik, Goncalo R. Abecasis, Linda S. Adair, Carlos Alberto Aguilar-Salinas, Marta E. Alarcón-Riquelme, Ping An, Larissa Aviles-Santa, Diane M. Becker, Lawrence J. Beilin, Sven Bergmann, Hans Bisgaard, Corri Black, Michael Boehnke, Eric Boerwinkle, Bernhard O. Böhm, Klaus Bønnelykke, D. I. Boomsma, Erwin P. Bottinger, Thomas A. Buchanan, Mickaël Canouil, Mark J. Caulfield, John C. Chambers, Daniel I. Chasman, Yii Der Ida Chen, Ching Yu Cheng, Francis S. Collins, Adolfo Correa, Francesco Cucca, H. Janaka de Silva, George Dedoussis, Sölve Elmståhl, Michele K. Evans, Ele Ferrannini, Luigi Ferrucci, Jose C. Florez, Paul W. Franks, Timothy M. Frayling, Philippe Froguel, Bruna Gigante, Mark O. Goodarzi, Penny Gordon-Larsen, Harald Grallert, Niels Grarup, Sameline Grimsgaard, Leif Groop, Vilmundur Gudnason, Xiuqing Guo, Anders Hamsten, Torben Hansen, Caroline Hayward, Susan R. Heckbert, Bernardo L. Horta, Wei Huang, Erik Ingelsson, Pankow S. James, Marjo Ritta Jarvelin, Jost B. Jonas, J. Wouter Jukema, Pontiano Kaleebu, Robert Kaplan, Sharon L.R. Kardia, Norihiro Kato, Sirkka M. Keinanen-Kiukaanniemi, Bong Jo Kim, Mika Kivimaki, Heikki A. Koistinen, Jaspal S. Kooner, Antje Körner, Peter Kovacs, Diana Kuh, Meena Kumari, Zoltan Kutalik, Markku Laakso, Timo A. Lakka, Lenore J. Launer, Karin Leander, Huaixing Li, Xu Lin, Lars Lind, Cecilia Lindgren, Simin Liu, Ruth J.F. Loos, Patrik K.E. Magnusson, Anubha Mahajan, Andres Metspalu, Dennis O. Mook-Kanamori, Trevor A. Mori, Patricia B. Munroe, Inger Njølstad, Jeffrey R. O'Connell, Albertine J. Oldehinkel, Ken K. Ong, Sandosh Padmanabhan, Colin N.A. Palmer, Nicholette D. Palmer, Oluf Pedersen, Craig E. Pennell, David J. Porteous, Peter P. Pramstaller, Michael A. Province, Bruce M. Psaty, Lu Qi, Leslie J. Raffel, Rainer Rauramaa, Susan Redline, Paul M. Ridker, Frits R. Rosendaal, Timo E. Saaristo, Manjinder Sandhu, Jouko Saramies, Neil Schneiderman, Peter Schwarz, Laura J. Scott, Elizabeth Selvin, Peter Sever, Xiao Ou Shu, P. Eline Slagboom, Kerrin S. Small, Blair H. Smith, Harold Snieder, Tamar Sofer, Thorkild I.A. Sørensen, Tim D. Spector, Alice Stanton, Claire J. Steves, Michael Stumvoll, Liang Sun, Yasuharu Tabara, E. Shyong Tai, Nicholas J. Timpson, Anke Tönjes, Jaakko Tuomilehto, Teresa Tusie, Matti Uusitupa, Pim van der Harst, Cornelia van Duijn, Veronique Vitart, Peter Vollenweider, Tanja G.M. Vrijkotte, Lynne E. Wagenknecht, Mark Walker, Ya X. Wang, Nick J. Wareham, Richard M. Watanabe, Hugh Watkins, Wen B. Wei, Ananda R. Wickremasinghe, Gonneke Willemsen, James F. Wilson, Tien Yin Wong, Jer Yuarn Wu, Anny H. Xiang, Lisa R. Yanek, Loïc Yengo, Mitsuhiro Yokota, Eleftheria Zeggini, Wei Zheng, Alan B. Zonderman, Jerome I. Rotter, Anna L. Gloyn, Mark I. McCarthy, Josée Dupuis, James B. Meigs, Robert A. Scott, Inga Prokopenko, Aaron Leong, Ching Ti Liu, Stephen C.J. Parker, Karen L. Mohlke, Claudia Langenberg, Eleanor Wheeler, Andrew P. Morris, Inês Barroso, Urmo Võsa, Keith Burling, Lindsay Walker, John Ord, Peter Barker, James Warner, Amy Frary, Karola Renhstrom, Sofie E. Ashford, Jo Piper, Gail Biggs, Wendy N. Erber, Gary J. Hoffman, Nadia Schoenmakers, Klaus Rieneck, Morten H. Dziegiel, Vian Azzu, Michele Vacca, Hugo Javier Aparicio, Qin Hui, Kelly Cho, Yan V. Sun, Peter W. Wilson, Omer A. Bayraktar, Antonio Vidal-Puig, Sisse R. Ostrowski, William J. Astle, Martin L. Olsson, Jill R. Storry, Ole B. Pedersen, Willem H. Ouwehand, Krishna Chatterjee, Dragana Vuckovic, Mattia Frontini

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Obesity rates have nearly tripled in the past 50 years, and by 2030 more than 1 billion individuals worldwide are projected to be obese. This creates a significant economic strain due to the associated non-communicable diseases. The root cause is an energy expenditure imbalance, owing to an interplay of lifestyle, environmental, and genetic factors. Obesity has a polygenic genetic architecture; however, single genetic variants with large effect size are etiological in a minority of cases. These variants allowed the discovery of novel genes and biology relevant to weight regulation and ultimately led to the development of novel specific treatments. Methods: We used a case-control approach to determine metabolic differences between individuals homozygous for a loss-of-function genetic variant in the small integral membrane protein 1 (SMIM1) and the general population, leveraging data from five cohorts. Metabolic characterization of SMIM1−/− individuals was performed using plasma biochemistry, calorimetric chamber, and DXA scan. Findings: We found that individuals homozygous for a loss-of-function genetic variant in SMIM1 gene, underlying the blood group Vel, display excess body weight, dyslipidemia, altered leptin to adiponectin ratio, increased liver enzymes, and lower thyroid hormone levels. This was accompanied by a reduction in resting energy expenditure. Conclusion: This research identified a novel genetic predisposition to being overweight or obese. It highlights the need to investigate the genetic causes of obesity to select the most appropriate treatment given the large cost disparity between them. Funding: This work was funded by the National Institute of Health Research, British Heart Foundation, and NHS Blood and Transplant.

Original languageEnglish
Pages (from-to)1083-1095.e6
JournalMed
Volume5
Issue number9
DOIs
StatePublished - Sep 13 2024

Keywords

  • BMI
  • SMIM1
  • Translation to patients
  • Vel
  • blood groups
  • dyslipidemia
  • metabolism
  • obesity
  • population genetics
  • weight

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