Researchers have linked a genetic variant that deactivates the SMIM1 gene to increased obesity risk. The findings could lead to new obesity treatments and help reduce related stigma.
Researchers have discovered a new cause of why people who lack a specific blood group are genetically predisposed to be overweight or obese.
A genetic study led by the University of Exeter identified a link between the SMIM1 gene variant and obesity. This variant, found in individuals without the Vel blood group, causes decreased resting energy expenditure and could impact around 300,000 people globally.
Genetic Link to Obesity Found in Blood Group Research
A team of international scientists, led by the University of Exeter, discovered that people with a genetic variant that disables the SMIM1 gene have higher body weight because they expend less energy when at rest.
SMIM1 was only identified 10 years ago, while searching for the gene encoding a specific blood group, known as Vel. One in 5,000 people lack both copies of the gene, making them Vel-negative. The findings from the new research suggest that this group is also more likely to be overweight, a conclusion that could one day lead to new treatments. The study found that people without both copies of the gene have other measures linked to obesity including high levels of fat in the blood, signs of fat tissue dysfunction, increased liver enzymes as well as lower levels of thyroid hormones.
Implications for Healthcare and Treatment
The study was published today (June 20) in the medical journal Med and was funded by the National Institute for Health (NIH) and Care Research and the British Heart Foundation. The collaboration included partners at the University of Cambridge, the Sanger Institute, the Copenhagen University in Denmark, and the Lund University in Sweden.
Lead author Mattia Frontini, Associate Professor of Cell Biology at the University of Exeter Medical School, said: “Obesity rates have nearly tripled in the past 50 years, and by 2030, more than one billion individuals worldwide are projected to be obese. The associated diseases and complications create significant economic burden on healthcare systems. Obesity is due to an imbalance between energy intake and expenditure, often a complex interplay of lifestyle, environmental, and genetic factors.
“In a small minority of people, obesity is caused by genetic variants. When this is the case, new treatments can sometimes be found to benefit these people. Our findings highlight the need to investigate the genetic cause of obesity, to select the most appropriate and effective treatment, but also to reduce the social stigma associated to it.”
Genetic Studies Reveal New Insights
To make the discovery, the team analyzed the genetics of nearly 500,000 participants in the UK Biobank cohort, identifying 104 people with the variant that leads to loss of function in the SMIM1 gene (46 females and 44 males). The team also used the NIHR National BioResource to obtain fresh blood samples from both Vel negative and positive individuals.
The NIHR National BioResource worked in partnership with NHS Blood and Transplant (NHSBT) – which includes more than 100,000 blood donors who signed up to support genetic research studies. Extrapolating the frequencies identified in these cohorts would mean the SMIM1 variant could be a significant factor contributing to obesity for around 300,000 people across the world.
The team interrogated the effects they found in four additional cohorts of people with the SMIM1 gene variant. They found that having the variant had an impact on weight, equating to an average extra 4.6kg in females and 2.4kg in males.
Future Research and Practical Applications
Co-author Jill Storry, Adjunct Professor at Lund University, Sweden, said: “SMIM1 was only discovered a decade ago, as a long-sought blood group protein on red blood cells, but its other function has remained unknown until now. It’s very exciting to find that it has a more general role in human metabolism.”
Co-author Professor Ole Pedersen, at the University of Copenhagen, Denmark, said: “The whole team is very much looking forward to seeing how this new knowledge can be translated into practical solutions for people with this genetic make-up.
First author Dr Luca Stefanucci, at the University of Cambridge, said: “With the increased availability of genetic data, and more information on SMIM1 mechanism, we would like to see that when individuals lacking SMIM1 are identified, they receive information and support.”
Reference: “SMIM1 absence is associated with reduced energy expenditure and excess weight” by 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 Dowsett, Christian 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, 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, … Jo Piper, Gail Biggs, Wendy N. Erber, Gary J. Hoffman, Nadia Schoenmakers, Christian Erikstrup, Klaus Rieneck, Morten H. Dziegiel, Henrik Ullum, 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 and Mattia Frontini, 20 June 2024, Med.
DOI: 10.1016/j.medj.2024.05.015
