TY - JOUR
T1 - SMIM1 absence is associated with reduced energy expenditure and excess weight
AU - DBDS Genetic Consortium
AU - MAGIC
AU - Stefanucci, Luca
AU - Moslemi, Camous
AU - Tomé, Ana R.
AU - Virtue, Samuel
AU - Bidault, Guillaume
AU - Gleadall, Nicholas S.
AU - Watson, Laura P.E.
AU - Kwa, Jing E.
AU - Burden, Frances
AU - Farrow, Samantha
AU - Banasik, Karina
AU - Bay, Jakob
AU - Boldsen, Jens Kjærgaard
AU - Brodersen, Thorsten
AU - Brunak, Søren
AU - Burgdorf, Kristoffer
AU - Chalmer, Mona Ameri
AU - Didriksen, Maria
AU - Dinh, Khoa Manh
AU - Dowsett, Joseph
AU - Erikstrup, Christian
AU - Feenstra, Bjarke
AU - Geller, Frank
AU - Gudbjartsson, Daniel
AU - Hansen, Thomas Folkmann
AU - Wu, Ying
AU - Claringbould, Annique
AU - Nolte, Ilja M.
AU - Demirkan, Ayse
AU - Kim, Young Jin
AU - Li, Man
AU - Sanna, Serena
AU - Smith, Albert V.
AU - van der Most, Peter J.
AU - Verweij, Niek
AU - Xie, Tian
AU - Zhao, Jing Hua
AU - Zhao, Wei
AU - Bakker, Stephan J.L.
AU - Hartman, Catharina A.
AU - Raven, Dennis
AU - Van Vliet-Ostaptchouk, Jana V.
AU - Boomsma, D. I.
AU - Huang, Wei
AU - Kumari, Meena
AU - Oldehinkel, Albertine J.
AU - Snieder, Harold
AU - van der Harst, Pim
AU - Wang, Ya X.
AU - Võsa, Urmo
N1 - Publisher Copyright:
© 2024 The Author(s)
PY - 2024/6/20
Y1 - 2024/6/20
N2 - 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.
AB - 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.
KW - blood groups
KW - BMI
KW - dyslipidemia
KW - metabolism
KW - obesity
KW - population genetics
KW - SMIM1
KW - Translation to patients
KW - Vel
KW - weight
UR - http://www.scopus.com/inward/record.url?scp=85198207889&partnerID=8YFLogxK
U2 - 10.1016/j.medj.2024.05.015
DO - 10.1016/j.medj.2024.05.015
M3 - Article
C2 - 38906141
AN - SCOPUS:85198207889
SN - 2666-6359
JO - Med
JF - Med
ER -