Genetic variant linked to obesity: New insights into SMIM1 gene’s role in metabolism
A groundbreaking study has unveiled a novel genetic factor contributing to obesity, shedding light on the complex interplay between genetics and body weight regulation.
The research, spearheaded by the University of Exeter and published in Med [1], reveals that individuals with a genetic variant disabling the SMIM1 gene exhibit higher body weight due to reduced resting energy expenditure.
Vel-negative blood group and obesity: An unexpected connection
The SMIM1 gene, identified merely a decade ago during the search for the gene encoding the Vel blood group, has now been linked to metabolic function. Approximately one in 5,000 individuals lack both copies of this gene, rendering them Vel-negative. The study’s findings suggest that this rare group is predisposed to obesity, potentially paving the way for targeted therapeutic interventions.
Researchers analysed the genetics of nearly 500,000 participants from the UK Biobank cohort, identifying 104 individuals with the SMIM1 loss-of-function variant. The team also utilised the NIHR National BioResource, in collaboration with NHS Blood and Transplant, to obtain fresh blood samples from both Vel-negative and Vel-positive individuals.
The study’s results were further validated across four additional cohorts of people with the SMIM1 gene variant. The impact on weight was quantified, revealing an average increase of 4.6kg in females and 2.4kg in males carrying the variant.
Broader implications for obesity research and treatment
Lead author Mattia Frontini, Associate Professor of Cell Biology at the University of Exeter Medical School, emphasised the significance of these findings in the context of rising global obesity rates. He said: “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.”
The research also uncovered additional metabolic abnormalities associated with the SMIM1 variant, including elevated blood lipid levels, signs of adipose tissue dysfunction, increased liver enzymes, and reduced thyroid hormone levels.
Future directions and clinical implications
Co-author Jill Storry, Adjunct Professor at Lund University, Sweden, highlighted the novelty of this discovery, stating: “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.”
The findings underscore the importance of investigating genetic causes of obesity to develop tailored treatments and reduce associated social stigma. As genetic data becomes increasingly available, the researchers advocate for providing targeted information and support to individuals lacking SMIM1.
This collaborative effort, funded by the National Institute for Health and Care Research and the British Heart Foundation, involved partners from the University of Cambridge, the Sanger Institute, the University of Copenhagen in Denmark, and Lund University in Sweden.
Reference:
- Stefanucci L., Moslemi C., Tomé A., et. al. SMIM1 absence is associated with reduced energy expenditure and excess weight. Med, 20 June 2024. https://doi.org/10.1016/j.medj.2024.05.015
