SMIM1 absence is associated with reduced energy expenditure and excess weight

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Background Obesity rates have nearly tripled in the past 50 years, and by 2030, more than one 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 aetiological 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 SMIM1 and the general population, leveraging data from 5 cohorts. Metabolic characterization of SMIM1-/- individuals was performed using plasma biochemistry, calorimetric chamber and DEXA scan. Findings We found that individuals homozygous for a loss-of-function genetic variant in the Small Integral Membrane Protein 1 (SMIM1) gene, underlying the blood group Vel, display excess body weight, dyslipidemia, altered leptin-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.

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