SMIM1 absence is associated with reduced energy expenditure and excess weight

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.

Keywords: BMI; SMIM1; Translation to patients; Vel; blood groups; dyslipidemia; metabolism; obesity; population genetics; weight.

Stefanucci et al. show that a 17-bp loss-of-function variant in the open reading frame of SMIM1 is associated with excess weight and other traits (dyslipidemia and insulin resistance) resembling metabolic syndrome. This is due to reduced energy expenditure, a major risk factor for obesity.

Figure 1. Differences between SMIM1^+/+ and SMIM1^−/− individuals in the UKB cohort

(A) Boxplots for UKB participants’ weight (kg) grouped according to their genotype. Sex-stratified data are shown for the three genotype groups, with females on the left and males on the right, respectively. Boxplot whiskers indicate the 95% confidence interval. (B) Boxplots for BMI, waist circumference, and levels of triglycerides (TG), alanine aminotransferase (ALT), aspartate transaminase (AST), gamma-glutamyl transferase (GGT), and urate. Boxplot whiskers indicate the 95% confidence interval. (C) Forest plot illustrating the effect size ($\widehat{\beta }$ percentage of standard deviation) of SMIM1^+/+ (blue) versus SMIM1^−/− (red) for each trait. Bold characters highlight the measurements that are shown in (B). Effect sizes corrected for BMI are shown in yellow, and the non-corrected ones are in dark gray; β is represented by the dots and the 95% confidence intervals by the horizontal lines.

Figure 2. Differences between SMIM1^+/+ and SMIM1^−/− individuals in the NIHR-NBR cohort and DXA body scan

(A) Boxplots for free fatty acids (FFA), alanine aminotransferase (ALT), aspartate transaminase (AST), ferritin, leptin to adiponectin ratio (LAR), total triiodothyronine (T3), and total thyroxine (T4). Boxplot whiskers indicate the 95% confidence interval. (B) Forest plot illustrating the effect size ($\widehat{\beta }$ percentage of standard deviation) of SMIM1^+/+ versus SMIM1^−/− for each trait. Effect sizes corrected for BMI and non-corrected ones are in yellow and dark gray, respectively. β is represented by the dots and the 95% confidence intervals by the horizontal lines. (C) Scatterplot of Z scores for resting energy expenditure (REE) (x axis) and lean mass (LM) (y axis). SMIM1⁺ individuals, light blue; SMIM1^−/− individuals, pink. The three SMIM1^−/− individuals shown in (D) are indicated by the pink dots with a black circumference. (D) Representative DXA scans showing fat volume and distribution in three SMIM1⁺ participants from the control group (top row, light blue borders) and three participants from the SMIM1^−/− group (bottom row, pink borders).