Novel genetic predisposition to being overweight or obese identified

In a recent study published in Med, researchers performed a case-control study to compare metabolic changes between individuals homozygous for a loss-of-function (LoF) genetic variation in small integral membrane protein 1 (SMIM1) and the general population.

Background

Obesity is an increasingly prevalent condition that causes enormous economic hardship owing to the accompanying non-communicable illnesses. The underlying reason is an imbalance in energy expenditure due to a combination of lifestyle habits, environmental factors, and hereditary variables.

Despite the polygenic architecture of obesity, singular genetic variations with significant effect sizes are responsible for only a small proportion of cases. The polymorphisms facilitated the identification of new genes and biological mechanisms related to weight control, ultimately leading to the creation of innovative, tailored therapies.

About the study

In the present study, researchers evaluated the impact of SMIM1 absence on human health using phenotypic population biobanks to explore genetic susceptibility to overweight or obesity.

The study comprised 248 SMIM1-/- unrelated Europeans (105 females and 143 men) from four distinct cohorts. The study’s cohorts included the United Kingdom Biobank (UKB) cohort, the National Institute for Health and Care Research (NIHR)-NBR cohort, the Danish Blood Donor Study (DBDS) and Copenhagen Hospital Biobank (CHB) cohorts, and the Million Veteran Program (MVP) cohort. The genotype at rs566629828 was validated by an orthogonal test utilizing deoxyribonucleic acid (DNA) extracted from DBDS and 34 CHB blood samples obtained from their respective sample repositories.

The metabolic profile of SMIM1^-/- participants was examined using serum biochemistry, calorimetry, and dual-energy X-ray absorptiometry (DXA) scans. DXA assessed the effect of SMIM1 deficiency on resting energy expenditure (REE) and body mass composition. They investigated the potential role of SMIM1 in the hypothalamic-pituitary-thyroid axis. The researchers examined single-cell ribonucleic acid (RNA) sequencing data from mouse hypothalamus, human fetal pituitary, mouse pituitary, rat pituitary, and mouse thyroid organoids.

Researchers examined UK Biobank data to see if the SMIM1 LoF mutation was linked to any features other than those seen in the blood. They collected blood samples and health data from 25 British SMIM1^-/- individuals and compared them to 180 individuals who contained at least one reference allele for variation rs566629828. They confirmed relationships between the rs566629828 genotype and phenotypes found in the UKB and NIHR-NBR cohorts in 73 Danish SMIM1-/- participants from the Danish Blood Donor Study and the Copenhagen Hospital Biobank. They used linear regressions to analyze the data, correcting for factors including age, gender, and BMI.

Results

The data revealed that SMIM1^-/- individuals are heavier than their SMIM1^+/+ peers. SMIM1-/- individuals have dyslipidemia and are more likely to be on statins. SMIM1^-/- individuals have characteristics that mirror metabolic syndrome start, and lower energy expenditure owing to moderate hypothyroidism might be the underlying reason. Individuals homozygous for the LoF variation in the SMIM1 gene, which causes the Vel blood group, had altered leptin-to-adiponectin ratios, elevated hepatic enzymes, and lower thyroid hormone expression, as well as a decrease in REE.

Researchers identified 104 people with SMIM1-/- status, 90 of whom had European ancestry. The 17-base pair deletion was in strong linkage disequilibrium with the predominant allelic component of rs1175550, indicating the A genetic allele as origin. The rs1175550 variation was found to be a robust sentinel expression quantitative trait locus (eQTL) for the SMIM1 gene in blood linked to red cell characteristics independent of rs566629828.z.

Individuals with SMIM1^-/- had a higher body mass index (BMI), waist circumference, and fat mass on both arms. Among UKB individuals, 29% of 90 SMIM1-/- ones (11 men and 29% women) had BMI values above 30 kg per m2, which is higher than the whole cohort. SMIM1^-/- individuals also showed gender-specific effects, with females having higher mean fat-free mass values for arms and legs with lower mean sex hormone-binding globulin levels. However, the data suggested that thyroid dyshormonogenesis was an unlikely explanation for their abnormal thyroid status.

Conclusion

The study found that a 17-bp LoF mutation in SMIM1 is associated with excess body weight, dyslipidemia, insulin resistance, and metabolic syndrome, which is a risk factor for obesity. This is attributed to lower energy use. SMIM1^-/- individuals have metabolic abnormalities such as increased fat mass, inflammation, impaired liver function, triglycerides, and altered lipoprotein metabolism.

These effects have the potential to cause insulin resistance, the establishment of metabolic syndrome, and an elevated risk of cardiovascular disease. They are more likely to be administered statins and may have a higher risk of brain bleeding and thrombotic strokes. Due to the significant cost differential, the findings underscore the need to investigate the genetic origins of obesity in order to identify the most effective treatment.