Loss of function variant in SMIM1 is associated with reduced energy expenditure and weight gain

Blood group antigens are the archetypal example of human genetic variation. Here, we characterised the functional metabolic consequences in individuals homozygous for a 17bp deletion in SMIM1 (rs566629828; minor allele frequency 0.0147) and thus lacking the protein defining the Vel blood group. Our analysis, in separate cohorts of SMIM1-/- individuals (UK Biobank, NHS Blood and Transplant, Danish Blood Donor Study, Copenhagen Hospital Biobank) and a mouse model, identified an increase in body weight accompanied by a range of metabolic differences, including dyslipidemia, changes in the leptin-adiponectin ratio, increased liver enzymes and lower total thyroid hormone levels. These changes in the metabolic state were at least in part due to a reduction in resting energy expenditure, as assessed during an in-depth clinical assessment of SMIM1-/- individuals. Additionally, electronic health records suggest that individuals lacking this 78-amino-acid type II transmembrane protein may be more prone to cerebral bleeds and thrombotic stroke.