PB0159 - Loss of function variant in SMIM1 is associated with reduced energy expenditure, weight gain and an increased risk for cardiovascular events.

Background: Blood groups have been extensively studied because of their importance in transfusion medicine, and variants in the ABO group are also associated with a slightly increased risk of thrombotic and bleeding events. In sharp contrast, we describe a 17-bp nonsense-deletion in SMIM1 present in homozygosity in 1 in 5,000 of the UK Biobank (UKB) participants (who thus lack the Vel blood group), that is associated with a significant gain in weight and an increased risk of cardiovascular events.

Aims: To characterise the metabolic and cardiovascular consequences of SMIM1 absence.

Methods: We performed logistic regression on the UKB (90 SMIM1-/-) to investigate genotype-phenotype associations. Findings were replicated in English and Danish blood donor cohorts, as well as Smim1-/- mice. scRNA-Seq was used to investigate possible mechanisms.

Results: In SMIM1-/- UKB participants we found an association with increased weight (=0.22, p=FDR=4.61e-02), more prominent in women than men, of 4.6 and 2.4 kg on average respectively (Fig.1). This observation was replicated in the blood donor cohorts and in Smim1-/- mice. Analysis of UKB-plasma biochemistry showed increased triglycerides, urate and liver-enzymes levels. A clinical metabolic assessment showed reduced energy expenditure (Fig.1). Association analysis for cardiovascular events in UKB showed an increased odds ratio for cerebral bleeds (OR=5.53, FDR=6.88e-04) and thrombotic stroke (OR=3.46, FDR=2.32e-02). scRNA-seq showed expression of SMIM1-transcript in the pituitary and thyroid glands.

Conclusion(s): We showed that individuals lacking SMIM1 (Vel-negative) exhibit altered lipid metabolism, due, at least in part, to reduced energy expenditure. These data also suggest mild hypothyroidism and an increased risk of cerebral bleeds and thrombotic stroke. Further studies are required to understand the role of this small transmembrane-protein in the pituitary-thyroid axis and whether thyroid hormone supplementation can reverse cardiometabolic risks associated with this condition.