Background Variation in adiposity is associated with cardiometabolic disease outcomes, but mechanisms leading from this exposure to disease are unclear. This study aimed to estimate effects of body mass index (BMI) on an extensive set of circulating proteins. Methods We used SomaLogic proteomic data from up to 2737 healthy participants from the INTERVAL study. Associations between self-reported BMI and 3622 unique plasma proteins were explored using linear regression. These were complemented by Mendelian randomisation (MR) analyses using a genetic risk score (GRS) comprised of 654 BMI-associated polymorphisms from a recent genome-wide association study (GWAS) of adult BMI. A disease enrichment analysis was performed using DAVID Bioinformatics 6.8 for proteins which were altered by BMI. Results Observationally, BMI was associated with 1576 proteins (P < 1.4 × 10−5), with particularly strong evidence for a positive association with leptin and fatty acid-binding protein-4 (FABP4), and a negative association with sex hormone-binding globulin (SHBG). Observational estimates were likely confounded, but the GRS for BMI did not associate with measured confounders. MR analyses provided evidence for a causal relationship between BMI and eight proteins including leptin (0.63 standard deviation (SD) per SD BMI, 95% CI 0.48–0.79, P = 1.6 × 10−15), FABP4 (0.64 SD per SD BMI, 95% CI 0.46–0.83, P = 6.7 × 10−12) and SHBG (−0.45 SD per SD BMI, 95% CI −0.65 to −0.25, P = 1.4 × 10−5). There was agreement in the magnitude of observational and MR estimates (R2 = 0.33) and evidence that proteins most strongly altered by BMI were enriched for genes involved in cardiovascular disease. Conclusions This study provides evidence for a broad impact of adiposity on the human proteome. Proteins strongly altered by BMI include those involved in regulating appetite, sex hormones and inflammation; such proteins are also enriched for cardiovascular disease-related genes. Altogether, results help focus attention onto new proteomic signatures of obesity-related disease.
Three small conductance calcium-activated potassium channel (SK) subunits have been cloned and found to preferentially form heteromeric channels when expressed in a heterologous expression system. The original cloning of the gene encoding the intermediate conductance calcium-activated potassium channel (IKCa) was termed SK4 because of the high homology between channel subtypes. Recent immunovisualization suggests that IKCa is expressed in the same subcellular compartments of some neurons as SK channel subunits. Stochastic optical reconstruction microscopy super-resolution microscopy revealed that coexpressed IKCa and SK1 channel subunits were closely associated, a finding substantiated by measurement of fluorescence resonance energy transfer between coexpressed fluorophore-tagged subunits. Expression of homomeric SK1 channels produced current that displayed typical sensitivity to SK channel inhibitors, while expressed IKCa channel current was inhibited by known IKCa channel blockers. Expression of both SK1 and IKCa subunits gave a current that displayed no sensitivity to SK channel inhibitors and a decreased sensitivity to IKCa current inhibitors. Single channel recording indicated that coexpression of SK1 and IKCa subunits produced channels with properties intermediate between those observed for homomeric channels. These data indicate that SK1 and IKCa channel subunits preferentially combine to form heteromeric channels that display pharmacological and biophysical properties distinct from those seen with homomeric channels.
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