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Objective: To study genetic variants and their function within genes coding for complement receptors in pre‐eclampsia. Design: A case–control study. Setting: Pre‐eclampsia is a common vascular disease of pregnancy. The clearance of placenta‐derived material is one of the functions of the complement system in pregnancy. Population: We genotyped 500 women with pre‐eclamptic pregnancies and 190 pregnant women without pre‐eclampsia, as controls, from the FINNPEC cohort, and 122 women with pre‐eclamptic pregnancies and 1905 controls from the national FINRISK cohort. Methods: The functional consequences of genotypes discovered by targeted exomic sequencing were explored by analysing the binding of the main ligand iC3b to mutated CR3 or CR4, which were transiently expressed on the surface of COS‐1 cells. Main outcome measures: Allele frequencies were compared between pre‐eclamptic pregnancies and controls in genetic studies. The functional consequences of selected variants were measured by binding assays. Results: The most significantly pre‐eclampsia‐linked CR3 variant M441K (P = 4.27E‐4, OR = 1.401, 95% CI = 1.167–1.682) displayed a trend of increased adhesion to iC3b (P = 0.051). The CR4 variant A251T was found to enhance the adhesion of CR4 to iC3b, whereas W48R resulted in a decrease of the binding of CR4 to iC3b. Conclusions: Results suggest that changes in complement‐facilitated phagocytosis are associated with pre‐eclampsia. Further studies are needed to ascertain whether aberrant CR3 and CR4 activity leads to altered pro‐ and anti‐inflammatory cytokine responses in individuals carrying the associated variants, and the role of these receptors in pre‐eclampsia pathogenesis. Genetic variants of complement receptors CR3 and CR4 have functional consequences that are associated with pre‐eclampsia. Genetic variants of complement receptors CR3 and CR4 have functional consequences that are associated with pre‐eclampsia. This article includes Author Insights, a video abstract available at https://vimeo.com/bjog/authorinsights16660 [ABSTRACT FROM AUTHOR]

Introduction: Glycogen storage disease V (GSDV, McArdle disease) and GSDVII (Tarui disease) are the most common of the rare disorders of glycogen metabolism. Both are associated with low lactate levels on exercise. Our aim was to find out whether lactate response associated with exercise testing could distinguish between these disorders., Methods: Two siblings with Tarui disease, two patients with McArdle disease and eight healthy controls were tested on spiroergometric exercise tests with follow-up of venous lactate and ammonia., Results: A late increase of lactate about three times the basal level was seen 10-30 min after exercise in patients with Tarui disease being higher than in McArdle disease and lower than in the controls. Ammonia was increased in Tarui disease., Discussion: Our results suggest that follow-up of lactate associated with exercise testing can be utilized in diagnostics to distinguish between different GSD diseases.

Integrins are adhesion molecules on the surface of cells. In blood cells they are responsible for rapid changes during adhesion of the cell to the endothelium. Deficiency or defective function of integrins will result in severe illnesses. Surprisingly, certain variants of integrins are associated with an increased risk of developing SLE. In autoimmune diseases and as a result of organ transplantations integrins participate in reactions in which leukocytes attack the body's own tissues. This has resulted in the development of drugs in antibody form for inhibition of the action of integrins. These drugs may, however, exhibit severe adverse effects.

Beta2-integrins are important in leukocyte trafficking and function, and are regulated through the binding of cytoplasmic proteins, such as kindlin-3, to their intracellular domain. Here, we investigate the involvement of beta2-integrins in the regulation of metabolic disease using mice where the kindlin-3 binding site in the beta2-integrin cytoplasmic tail has been mutated (TTT/AAA-beta2-integrin knock-in (KI) mice), leading to expressed but dysfunctional beta2-integrins and significant neutrophilia in vivo. Beta2-integrin KI mice fed on a high fat diet showed normal weight gain, and normal accumulation of macrophages and lymphocytes in white adipose tissue (WAT) and liver, but increased neutrophil numbers especially in WAT. In addition, beta2-integrin KI mice fed on a high fat diet showed significantly increased peripheral insulin resistance in response to high-fat feeding. However, this was associated with improved glucose disposal following glucose load. Interestingly, beta2-integrin KI neutrophils produced more elastase in vitro, in response to stimulation. Beta2-integrin KI mice displayed variability of tissue inflammatory status, with liver and WAT exhibiting little or no difference in inflammation compared to high fat fed controls, whereas skeletal muscle demonstrated a raised inflammatory profile in association with higher elastase levels and diminished signalling through the IRS1-PKB pathway. In conclusion, although expression of dysfunctional beta2-integrins increased neutrophil production and infiltration into tissue, skeletal muscle was the most affected tissue exhibiting evidence of higher neutrophil activity and insulin resistance. Thus, beta2-integrins modulate glucose homeostasis during high fat feeding predominantly through actions on skeletal muscle to affect metabolic phenotype in vivo.