Functional IL6R 358Ala allele impairs classical IL-6 receptor signaling and influences risk of diverse inflammatory diseases.

Inflammation, which is directly regulated by interleukin-6 (IL-6) signaling, is implicated in the etiology of several chronic diseases. Although a common, non-synonymous variant in the IL-6 receptor gene (IL6R Asp358Ala; rs2228145 A>C) is associated with the risk of several common diseases, with the 358Ala allele conferring protection from coronary heart disease (CHD), rheumatoid arthritis (RA), atrial fibrillation (AF), abdominal aortic aneurysm (AAA), and increased susceptibility to asthma, the variant's effect on IL-6 signaling is not known. Here we provide evidence for the association of this non-synonymous variant with the risk of type 1 diabetes (T1D) in two independent populations and confirm that rs2228145 is the major determinant of the concentration of circulating soluble IL-6R (sIL-6R) levels (34.6% increase in sIL-6R per copy of the minor allele 358Ala; rs2228145 [C]). To further investigate the molecular mechanism of this variant, we analyzed expression of IL-6R in peripheral blood mononuclear cells (PBMCs) in 128 volunteers from the Cambridge BioResource. We demonstrate that, although 358Ala increases transcription of the soluble IL6R isoform (P = 8.3×10⁻²²) and not the membrane-bound isoform, 358Ala reduces surface expression of IL-6R on CD4+ T cells and monocytes (up to 28% reduction per allele; P≤5.6×10⁻²²). Importantly, reduced expression of membrane-bound IL-6R resulted in impaired IL-6 responsiveness, as measured by decreased phosphorylation of the transcription factors STAT3 and STAT1 following stimulation with IL-6 (P≤5.2×10⁻7). Our findings elucidate the regulation of IL-6 signaling by IL-6R, which is causally relevant to several complex diseases, identify mechanisms for new approaches to target the IL-6/IL-6R axis, and anticipate differences in treatment response to IL-6 therapies based on this common IL6R variant.

Preschool children who are frequent attenders in emergency departments: an observational study of associated demographics and clinical characteristics.

BACKGROUND: Unscheduled visits to emergency departments (ED) have increased in the UK in recent years. Children who are repeat attenders are relatively understudied. AIMS: To describe the sociodemographic and clinical characteristics of preschoolers who attend ED a large District General Hospital. METHOD/STUDY DESIGN: Observational study analysing routinely collected ED operational data. Children attending four or more visits per year were considered as 'frequent attenders'. Poisson regression was used with demographic details (age, sex, ethnicity, sociodemographic status) to predict number of attendances seen in the year. We further analysed detailed diagnostic characteristics of a random sample of 10% of attendees. MAIN FINDINGS: 10 169 patients visited in the 12-month period with 16 603 attendances. 655 individuals attended on 3335 occasions. 6.4% of this population accounted for 20.1% of total visits. In the 10% sample, there were 304 attendances, and 69 (23%) had an underlying chronic long-standing illness (CLSI). This group were 2.4 times more likely to be admitted as inpatients compared with those without such conditions, median length of stay of 6.2 hours versus 2.5 hours (p=NS). CONCLUSIONS: Frequent ED attenders fall broadly into two distinct clinical groups: those who habitually return with self-limiting conditions and those with or without exacerbation of underlying CLSI. Both groups may be amenable to both additional nursing and other forms of community support to enhance self-care and continuity of care. Further research is required to increase our understanding of specific individual family and health system factors that predict repeat attendance in this age group.