BACKGROUND
IL-1 receptor-like 1 (IL1RL1) is a membrane receptor involved in T(H)2 inflammatory responses and eosinophilia. Single nucleotide polymorphisms (SNPs) in IL1RL1 have been associated with blood eosinophil counts in a genome-wide association study and with asthma in family-based and case-control studies.


OBJECTIVE
We assessed in the prospective birth cohort Prevention and Incidence of Asthma and Mite Allergy (PIAMA) whether IL1RL1 SNPs associate with levels of its soluble transcript IL1RL1 (IL1RL1-a) in serum, blood eosinophil counts, and asthma prevalence from birth to age 8 years, and whether IL1RL1-a serum levels associate with blood eosinophil counts.


METHODS
Fifteen IL1RL1 SNPs were genotyped. Serum IL1RL1-a levels were measured in 2 independent subsets within PIAMA, at 4 and 8 years. Blood eosinophil counts were measured in 4-year-old children.


RESULTS
In 2 independent subsets of children, 13 of 15 SNPs were associated with serum IL1RL1-a levels at ages 4 and 8 years with a consistent direction of effect for each allele. Rs11685480 allele A and rs1420102 allele A were significantly associated with lower numbers of blood eosinophils. In the total cohort, rs1041973 allele A was associated with a decreased risk of developing asthma (odds ratio, 0.70; 95% CI, 0.54-0.90). Rs1420101, recently identified in a genome-wide association study in the Icelandic population, was not associated with asthma in this study. IL1RL1-a levels were not associated with eosinophil counts.


CONCLUSION
We demonstrate that IL1RL1 polymorphisms are associated with serum IL1RL1-a, blood eosinophils, and asthma in childhood.

Iconographies supplémentaires de l'article : Interleukin-1 receptor–like 1 polymorphisms are associated with serum IL1RL1-a, eosinophils, and asthma in childhood

There is evidence across several species for genetic control of phenotypic variation of complex traits1, 2, 3, 4, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ~170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype)5, 6, 7, is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ~0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI8, possibly mediated by DNA methylation9, 10. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.

FTO genotype is associated with phenotypic variability of body mass index

Insights on aortic aneurysm and dissection: Role of the extracellular environment in vascular homeostasis.

Macrophages play crucial roles in abdominal aortic aneurysm (AAA) formation through the inflammatory response and extracellular matrix degradation; therefore, regulating macrophages may suppress AAA formation. Interleukin‐38 (IL‐38) is a member of the IL‐1 family, which binds to IL‐36 receptor (IL1RL2) and has an anti‐inflammation effect. Because macrophages express IL1RL2, we hypothesized that IL‐38 suppresses AAA formation by controlling macrophages. We assessed a C57BL6/J mouse angiotensin II‐induced AAA model with or without IL‐38 treatment. RAW 264.7 cells were cultured with tumor necrosis factor‐α and treated with or without IL‐38. Because p38 has important roles in inflammation, we assessed p38 phosphorylation in vitro and in vivo. To clarify whether the IL‐38 effect depends on the p38 pathway, we used SB203580 to inhibit p38 phosphorylation. IL1RL2+ macrophage accumulation along with matrix metalloproteinase (MMP)‐2 and ‐9 expression was observed in mouse AAA. IL‐38 reduced the incidence of AAA formation along with reduced M1 macrophage accumulation and MMP‐2 and ‐9 expression in the AAA wall. Macrophage activities including inducible nitric oxide, MMP‐2, and MMP‐9 production and spindle‐shaped changes were significantly suppressed by IL‐38. Furthermore, we revealed that inhibition of p38 phosphorylation diminished the effects of IL‐38 on regulating macrophages to reduce AAA incidence, indicating the protective effects of IL‐38 depend on the p38 pathway. IL‐38 plays protective roles against AAA formation through regulation of macrophage accumulation in the aortic wall and modulating the inflammatory phenotype. Using IL‐38 may be a novel therapy for AAA patients.

Interleukin‐38 suppresses abdominal aortic aneurysm formation in mice by regulating macrophages in an IL1RL2‐p38 pathway‐dependent manner

An impossible paradigm has been proposed by recent medico-legal cases in Australia. These have the potential to cause patient harm, inhibit good clinical practice and place a heavy burden on ED clinicians and the health system. The most fundamental principle in emergency medicine is identifying patients with critical illness who need urgent intervention; this frequently involves rapid clinical assessment with limited information. Not all serious illness can be easily identified by clinical assessment and basic investigations available at all times in EDs. Every test or intervention carries both a potential benefit and a risk, which varies with each patient. Knowing when to apply an intervention should be based, when possible, on strong research evidence. The article by Kelly et al. published in this issue demonstrates the conundrum faced by clinicians when seeing a patient with a rare condition that has potentially fatal consequences if missed.Aortic dissection (AD)usually (but not always) presents with chest or abdominal pain; the vast majority of patients with chest pain or abdominal pain do not have AD. The distinguishing features that make the diagnosis more likely are often absent and there are no validated clinical decision rules. The Australian medico-legal experience highlighted by Kelly et al. appears to be following that experienced in the USA. In a 12-year period, there were 150 medical malpractice cases involving AD, most for failure to diagnose and treat. Although the majority of cases were ruled in favour of the defendants, increased use of CT scans is suggested as a potential solution to reducing the incidence of missed ADs in the ED. AD is not alone, with similar conundrums faced in patients with ischaemic bowel presenting as abdominal pain, spinal cord compression presenting as back pain and subarachnoid haemorrhage presenting as headache. Liberal use of advanced imaging such as CT scans with contrast as a screening tool is fraught with risks, including malignancy, anaphylaxis and the physical and psychological trauma associated with incidental diagnoses of benign conditions resulting in further diagnostic tests. To chase all rare diagnoses that present with common symptoms will tip the risk– benefit ledger towards nett harm for most patients. Apart from individual patient harm, the systemic impact will be reduced equity of medical care, and many patients with stroke, trauma and other critical illnesses will have less access to CT scanning. It will also cause worse patient flow and bed access, particularly after hours. Also, each scan will generate hundreds of images, with and without contrast, that will demand expert reporting. If emergency clinicians are expected to have negative predictive values of 100% for all serious diagnoses among patients presenting to the ED, the impact on the health system, from the perspective of service provision and cost, will not be sustainable. The only logical solutions are the use of better screening tools and acceptance of some level of evidence-based risk. In the future, biomarkers for screening may offer a solution. For AD assessment, widespread use of the D-dimer levels is limited by low specificity, but newer biomarkers such as Aggrecan, IL1R1 and soluble ST2 have shown some potential in pre-clinical studies. Other potential targets include biomarkers from the aortic extracellular matrix such as metalloproteinases, TGF-β, elastin fragments and those associated with vascular smooth muscle. Similarly, micro RNAs (non-coding, small RNA sequences that are stable and detectable in circulating blood) show promise, but all are a long way from demonstrated diagnostic utility in humans. As patient advocates, we cannot allow the current paradigm to continue. Our specialist colleges, the Australian Medical Association and patient consumer groups should advocate for common sense. Clinical pathways, based on available evidence should be agreed and followed across Australia, and adherence to such guidelines should define reasonable practice. Evidence-based guidelines for most serious conditions are available, and most accept that a small risk of delayed or missed diagnosis exists and may cause harm. Such adverse events are understandably distressing for the individual patient and their family, but the system should not be influenced into causing more harm. Clinicians following these evidence-based pathways should not be subject to inappropriate censure by courts, coroners or other external bodies who do not, or cannot, appreciate the impossibility of always being right and the impacts of chasing rare diagnoses. In this current climate, as described by Kelly et al., there is an even greater need for regular optimisation of clinical pathways, research to improve diagnostics and benchmarking of practice, funded and governed at a federal level.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/1742-6723.14140

Zero risk is not possible in emergency medicine

Objective: Aortic dissection (AD) is characterized by an acute onset, rapid progress, and high mortality. Levels of soluble ST2 (sST2) on presentation are elevated in patients with acute AD, which can be used to discriminate AD patients from patients with chest pain. sST2 concentrations were found to be highly heritable in the general population. The aim of this study was to investigate the associations of variations in ST2-related gene expression with sST2 concentrations and AD risk. Methods: This case-control study involving a total of 2,277 participants were conducted, including 435 AD patients and age- and sex-matched 435 controls in the discovery stage, and 464 patients and 943 controls in the validation stage. Eight ST2-related genes were selected by systematic review. Tag single-nucleotide polymorphisms (SNPs) were screened out from the Chinese population of the 1,000 Genomes Database. Twenty-one ST2-related SNPs were genotyped, and plasma sST2 concentrations were measured. Results: In the discovery stage, rs13019803 located in IL1R1 was significantly associated with AD after Bonferroni correction (p = 0.0009) and was correlated with circulating sST2 levels in patients with type A AD(AAD) [log-sST2 per C allele increased by 0.180 (95%) CI: 0.002 - 0.357] but not in type B. Combining the two stages together, rs13019803C was associated with plasma sST2 level in AAD patients [log-sST2 increased by 0.141 (95% CI: 0.055-0.227) for per C allele]. Odds ratio of rs13019803 on the risk of AAD is 1.67 (95% CI: 1.33-2.09). Conclusions: The IL1R1 SNP rs13019803C is associated with higher sST2 levels and increased risk of AAD.

/pdf/association-of-il1r1-coding-variant-with-plasma-level-4sfsa745o8.pdf

Association of IL1R1 Coding Variant With Plasma-Level Soluble ST2 and Risk of Aortic Dissection.

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Association of IL1R1 Coding Variant With Plasma-Level Soluble ST2 and Risk of Aortic Dissection.