A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma.

Efst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinnIL-33 is a tissue-derived cytokine that induces and amplifies eosinophilic inflammation and has emerged as a promising new drug target for asthma and allergic disease. Common variants at IL33 and IL1RL1, encoding the IL-33 receptor ST2, associate with eosinophil counts and asthma. Through whole-genome sequencing and imputation into the Icelandic population, we found a rare variant in IL33 (NM_001199640:exon7:c.487-1G>C (rs146597587-C), allele frequency = 0.65%) that disrupts a canonical splice acceptor site before the last coding exon. It is also found at low frequency in European populations. rs146597587-C associates with lower eosinophil counts (β = -0.21 SD, P = 2.5×10-16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95%CI: 0.32, 0.70, P = 1.8×10-4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non-carriers and allele-specific analysis based on RNA sequencing and phased genotypes shows that only 20% of the total expression is from the mutated chromosome. In half of those transcripts the mutation causes retention of the last intron, predicted to result in a premature stop codon that leads to truncation of 66 amino acids. The truncated IL-33 has normal intracellular localization but neither binds IL-33R/ST2 nor activates ST2-expressing cells. Together these data demonstrate that rs146597587-C is a loss of function mutation and support the hypothesis that IL-33 haploinsufficiency protects against asthma.Netherlands Asthma Foundation University Medical Center Groningen Ministry of Health and Environmental Hygiene of Netherlands Netherlands Asthma Stichting Astma Bestrijding BBMRI European Respiratory Society private and public research funds AstraZeneca ALK-Abello, Denmar

Phosphatidylethanol as a sensitive and specific biomarker-comparison with gamma-glutamyl transpeptidase, mean corpuscular volume and carbohydrate-deficient transferrin

Phosphatidylethanol (PEth), a direct ethanol metabolite, is detectable in blood for more than 2 weeks after sustained ethanol intake. Our aim was to assess the usefulness of PEth [comparing sensitivity, specificity and the area under the curve (AUC)] as compared with carbohydrate-deficient transferrin (CDT), gamma-glutamyl transpeptidase (GGT) and mean corpuscular volume (MCV), calculating the results from sober patients against those from alcohol-dependent patients during withdrawal. Fifty-six alcohol-dependent patients (ICD-10 F 10.25) in detoxification, age 43 years, GGT 81 U/l, MCV 96.4 fl, %CDT 4.2, 1400 g ethanol intake in the last 7 days (median), were included in the study. Over the time of 1 year, 52 samples from 35 sober forensic psychiatric addicted in-patients [age 34 years, GGT 16 U/l, MCV 91 fl, CDT 0.5 (median)] in a closed ward were drawn and used for comparison . PEth was measured in heparinized whole blood with a high-performance liquid chromatography method. GGT, MCV and %CDT were measured using routine methods. A receiver operating characteristic curve analysis was carried out, with 'current drinking status' (sober/drinking) as the state variable and PEth, MCV, GGT and CDT as test variables. The resulting AUC was 0.974 (P < 0.0001, confidence interval 0.932-1.016) for PEth. At a cut-off of 0.36 mu mol/l, the sensitivity was 94.5% and specificity 100%. The AUC for CDT, GGT and MCV were 0.931, 0.894 and 0.883, respectively. A significant Spearman's rank correlation was found between PEth and GGT (r = 0.739), CDT (r = 0.643), MVC (r = 0.639) and grams of ethanol consumed in the last 7 days (r = 0.802). Our data suggest that PEth has potential to be a sensitive and specific biomarker, having been found in previous studies to indicate longer lasting intake of higher amounts of alcohol

World Health Organization/International Society for Biomedical Research on Alcoholism study on state and trait markers of alcohol use and dependence: Back to the future

This article summarizes content proceedings of a symposium held at the 2004 International Society for Biomedical Research on Alcoholism Congress in Mannheim, Germany. The chairs were Boris Tabakoff and Friedrich M. Wurst. The presentations were (1) Genetic associations with alcoholism and affective disorders, by Paula Hoffman; (2) Proteomic analysis of blood constituents in alcoholism, by Boris Tabakoff; (3) Contrasts between the responses of GGT and CDT to high alcohol intake, and a test of their combined use, by John Whitfield; (4) Direct ethanol metabolites such as ethyl glucuronide, fatty acid ethyl esters, phosphatidylethanol and ethyl sulfate: a new line of sensitive and specific biomarkers, by Friedrich Martin Wurst; and (5) Genetic studies of alcoholism subtypes in a Han Taiwanese population, by Ru-Band Lu

Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks.

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms

Conditional analysis for eosinophil counts associations in the region around <i>IL1RL1</i>.

<p>Plot shows an 800kb overview around the <i>IL1RL1</i> gene on chromosome 2. Black circles (o) show-log₁₀ <i>P</i> as a function of hg38 coordinates for unadjusted associations with eosinophil counts; red crosses (+) correspond to eosinophil counts associations after adjusting for the variant rs13020553; blue ‘x’ symbols correspond to eosinophil counts associations after adjusting for both rs13020553 and rs6719123. The position of the two variants rs13020553 and rs6719123 are indicated by vertical broken lines. Genes are shown in blue and recombination rates are reported in cM/Mb.</p

Activity of IL-33 variants in human CD4 T cell bioassay.

<p>Purified human blood CD4 T cells were incubated in the presence or absence of IL-2 and IL-12 for 72 hours and IFN-γ was measured in the cell-free supernatants (as described in online methods). Both IL-33 (95–270) (Amgen) and IL-33(112–270) (R&D Systems) were used as positive controls and two independent lots of IL-33(95–204) were tested. (<b>A</b>) IL-33, IL-2 and IL-12 dependence of assay with IL-33 at 10ng/mL; (<b>B</b>) Dose titration of IL-33 variants (in the presence of 10 ng/mL IL-2 and 10 ng/mL IL-12). (<b>C</b>) ST2 dependence of response. IL-33 variants (10 ng/mL plus IL-2 and IL-12) were tested in the presence of 25 ug/mL human IgG2 control antibody or IgG2 anti-human ST2 blocking antibody.</p

Association of common sequence variants in <i>IL33</i> and <i>IL1RL1</i> with eosinophil counts and asthma in Iceland.

<p>Association of common sequence variants in <i>IL33</i> and <i>IL1RL1</i> with eosinophil counts and asthma in Iceland.</p