Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma

Asthma is caused by a combination of poorly understood genetic and environmental factors(1,2). We have systematically mapped the effects of single nucleotide polymorphisms ( SNPs) on the presence of childhood onset asthma by genome-wide association. We characterized more than 317,000 SNPs in DNA from 994 patients with childhood onset asthma and 1,243 non-asthmatics, using family and case-referent panels. Here we show multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined P value of P < 10(-12). In independent replication studies the 17q21 locus showed strong association with diagnosis of childhood asthma in 2,320 subjects from a cohort of German children (P=0.0003) and in 3,301 subjects from the British 1958 Birth Cohort (P=0.0005). We systematically evaluated the relationships between markers of the 17q21 locus and transcript levels of genes in Epstein - Barr virus (EBV)-transformed lymphoblastoid cell lines from children in the asthma family panel used in our association study. The SNPs associated with childhood asthma were consistently and strongly associated (P < 10(-22)) in cis with transcript levels of ORMDL3, a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum(3). The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62682/1/nature06014.pd

A Phase I Dose-Escalation Study of AZD3965, an Oral Monocarboxylate Transporter 1 Inhibitor, in Patients with Advanced Cancer.

PURPOSE: Inhibition of monocarboxylate transporter (MCT) 1-mediated lactate transport may have cytostatic/cytotoxic effects on tumour cells. We report results from the dose-escalation part of a first‑in‑human trial of AZD3965, a first-in-class MCT1 inhibitor, in advanced cancer. EXPERIMENTAL DESIGN: This multicentre, Phase 1, dose-escalation and dose-expansion trial enrolled patients with advanced solid tumours or lymphoma and no standard therapy options. Exclusion criteria included history of retinal/cardiac disease, due to MCT1 expression in the eye and heart. Patients received daily oral AZD3965 according to a 3+3 then rolling 6 design. Primary objectives were to assess safety and determine the maximum tolerated dose and/or recommended Phase 2 dose (RP2D). Secondary objectives for dose-escalation included measurement of pharmacokinetics and pharmacodynamic activity. Exploratory biomarkers included tumour expression of MCT1 and MCT4, functional imaging of biological impact and metabolomics. RESULTS: During dose-escalation, 40 patients received AZD3965 at 5-30 mg once daily or 10 or 15 mg twice daily (BD). Treatment‑emergent adverse events were primarily Grade 1/2, most commonly electroretinogram changes (retinopathy), fatigue, anorexia and constipation. Seven patients receiving ≥20 mg daily experienced dose-limiting toxicities (DLTs): Grade 3 cardiac troponin rise (n=1), asymptomatic ocular DLTs (n=5) and Grade 3 acidosis (n=1). Plasma pharmacokinetics demonstrated attainment of target concentrations; pharmacodynamic measurements indicated on‑target activity. CONCLUSIONS: AZD3965 is tolerated at doses that produce target engagement. DLTs were on-target and primarily dose-dependent, asymptomatic, reversible ocular changes. An RP2D of 10 mg BD was established for use in dose-expansion in cancers that generally express high MCT1/low MCT4 (not yet published)

Dietary biomarkers: advances, limitations and future directions

<p>Abstract</p> <p>The subjective nature of self-reported dietary intake assessment methods presents numerous challenges to obtaining accurate dietary intake and nutritional status. This limitation can be overcome by the use of dietary biomarkers, which are able to objectively assess dietary consumption (or exposure) without the bias of self-reported dietary intake errors. The need for dietary biomarkers was addressed by the Institute of Medicine, who recognized the lack of nutritional biomarkers as a knowledge gap requiring future research. The purpose of this article is to review existing literature on currently available dietary biomarkers, including novel biomarkers of specific foods and dietary components, and assess the validity, reliability and sensitivity of the markers. This review revealed several biomarkers in need of additional validation research; research is also needed to produce sensitive, specific, cost-effective and noninvasive dietary biomarkers. The emerging field of metabolomics may help to advance the development of food/nutrient biomarkers, yet advances in food metabolome databases are needed. The availability of biomarkers that estimate intake of specific foods and dietary components could greatly enhance nutritional research targeting compliance to national recommendations as well as direct associations with disease outcomes. More research is necessary to refine existing biomarkers by accounting for confounding factors, to establish new indicators of specific food intake, and to develop techniques that are cost-effective, noninvasive, rapid and accurate measures of nutritional status.</p

Birth order modifies the effect of IL13 gene polymorphisms on serum IgE at age 10 and skin prick test at ages 4, 10 and 18: a prospective birth cohort study

Background:Susceptibility to atopy originates from effects of the environment on genes. Birth order has been identified as a risk factor for atopy and evidence for some candidate genes has been accumulated; however no study has yet assessed a birth order-gene interaction.Objective:To investigate the interaction of IL13 polymorphisms with birth order on allergic sensitization at ages 4, 10 and 18 years.Methods:Mother-infant dyads were recruited antenatally and followed prospectively to age 18 years. Questionnaire data (at birth, age 4, 10, 18); skin prick test (SPT) at ages 4, 10, 18; total serum IgE and specific inhalant screen at age 10; and genotyping for IL13 were collected. Three SNPs were selected from IL13: rs20541 (exon 4, nonsynonymous SNP), rs1800925 (promoter region) and rs2066960 (intron 1). Analysis included multivariable log-linear regression analyses using repeated measurements to estimate prevalence ratios (PRs).Results:Of the 1456 participants, birth order information was available for 83.2% (1212/1456); SPT was performed on 67.4% at age 4, 71.2% at age 10 and 58.0% at age 18. The prevalence of atopy (sensitization to one or more food or aeroallergens) increased from 19.7% at age 4, to 26.7% at 10 and 41.1% at age 18. Repeated measurement analysis indicated interaction between rs20541 and birth order on SPT. The stratified analyses demonstrated that the effect of IL13 on SPT was restricted only to first-born children (p = 0.007; adjusted PR = 1.35; 95%CI = 1.09, 1.69). Similar findings were noted for firstborns regarding elevated total serum IgE at age 10 (p = 0.007; PR = 1.73; 1.16, 2.57) and specific inhalant screen (p = 0.034; PR = 1.48; 1.03, 2.13).Conclusions:This is the first study to show an interaction between birth order and IL13 polymorphisms on allergic sensitization. Future functional genetic research need to determine whether or not birth order is related to altered expression and methylation of the IL13 gene