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Park J.E.,University of British Columbia | Yung R.,University of British Columbia | Stefanowicz D.,University of British Columbia | Shumansky K.,University of British Columbia | And 7 more authors.
Genes and Immunity | Year: 2011

Cystic fibrosis (CF) is one of the most common life-shortening genetic disorders, and the CF transmembrane conductance regulator (CFTR) is the major causal gene. However, a substantial clinical variability among patients with identical CFTR genotypes suggests the presence of modifier genes. We tested the effect of four genes involved in Pseudomonas aeruginosa infection. Analysis of a primary cohort detected eight candidate polymorphisms that were genotyped in the secondary cohort of 1579 patients; lung function and age at first infection with P. aeruginosa were considered as the phenotypes. Both additive and codominant models were considered, adjusting for confounding variables but not for multiple comparisons. In the secondary cohort, heme oxygenase-1 (HMOX1) rs2071749 had the most significant effect on lung function in the pediatric group (P=0.01; P corrected 0.03), and complement factor 3 (C3) rs11569393 and HMOX1 rs2071746 in the adult groups (P=0.03 for both variants; P corrected 0.16, 0.09). No polymorphism of complement factor B (CFB) or toll-like receptor 4 (TLR4) had a significant modifying effect on lung function in either group. We have identified two genes that showed nominal association with disease severity among CF patients. However, because of the multiple comparisons made, further studies are required to confirm the interaction between these modifying genes and CFTR. © 2011 Macmillan Publishers Limited All rights reserved. Source

Li W.,Child Health Evaluative science Program | Sun L.,University of Toronto | Corey M.,Child Health Evaluative science Program | Corey M.,University of Toronto | And 16 more authors.
Clinical Genetics | Year: 2011

It is generally presumed that the cystic fibrosis (CF) population is relatively homogeneous, and predominantly of European origin. The complex ethnic make-up observed in the CF patients collected by the North American CF Modifier Gene Consortium has brought this assumption into question, and suggested the potential for population substructure in the three CF study samples collected from North America. It is well appreciated that population substructure can result in spurious genetic associations. To understand the ethnic composition of the North American CF population, and to assess the need for population structure adjustment in genetic association studies with North American CF patients, genome-wide single-nucleotide polymorphisms on 3076 unrelated North American CF patients were used to perform population structure analyses. We compared self-reported ethnicity to genotype-inferred ancestry, and also examined whether geographic distribution and cystic fibrosis transmembrane regulator (CFTR) mutation type could explain the population structure observed. Although largely Caucasian, our analyses identified a considerable number of CF patients with admixed African-Caucasian, Mexican-Caucasian and Indian-Caucasian ancestries. Population substructure was present and comparable across the three studies of the consortium. Neither geographic distribution nor CFTR mutation type explained the population structure. Given the ethnic diversity of the North American CF population, it is essential to carefully detect, estimate and adjust for population substructure to guard against potential spurious findings in CF genetic association studies. Other Mendelian diseases that are presumed to predominantly affect single ethnic groups may also benefit from careful analysis of population structure. © 2010 John Wiley & Sons A/S. Source

Choufani S.,Program in Genetics and Genome Biology | Shapiro J.S.,Program in Genetics and Genome Biology | Shapiro J.S.,University of Toronto | Susiarjo M.,University of Pennsylvania | And 17 more authors.
Genome Research | Year: 2011

Imprinted genes are critical for normal human growth and neurodevelopment. They are characterized by differentially methylated regions (DMRs) of DNA that confer parent of origin-specific transcription. We developed a new strategy to identify imprinted gene-associated DMRs. Using genome-wide methylation profiling of sodium bisulfite modified DNA from normal human tissues of biparental origin, candidate DMRs were identified by selecting CpGs with methylation levels consistent with putative allelic differential methylation. In parallel, the methylation profiles of tissues of uniparental origin, i.e., paternally-derived androgenetic complete hydatidiform moles (AnCHMs), and maternally-derived mature cystic ovarian teratoma (MCT), were examined and then used to identify CpGs with parent of origin-specific DNA methylation. With this approach, we found known DMRs associated with imprinted genomic regions as well as new DMRs for known imprinted genes, NAP1L5 and ZNF597, and novel candidate imprinted genes. The paternally methylated DMR for one candidate, AXL, a receptor tyrosine kinase, was also validated in experiments with mouse embryos that demonstrated Axl was expressed preferentially from the maternal allele in a DNA methylation-dependent manner. © 2011 by Cold Spring Harbor Laboratory Press. Source

Diamond I.R.,Group for Improvement of Intestinal Function and Treatment GIFT | Diamond I.R.,University of Toronto | Grant R.C.,Group for Improvement of Intestinal Function and Treatment GIFT | Grant R.C.,University of Toronto | And 11 more authors.
Journal of Parenteral and Enteral Nutrition | Year: 2014

Objective: To determine expert beliefs regarding the probability of intestinal failure-associated liver disease (IFALD) with novel lipid-based approaches (lipid minimization/ω-3 lipids) in managing IFALD to facilitate Bayesian analyses of clinical trials of these therapies. Study Design: Structured interviews were conducted using a validated approach to belief elicitation with 60 intestinal failure (IF) experts from across North America. Participants were asked to estimate, in an average population of infants referred for management of IF with early IFALD, the probability of advanced IFALD at 3 months following referral in each of 3 scenarios: (1) conventional lipid, (2) ω-3 lipids, and (3) lipid minimization. Probability distributions of the risk of advanced IFALD with each strategy were developed. Distributions of the elicited treatment effect for the novel approaches, relative to conventional lipid, were calculated. Results: Median duration of experience of participants managing patients with IF was 8.5 (range, 2-35) years. The median probability of advanced IFALD using conventional lipid was 32.5%; ω-3 lipids, 17.5%; and lipid minimization, 13%. The median of the elicited treatment effects relative to conventional lipid was a relative risk of 0.53 for the ω-3 lipid and 0.45 for lipid minimization. Conclusions: There was consistent expert opinion that the novel lipid-based approaches are superior to conventional therapy, with similar estimates of treatment efficacy for the 2 approaches. The distributions of the elicited treatment effects can be used as prior distributions in Bayesian analyses of clinical trials of these novel strategies. © 2013 American Society for Parenteral and Enteral Nutrition. Source

Diamond I.R.,Group for Improvement of Intestinal Function and Treatment GIFT | Diamond I.R.,University of Toronto | De Silva N.T.,Group for Improvement of Intestinal Function and Treatment GIFT | Tomlinson G.A.,University of Toronto | And 8 more authors.
Journal of Parenteral and Enteral Nutrition | Year: 2011

Background: Given the recent interest in the role of ω-6 lipids in the development of intestinal failure-associated liver disease (IFALD), the authors sought to examine the role of parenteral lipids in the development of a serum conjugated bilirubin >100 μmol/L (5.9 mg/dL; CB100) in infants. Method: Between 2003 and 2004, data were collected prospectively on infants undergoing an abdominal surgical procedure. Univariate logistic regression models for the prediction of CB100 by 1 year postoperatively were developed. Predictors significant at the 0.2 level on univariate analysis were entered into a backward stepwise multiple variable logistic regression. Results: Of 152 infants who received parenteral nutrition (PN) postoperatively, 22 developed CB100. Predictors that met criteria for consideration in the multiple-variable model were age, weight, small bowel length, presence of a stoma, proportion of enteral feeds postoperatively, septic episodes, days of maximal PN amino acid (>2.5 g/kg/d), days of maximal lipid (>2.5 g/kg/d), and PN duration. The final model included septic episodes (odds ratio, 3.23; 95% confidence interval, 1.8-5.9) and days of lipid >2.5 g/kg/d (1.04; 1.003-1.06). At 60 days of maximal lipid, the odds of advanced IFALD were increased 10-fold. Conclusions: This model suggests a key role of parenteral lipids and septic events in the development of CB100 from IFALD. These data may provide targets, such as careful line care, reduction in maximal lipid dose, or alternate lipids such as ω-3 fatty acids, to prevent CB100, an identified marker of subsequent liver failure from IFALD. © 2011 The American Society for Parenteral and Enteral Nutrition. Source

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