Publications (8)65.82 Total impact
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Article: Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2.
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ABSTRACT: A combined genome-wide association and linkage study was used to identify loci causing variation in cystic fibrosis lung disease severity. We identified a significant association (P = 3.34 × 10(-8)) near EHF and APIP (chr11p13) in p.Phe508del homozygotes (n = 1,978). The association replicated in p.Phe508del homozygotes (P = 0.006) from a separate family based study (n = 557), with P = 1.49 × 10(-9) for the three-study joint meta-analysis. Linkage analysis of 486 sibling pairs from the family based study identified a significant quantitative trait locus on chromosome 20q13.2 (log(10) odds = 5.03). Our findings provide insight into the causes of variation in lung disease severity in cystic fibrosis and suggest new therapeutic targets for this life-limiting disorder.Nature Genetics 06/2011; 43(6):539-46. · 35.53 Impact Factor -
Article: A novel lung disease phenotype adjusted for mortality attrition for cystic fibrosis genetic modifier studies.
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ABSTRACT: Genetic studies of lung disease in cystic fibrosis (CF) are hampered by the lack of a severity measure that accounts for chronic disease progression and mortality attrition. Further, combining analyses across studies requires common phenotypes that are robust to study design and patient ascertainment. Using data from the North American Cystic Fibrosis Modifier Consortium (Canadian Consortium for CF Genetic Studies, Johns Hopkins University CF Twin and Sibling Study, and University of North Carolina/Case Western Reserve University Gene Modifier Study), the authors calculated age-specific CF percentile values of FEV1 which were adjusted for CF age-specific mortality data. The phenotype was computed for 2,061 patients representing the Canadian CF population, 1,137 extreme phenotype patients in the UNC/Case Western study, and 1,323 patients from multiple CF sib families in the CF Twin and Sibling Study. Despite differences in ascertainment and median age, our phenotype score was distributed in all three samples in a manner consistent with ascertainment differences, reflecting the lung disease severity of each individual in the underlying population. The new phenotype score was highly correlated with the previously recommended complex phenotype, but the new phenotype is more robust for shorter follow-up and for extreme ages. A disease progression and mortality-adjusted phenotype reduces the need for stratification or additional covariates, increasing statistical power, and avoiding possible distortions. This approach will facilitate large-scale genetic and environmental epidemiological studies which will provide targeted therapeutic pathways for the clinical benefit of patients with CF.Pediatric Pulmonology 04/2011; 46(9):857-69. · 2.53 Impact Factor -
Article: Modulatory effect of the SLC9A3 gene on susceptibility to infections and pulmonary function in children with cystic fibrosis.
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ABSTRACT: In cystic fibrosis (CF), CFTR dysfunction leads to salt and water imbalance across airway epithelia, depleted surface liquid layer, and impaired mucociliary clearance. This provides optimal conditions for chronic bacterial infections leading to excessive inflammation and progressive obstructive lung disease. We hypothesized that other epithelial channels affecting salt balance across the airways may play a role in the susceptibility to bacterial infections and modulate severity of CF lung disease. The SLC9A3 gene encoding a Na(+) /H(+) exchanger was demonstrated to be a modifier intestinal disease in a murine model of CF. We examined the potential role of SLC9A3 as a modifier of CF lung disease severity. We analyzed 11 SLC9A3 gene variants for association with age of first Pseudomonas aeruginosa infection and lung function in children with CF. The T allele of an intronic variant in the SLC9A3 gene (rs4957061) was significantly (P = 0.02) associated with earlier acquisition of Pseudomonas infection in a cohort of 1,004 pediatric patients. Analysis of lung function in a subset of these patients (752) revealed that patients homozygous for the T allele had substantially reduced lung function and accelerated rate of decline. Although the functional basis for the modulatory effects of this SLC9A3 variant on CF lung disease remains to be elucidated, altered function of the Na(+) /H(+) exchanger may further deplete the airway liquid surface, thereby enhancing susceptibility to Pseudomonas infections and worsening the severity of lung disease.Pediatric Pulmonology 10/2010; 46(4):385-92. · 2.53 Impact Factor -
Article: Complex two-gene modulation of lung disease severity in children with cystic fibrosis.
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ABSTRACT: Although cystic fibrosis (CF) is a monogenic disease, its clinical manifestations are influenced in a complex manner. Severity of lung disease, the main cause of mortality among CF patients, is likely modulated by several genes. The mannose-binding lectin 2 (MBL2) gene encodes an innate immune response protein and has been implicated as a pulmonary modifier in CF. However, reports have been conflicting, and interactions with other modifiers have not been investigated. We therefore evaluated the association of MBL2 with CF pulmonary phenotype in a cohort of 1,019 Canadian pediatric CF patients. MBL2 genotypes were combined into low-, intermediate-, and high-expression groups based on MBL2 levels in plasma. Analysis of age at first infection with Pseudomonas aeruginosa demonstrated that MBL2 deficiency was significantly associated with earlier onset of infection. This MBL2 effect was amplified in patients with high-producing genotypes of transforming growth factor beta 1 (TGFB1). Similarly, MBL2 deficiency was associated with more rapid decline of pulmonary function, most significantly in those carrying the high-producing TGFB1 genotype. These findings provide evidence of gene-gene interaction in the pathogenesis of CF lung disease, whereby high TGF-beta1 production enhances the modulatory effect of MBL2 on the age of first bacterial infection and the rate of decline of pulmonary function.Journal of Clinical Investigation 04/2008; 118(3):1040-9. · 15.39 Impact Factor -
Article: Distribution of CFTR mutations in Saguenay- Lac-Saint-Jean: proposal of a panel of mutations for population screening.
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ABSTRACT: Saguenay-Lac-Saint-Jean is a region located in the northeastern part of the Province of Quebec, Canada, and is characterized by a founder effect. In this region, it has been documented that the incidence of cystic fibrosis reached 1/902 live births between 1975 and 1988, three times higher than the average incidence of 1/2500 live births reported in other Caucasian populations. This corresponds to a carrier rate of 1/15. Using genotyping data from the Canadian Consortium for Cystic Fibrosis Genetic Studies, this article describes the cystic fibrosis transmembrane conductance regulator profile of the cystic fibrosis population living in the Saguenay-Lac-Saint-Jean region and compares it with cystic fibrosis populations living in three other regions of the Province of Quebec. Significant differences in allelic frequencies of common mutations (as DeltaF508, 621 + 1G>T and A455E), and in percentage of covered allele with three or six mutations, were found in Saguenay-Lac-Saint-Jean compared to other regions. Based on this result, two mutation panels exceeding 90% sensitivity threshold are now proposed for cystic fibrosis carrier screening in this region. The implementation of the proposed carrier screening program could diminish the incidence of this disease in this region and allow future parents to make informed decisions about family planning.Genetics in medicine: official journal of the American College of Medical Genetics 04/2008; 10(3):201-6. · 3.92 Impact Factor -
Article: One-stage design is empirically more powerful than two-stage design for family-based genome-wide association studies.
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ABSTRACT: Finding a genetic marker associated with a trait is a classic problem in human genetics. Recently, two-stage approaches have gained popularity in marker-trait association studies, in part because researchers hope to reduce the multiple testing problem by testing fewer markers in the final stage. We compared one two-stage family-based approach to an analogous single-stage method, calculating the empirical type I error rates and power for both methods using fully simulated data sets modeled on nuclear families with rheumatoid arthritis, and data sets of real single-nucleotide polymorphism genotypes from Centre d'Etude du Polymorphisme Humain pedigrees with simulated traits. In these analyses performed in the absence of population stratification, the single-stage method was consistently more powerful than the two-stage method for a given type I error rate. To explore the sources of this difference, we performed a case study comparing the individual steps of two-stage designs, the two-stage design itself, and the analogous one-stage design.BMC proceedings 02/2007; 1 Suppl 1:S137. -
Article: Multistage designs in the genomic era: providing balance in complex disease studies.
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ABSTRACT: In this summary paper, we describe the contributions included in the Multistage Design group (Group 14) at the Genetic Analysis Workshop 15, which was held during November 12-14, 2006. Our group contrasted and compared different approaches to reducing complexity in a genetic study through implementation of staged designs. Most groups used the simulated dataset (problem 3), which provided ample opportunities for evaluating various staged designs. A wide range of multistage designs that targeted different aspects of complexity were explored. We categorized these approaches as reducing phenotypic complexity, model complexity, analytic complexity or genetic complexity. In general we learned that: (1) when staged designs are carefully planned and implemented, the power loss compared to a single-stage analysis can be minimized and study cost is greatly reduced; (2) a joint analysis of the results from each stage is generally more powerful than treating the second stage as a replication analysis.Genetic Epidemiology 02/2007; 31 Suppl 1:S118-23. · 3.44 Impact Factor -
Article: Recursive partitioning models for linkage in COGA data.
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ABSTRACT: We have developed a recursive-partitioning (RP) algorithm for identifying phenotype and covariate groupings that interact with the evidence for linkage. This data-mining approach for detecting gene x environment interactions uses genotype and covariate data on affected relative pairs to find evidence for linkage heterogeneity across covariate-defined subgroups. We adapted a likelihood-ratio based test of linkage parameterized with relative risks to a recursive partitioning framework, including a cross-validation based deviance measurement for choosing optimal tree size and a bootstrap sampling procedure for choosing robust tree structure. ALDX2 category 5 individuals were considered affected, categories 1 and 3 unaffected, and all others unknown. We sampled non-overlapping affected relative pairs from each family; therefore, we used 144 affected pairs in the RP model. Twenty pair-level covariates were defined from smoking status, maximum drinks, ethnicity, sex, and age at onset. Using the all-pairs score in GENEHUNTER, the nonparametric linkage tests showed no regions with suggestive linkage evidence. However, using the RP model, several suggestive regions were found on chromosomes 2, 4, 6, 14, and 20, with detection of associated covariates such as sex and age at onset.BMC Genetics 01/2006; 6 Suppl 1:S38. · 2.47 Impact Factor
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2011
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SickKids
- Program in Child Health Evaluative Sciences
Toronto, Ontario, Canada
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