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Johanna M Rommens - One of the best experts on this subject based on the ideXlab platform.
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prevalence of Meconium ileus marks the severity of mutations of the cystic fibrosis transmembrane conductance regulator cftr gene
Genetics in Medicine, 2016Co-Authors: Annie Dupuis, Katherine Keenan, Ruslan Dorfman, Chee Y Ooi, Marci K Sontag, Lutz Naehrlich, Carlo Castellani, Lisa J Strug, Johanna M RommensAbstract:Prevalence of Meconium ileus marks the severity of mutations of the Cystic Fibrosis Transmembrane Conductance Regulator ( CFTR ) gene
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prevalence of Meconium ileus marks the severity of mutations of the cystic fibrosis transmembrane conductance regulator cftr gene
Genetics in Medicine, 2016Co-Authors: Annie Dupuis, Katherine Keenan, Ruslan Dorfman, Chee Y Ooi, Marci K Sontag, Lutz Naehrlich, Carlo Castellani, Lisa J Strug, Johanna M RommensAbstract:Meconium ileus (MI) is a perinatal complication in cystic fibrosis (CF), which is only minimally influenced by environmental factors. We derived and examined MI prevalence (MIP) scores to assess CFTR phenotype–phenotype correlation for severe mutations. MIP scores were established using a Canadian CF population (n = 2,492) as estimates of the proportion of patients with MI among all patients carrying the same CFTR mutation, focusing on patients with p.F508del as the second allele. Comparisons were made to the registries from the US CF Foundation (n = 43,432), Italy (Veneto/Trentino/Alto Adige regions) (n = 1,788), and Germany (n = 3,596). The prevalence of MI varied among the different registries (13–21%). MI was predominantly prevalent in patients with pancreatic insufficiency carrying “severe” CFTR mutations. In this severe spectrum MIP scores further distinguished between mutation types, for example, G542X (0.31) with a high, F508del (0.22) with a moderate, and G551D (0.08) with a low MIP score. Higher MIP scores were associated with more severe clinical phenotypes, such as a lower forced expiratory volume in 1 second (P = 0.01) and body mass index z score (P = 0.04). MIP scores can be used to rank CFTR mutations according to their clinical severity and provide a means to expand delineation of CF phenotypes. Genet Med 18 4, 333–340.
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multiple apical plasma membrane constituents are associated with susceptibility to Meconium ileus in individuals with cystic fibrosis
Nature Genetics, 2012Co-Authors: Lei Sun, Fan Lin, Ruslan Dorfman, Johanna M Rommens, Harriet Corvol, Theodore Chiang, Pierre Francois Busson, Rashmi V Parekh, Diana ZelenikaAbstract:Lisa Strug and colleagues report a genome-wide association study for Meconium ileus in individuals with cystic fibrosis. Conventional genome-wide approaches identified variants in SLC26A9 and SLC6A14 associated with Meconium ileus. The authors also performed a hypothesis-driven genome-wide association study (HD-GWAS) that upweighted 3,814 SNPs within 10 kb of 155 genes expressed in the apical plasma membrane. The HD-GWAS identified variants near SLC9A3 associated with Meconium ileus.
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multiple apical plasma membrane constituents are associated with susceptibility to Meconium ileus in individuals with cystic fibrosis
Nature Genetics, 2012Co-Authors: Lei Sun, Fan Lin, Ruslan Dorfman, Johanna M Rommens, Harriet Corvol, Theodore Chiang, Pierre Francois Busson, Rashmi V Parekh, Diana ZelenikaAbstract:Variants associated with Meconium ileus in cystic fibrosis were identified in 3,763 affected individuals by genome-wide association study (GWAS). Five SNPs at two loci near SLC6A14 at Xq23-24 (minimum P = 1.28 × 10(-12) at rs3788766) and SLC26A9 at 1q32.1 (minimum P = 9.88 × 10(-9) at rs4077468) accounted for ~5% of phenotypic variability and were replicated in an independent sample of affected individuals (n = 2,372; P = 0.001 and 0.0001, respectively). By incorporating the knowledge that disease-causing mutations in CFTR alter electrolyte and fluid flux across surface epithelium into a hypothesis-driven GWAS (GWAS-HD), we identified associations with the same SNPs in SLC6A14 and SLC26A9 and established evidence for the involvement of SNPs in a third solute carrier gene, SLC9A3. In addition, GWAS-HD provided evidence of association between Meconium ileus and multiple genes encoding constituents of the apical plasma membrane where CFTR resides (P = 0.0002; testing of 155 apical membrane genes jointly and in replication, P = 0.022). These findings suggest that modulating activities of apical membrane constituents could complement current therapeutic paradigms for cystic fibrosis.
Ruslan Dorfman - One of the best experts on this subject based on the ideXlab platform.
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prevalence of Meconium ileus marks the severity of mutations of the cystic fibrosis transmembrane conductance regulator cftr gene
Genetics in Medicine, 2016Co-Authors: Annie Dupuis, Katherine Keenan, Ruslan Dorfman, Chee Y Ooi, Marci K Sontag, Lutz Naehrlich, Carlo Castellani, Lisa J Strug, Johanna M RommensAbstract:Prevalence of Meconium ileus marks the severity of mutations of the Cystic Fibrosis Transmembrane Conductance Regulator ( CFTR ) gene
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prevalence of Meconium ileus marks the severity of mutations of the cystic fibrosis transmembrane conductance regulator cftr gene
Genetics in Medicine, 2016Co-Authors: Annie Dupuis, Katherine Keenan, Ruslan Dorfman, Chee Y Ooi, Marci K Sontag, Lutz Naehrlich, Carlo Castellani, Lisa J Strug, Johanna M RommensAbstract:Meconium ileus (MI) is a perinatal complication in cystic fibrosis (CF), which is only minimally influenced by environmental factors. We derived and examined MI prevalence (MIP) scores to assess CFTR phenotype–phenotype correlation for severe mutations. MIP scores were established using a Canadian CF population (n = 2,492) as estimates of the proportion of patients with MI among all patients carrying the same CFTR mutation, focusing on patients with p.F508del as the second allele. Comparisons were made to the registries from the US CF Foundation (n = 43,432), Italy (Veneto/Trentino/Alto Adige regions) (n = 1,788), and Germany (n = 3,596). The prevalence of MI varied among the different registries (13–21%). MI was predominantly prevalent in patients with pancreatic insufficiency carrying “severe” CFTR mutations. In this severe spectrum MIP scores further distinguished between mutation types, for example, G542X (0.31) with a high, F508del (0.22) with a moderate, and G551D (0.08) with a low MIP score. Higher MIP scores were associated with more severe clinical phenotypes, such as a lower forced expiratory volume in 1 second (P = 0.01) and body mass index z score (P = 0.04). MIP scores can be used to rank CFTR mutations according to their clinical severity and provide a means to expand delineation of CF phenotypes. Genet Med 18 4, 333–340.
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multiple apical plasma membrane constituents are associated with susceptibility to Meconium ileus in individuals with cystic fibrosis
Nature Genetics, 2012Co-Authors: Lei Sun, Fan Lin, Ruslan Dorfman, Johanna M Rommens, Harriet Corvol, Theodore Chiang, Pierre Francois Busson, Rashmi V Parekh, Diana ZelenikaAbstract:Lisa Strug and colleagues report a genome-wide association study for Meconium ileus in individuals with cystic fibrosis. Conventional genome-wide approaches identified variants in SLC26A9 and SLC6A14 associated with Meconium ileus. The authors also performed a hypothesis-driven genome-wide association study (HD-GWAS) that upweighted 3,814 SNPs within 10 kb of 155 genes expressed in the apical plasma membrane. The HD-GWAS identified variants near SLC9A3 associated with Meconium ileus.
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multiple apical plasma membrane constituents are associated with susceptibility to Meconium ileus in individuals with cystic fibrosis
Nature Genetics, 2012Co-Authors: Lei Sun, Fan Lin, Ruslan Dorfman, Johanna M Rommens, Harriet Corvol, Theodore Chiang, Pierre Francois Busson, Rashmi V Parekh, Diana ZelenikaAbstract:Variants associated with Meconium ileus in cystic fibrosis were identified in 3,763 affected individuals by genome-wide association study (GWAS). Five SNPs at two loci near SLC6A14 at Xq23-24 (minimum P = 1.28 × 10(-12) at rs3788766) and SLC26A9 at 1q32.1 (minimum P = 9.88 × 10(-9) at rs4077468) accounted for ~5% of phenotypic variability and were replicated in an independent sample of affected individuals (n = 2,372; P = 0.001 and 0.0001, respectively). By incorporating the knowledge that disease-causing mutations in CFTR alter electrolyte and fluid flux across surface epithelium into a hypothesis-driven GWAS (GWAS-HD), we identified associations with the same SNPs in SLC6A14 and SLC26A9 and established evidence for the involvement of SNPs in a third solute carrier gene, SLC9A3. In addition, GWAS-HD provided evidence of association between Meconium ileus and multiple genes encoding constituents of the apical plasma membrane where CFTR resides (P = 0.0002; testing of 155 apical membrane genes jointly and in replication, P = 0.022). These findings suggest that modulating activities of apical membrane constituents could complement current therapeutic paradigms for cystic fibrosis.
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Modifier gene study of Meconium ileus in cystic fibrosis: statistical considerations and gene mapping results.
Human genetics, 2009Co-Authors: Ruslan Dorfman, Fan Lin, Lei Sun, Yongqian Wang, Andrew J. Sandford, Peter D. Paré, Karen Mckay, Hana Kayserova, T. PiskackovaAbstract:Cystic fibrosis (CF) is a monogenic disease due to mutations in the CFTR gene. Yet, variability in CF disease presentation is presumed to be affected by modifier genes, such as those recently demonstrated for the pulmonary aspect. Here, we conduct a modifier gene study for Meconium ileus (MI), an intestinal obstruction that occurs in 16–20% of CF newborns, providing linkage and association results from large family and case–control samples. Linkage analysis of modifier traits is different than linkage analysis of primary traits on which a sample was ascertained. Here, we articulate a source of confounding unique to modifier gene studies and provide an example of how one might overcome the confounding in the context of linkage studies. Our linkage analysis provided evidence of a MI locus on chromosome 12p13.3, which was segregating in up to 80% of MI families with at least one affected offspring (HLOD = 2.9). Fine mapping of the 12p13.3 region in a large case–control sample of pancreatic insufficient Canadian CF patients with and without MI pointed to the involvement of ADIPOR2 in MI (p = 0.002). This marker was substantially out of Hardy–Weinberg equilibrium in the cases only, and provided evidence of a cohort effect. The association with rs9300298 in the ADIPOR2 gene at the 12p13.3 locus was replicated in an independent sample of CF families. A protective locus, using the phenotype of no-MI, mapped to 4q13.3 (HLOD = 3.19), with substantial heterogeneity. A candidate gene in the region, SLC4A4, provided preliminary evidence of association (p = 0.002), warranting further follow-up studies. Our linkage approach was used to direct our fine-mapping studies, which uncovered two potential modifier genes worthy of follow-up.
Chee Y Ooi - One of the best experts on this subject based on the ideXlab platform.
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differences in clinical outcomes of paediatric cystic fibrosis patients with and without Meconium ileus
Journal of Cystic Fibrosis, 2018Co-Authors: Su Min Joyce Tan, Chee Y Ooi, Michael J CoffeyAbstract:Abstract Background Meconium ileus (MI) affects up to 20% of newborns with cystic fibrosis (CF). We compared clinical outcomes between Australian paediatric CF patients with and without Meconium ileus (non-MI). Methods This was a retrospective case-control study of MI and non-MI patients in New South Wales, Australia, from 1988 to 2010. MI patients were matched 1:1 with pancreatic insufficient non-MI patients for age, sex and CF clinic. Clinical measurements, nutrition and gastrointestinal outcomes over this period were compared between groups using linear mixed models for continuous variables to account for age. Results There were 162 matched pairs (N=324, 52% female) with mean (SD) age of 15.3 (8.2) and 14.9 (7.9) years for MI and non-MI patients respectively (P=0.6). MI patients aged 5-23 had poorer FEV1% compared to non-MI patients (estimate -0.070 SE [0.02], P=0.003). There were no significant differences in P. aeruginosa isolation rates; however S. aureus isolation rates were lower in MI patients (72%) compared to non-MI (82%) (OR 0.6 [0.3-1.0], P=0.03). Chronic colonisation rates for P. aeruginosa and S. aureus were not significantly different between groups. MI patients aged 2-20 had significantly lower BMI Z-scores over time (estimate -0.25 SE [0.1], P=0.02). MI patients were more likely to receive oral feed supplements (OR 2.8 [1.4-6.1], P=0.003) and gastrostomy formation (OR 4.4 [1.1-24.6], P=0.02). Conclusions CF patients with MI may have worse lung function, growth and nutrition than non-MI patients over time. Meconium ileus may be an early poor prognostic factor for CF.
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prevalence of Meconium ileus marks the severity of mutations of the cystic fibrosis transmembrane conductance regulator cftr gene
Genetics in Medicine, 2016Co-Authors: Annie Dupuis, Katherine Keenan, Ruslan Dorfman, Chee Y Ooi, Marci K Sontag, Lutz Naehrlich, Carlo Castellani, Lisa J Strug, Johanna M RommensAbstract:Prevalence of Meconium ileus marks the severity of mutations of the Cystic Fibrosis Transmembrane Conductance Regulator ( CFTR ) gene
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prevalence of Meconium ileus marks the severity of mutations of the cystic fibrosis transmembrane conductance regulator cftr gene
Genetics in Medicine, 2016Co-Authors: Annie Dupuis, Katherine Keenan, Ruslan Dorfman, Chee Y Ooi, Marci K Sontag, Lutz Naehrlich, Carlo Castellani, Lisa J Strug, Johanna M RommensAbstract:Meconium ileus (MI) is a perinatal complication in cystic fibrosis (CF), which is only minimally influenced by environmental factors. We derived and examined MI prevalence (MIP) scores to assess CFTR phenotype–phenotype correlation for severe mutations. MIP scores were established using a Canadian CF population (n = 2,492) as estimates of the proportion of patients with MI among all patients carrying the same CFTR mutation, focusing on patients with p.F508del as the second allele. Comparisons were made to the registries from the US CF Foundation (n = 43,432), Italy (Veneto/Trentino/Alto Adige regions) (n = 1,788), and Germany (n = 3,596). The prevalence of MI varied among the different registries (13–21%). MI was predominantly prevalent in patients with pancreatic insufficiency carrying “severe” CFTR mutations. In this severe spectrum MIP scores further distinguished between mutation types, for example, G542X (0.31) with a high, F508del (0.22) with a moderate, and G551D (0.08) with a low MIP score. Higher MIP scores were associated with more severe clinical phenotypes, such as a lower forced expiratory volume in 1 second (P = 0.01) and body mass index z score (P = 0.04). MIP scores can be used to rank CFTR mutations according to their clinical severity and provide a means to expand delineation of CF phenotypes. Genet Med 18 4, 333–340.
Diana Zelenika - One of the best experts on this subject based on the ideXlab platform.
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multiple apical plasma membrane constituents are associated with susceptibility to Meconium ileus in individuals with cystic fibrosis
Nature Genetics, 2012Co-Authors: Lei Sun, Fan Lin, Ruslan Dorfman, Johanna M Rommens, Harriet Corvol, Theodore Chiang, Pierre Francois Busson, Rashmi V Parekh, Diana ZelenikaAbstract:Lisa Strug and colleagues report a genome-wide association study for Meconium ileus in individuals with cystic fibrosis. Conventional genome-wide approaches identified variants in SLC26A9 and SLC6A14 associated with Meconium ileus. The authors also performed a hypothesis-driven genome-wide association study (HD-GWAS) that upweighted 3,814 SNPs within 10 kb of 155 genes expressed in the apical plasma membrane. The HD-GWAS identified variants near SLC9A3 associated with Meconium ileus.
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multiple apical plasma membrane constituents are associated with susceptibility to Meconium ileus in individuals with cystic fibrosis
Nature Genetics, 2012Co-Authors: Lei Sun, Fan Lin, Ruslan Dorfman, Johanna M Rommens, Harriet Corvol, Theodore Chiang, Pierre Francois Busson, Rashmi V Parekh, Diana ZelenikaAbstract:Variants associated with Meconium ileus in cystic fibrosis were identified in 3,763 affected individuals by genome-wide association study (GWAS). Five SNPs at two loci near SLC6A14 at Xq23-24 (minimum P = 1.28 × 10(-12) at rs3788766) and SLC26A9 at 1q32.1 (minimum P = 9.88 × 10(-9) at rs4077468) accounted for ~5% of phenotypic variability and were replicated in an independent sample of affected individuals (n = 2,372; P = 0.001 and 0.0001, respectively). By incorporating the knowledge that disease-causing mutations in CFTR alter electrolyte and fluid flux across surface epithelium into a hypothesis-driven GWAS (GWAS-HD), we identified associations with the same SNPs in SLC6A14 and SLC26A9 and established evidence for the involvement of SNPs in a third solute carrier gene, SLC9A3. In addition, GWAS-HD provided evidence of association between Meconium ileus and multiple genes encoding constituents of the apical plasma membrane where CFTR resides (P = 0.0002; testing of 155 apical membrane genes jointly and in replication, P = 0.022). These findings suggest that modulating activities of apical membrane constituents could complement current therapeutic paradigms for cystic fibrosis.
Harriet Corvol - One of the best experts on this subject based on the ideXlab platform.
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multiple apical plasma membrane constituents are associated with susceptibility to Meconium ileus in individuals with cystic fibrosis
Nature Genetics, 2012Co-Authors: Lei Sun, Fan Lin, Ruslan Dorfman, Johanna M Rommens, Harriet Corvol, Theodore Chiang, Pierre Francois Busson, Rashmi V Parekh, Diana ZelenikaAbstract:Lisa Strug and colleagues report a genome-wide association study for Meconium ileus in individuals with cystic fibrosis. Conventional genome-wide approaches identified variants in SLC26A9 and SLC6A14 associated with Meconium ileus. The authors also performed a hypothesis-driven genome-wide association study (HD-GWAS) that upweighted 3,814 SNPs within 10 kb of 155 genes expressed in the apical plasma membrane. The HD-GWAS identified variants near SLC9A3 associated with Meconium ileus.
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multiple apical plasma membrane constituents are associated with susceptibility to Meconium ileus in individuals with cystic fibrosis
Nature Genetics, 2012Co-Authors: Lei Sun, Fan Lin, Ruslan Dorfman, Johanna M Rommens, Harriet Corvol, Theodore Chiang, Pierre Francois Busson, Rashmi V Parekh, Diana ZelenikaAbstract:Variants associated with Meconium ileus in cystic fibrosis were identified in 3,763 affected individuals by genome-wide association study (GWAS). Five SNPs at two loci near SLC6A14 at Xq23-24 (minimum P = 1.28 × 10(-12) at rs3788766) and SLC26A9 at 1q32.1 (minimum P = 9.88 × 10(-9) at rs4077468) accounted for ~5% of phenotypic variability and were replicated in an independent sample of affected individuals (n = 2,372; P = 0.001 and 0.0001, respectively). By incorporating the knowledge that disease-causing mutations in CFTR alter electrolyte and fluid flux across surface epithelium into a hypothesis-driven GWAS (GWAS-HD), we identified associations with the same SNPs in SLC6A14 and SLC26A9 and established evidence for the involvement of SNPs in a third solute carrier gene, SLC9A3. In addition, GWAS-HD provided evidence of association between Meconium ileus and multiple genes encoding constituents of the apical plasma membrane where CFTR resides (P = 0.0002; testing of 155 apical membrane genes jointly and in replication, P = 0.022). These findings suggest that modulating activities of apical membrane constituents could complement current therapeutic paradigms for cystic fibrosis.