Differential decay of parent-of-origin-specific genomic sharing in cystic fibrosis-affected sib pairs maps a paternally imprinted locus to 7q34

Stanke, Frauke; Davenport, Colin; Hedtfeld, Silke; Tümmler, Burkhard

doi:10.1038/ejhg.2009.229

Cited by 3 publications

(7 citation statements)

References 40 publications

(57 reference statements)

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“…After correction for multiple testing, significance was retained at the following loci and for the following phenotypes (figure 3): 7q31.1/ CFTR : P=0.0009 (NPD_Na+) and P raw =0.0008 (NPD_ATP); 7q34/D7Sat3: P raw =0.0005 (disease severity cis); 11q13/ GSTP1 P raw =0.0006 (NPD_ATP); 12p13/ TNFR P raw =0.0004 (NPD_Gl/Iso) and P raw =0.0003 (NPD_ATP); 12q13/ KRT8 P raw =0.0004 (ICM_Res); 16p13.3/ NHERF2 P raw =0.0001 (ICM_Res). We have previously reported an association with DIDS-sensitive residual chloride secretion in ICM at the CLCA -gene cluster15 and an association with disease severity for LEP ,16 CD95 ,17 TNFR ,18 SCNN1B ,18 SCNN1G ,18 at the CEACAM gene cluster,19 20 and at a paternally imprinted gene on 7q34 21. Association of these genes with other phenotypes are reported here for the first time.…”

Section: Resultssupporting

confidence: 55%

“…We have previously reported how informative patient pairs with extreme phenotypes can be selected from this cohort for candidate gene analysis 3 and described CF modifier genes on six chromosomes. 15–22 In this study, our objectives are: (1) to qualify the relative impact of the CFTR gene, environmental and other inherited factors on CF disease severity; (2) to identify genetic modifiers for the CF basic defect; and (3) to observe whether or not these are the same genes that modify CF disease severity. We have tested a total of 182 genetic markers targeting 52 candidate gene loci on 16 different chromosomes for their association with CF disease severity and the manifestation of the CFTR mediated basic defect, by genotyping a cohort composed of 101 families with a total of 171 F508del- CFTR homozygous patients.…”

Section: Introductionmentioning

confidence: 99%

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Genes that determine immunology and inflammation modify the basic defect of impaired ion conductance in cystic fibrosis epithelia

Stanke

Becker

Kumar

et al. 2010

Journal of Medical Genetics

114

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BackgroundThe cystic fibrosis (CF) basic defect, caused by dysfunction of the apical chloride channel CFTR in the gastrointestinal and respiratory tract epithelia, has not been employed so far to support the role of CF modifier genes.MethodsPatients were selected from 101 families with a total of 171 F508del-CFTR homozygous CF patients to identify CF modifying genes. A candidate gene based association study of 52 genes on 16 different chromosomes with a total of 182 genetic markers was performed. Differences in haplotype and/or diplotype distribution between case and reference CF subpopulations were analysed.ResultsVariants at immunologically relevant genes were associated with the manifestation of the CF basic defect (0.01

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Section: Resultssupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Genes that determine immunology and inflammation modify the basic defect of impaired ion conductance in cystic fibrosis epithelia

Stanke

Becker

Kumar

et al. 2010

Journal of Medical Genetics

114

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“…One study found that leptin 1 and 2 ( LEP1 , LEP2 ) were associated with increased disease severity . Another study analyzed the region 7q31 to 7qtel and found a locus on 7q34 that showed differential onset of parental recombination and differential imprinting between mildly and severely affected sibling pairs . However, both studies used composite measure of severity, which encompassed both respiratory and nutritional parameters.…”

Section: Resultsmentioning

confidence: 99%

“…Another epigenetic mechanism is imprinting, where one copy of a gene is silenced depending on which parent it was inherited from. Two separate studies from the European Twins and Siblings studies have hypothesized a relationship between imprinting of 7q34 and disease severity …”

Section: Resultsmentioning

confidence: 99%

“…69 Another study analyzed the region 7q31 to 7qtel and found a locus on 7q34 that showed differential onset of parental recombination and differential imprinting between mildly and severely affected sibling pairs. 70 However, both studies used composite measure of severity, which encompassed both respiratory and nutritional parameters. The authors of both studies hypothesized that the effect was most likely via an influence on nutrition.…”

Section: Cftr Vicinitymentioning

confidence: 99%

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Gene modifiers of cystic fibrosis lung disease: A systematic review

Shanthikumar

Neeland

Saffery

et al. 2019

Pediatric Pulmonology

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Background Lung disease is the major source of morbidity and mortality in cystic fibrosis (CF), with large variability in severity between patients. Although accurate prediction of lung disease severity would be extremely useful, no robust methods exist. Twin and sibling studies have highlighted the importance of non‐cystic fibrosis transmembrane conductance regulator (CFTR) genes in determining lung disease severity but how these impact on the severity in CF remains unclear. Methods A systematic review was undertaken to answer the question “In patients with CF which non‐CFTR genes modify the severity of lung disease?” The method for this systematic review was based upon the “Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA)” statement, with a narrative synthesis of results planned. Results A total of 1168 articles were screened for inclusion, with 275 articles undergoing detailed assessment for inclusion. One hundred and forty articles were included. Early studies focused on candidate genes, whereas more recent studies utilized genome‐wide approaches and also examined epigenetic mechanisms, gene expression, and therapeutic response. Discussion A large body of evidence regarding non‐CFTR gene modifiers of lung disease severity has been generated, examining a wide array of genes. Limitations to existing studies include heterogeneity in outcome measures used, limited replication, and relative lack of clinical impact. Future work examining non‐CFTR gene modifiers will have to overcome these limitations if gene modifiers are to have a meaningful role in the care of patients with CF.

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No one left behind: review of precision medicine and cystic fibrosis—how the changing approach to cystic fibrosis treatment might lead to tailored therapies for all

Sekowski¹,

Leung²,

Ferrara³

et al. 2023

Pharmacogenet Res Per Med

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Cystic fibrosis is an autosomal recessive, multisystem disorder that has been historically associated with poor life expectancy. Due to the defective cystic fibrosis transmembrane conductance regulator protein, patients with cystic fibrosis develop viscous secretions that are difficult to clear, resulting in numerous abnormalities such as chronic airway obstruction, maldigestion and malabsorption. While our understanding of the pathophysiology and disease management have improved, pulmonary disease remains the leading cause of morbidity and mortality in patients with cystic fibrosis. However, since the introduction of precision medicine, novel therapeutic agents have been developed to target the underlying defective protein, resulting in improved disease management and life expectancy. The goal of precision medicine is to provide timely diagnosis, phenotyping, and personalized treatments, based on an individualized analysis of a patient's genome. This article reviews current and potential precision medicine treatments for patients with cystic fibrosis, including cystic fibrosis transmembrane conductance regulator modulators and other modulators designed for patients who would not benefit from currently available therapies. We will also discuss other investigational treatment modalities, such as ribosomal read-though agents and RNA therapy, which may continue the advancement of cystic fibrosis treatment. Current research into methods aimed to better predict patients' responses to personalized treatment, such as theratyping, will also be discussed. Given the benefits of applying precision medicine in cystic fibrosis, future research in this therapeutic approach will also likely benefit other life-threatening monogenetic disorders.

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Differential decay of parent-of-origin-specific genomic sharing in cystic fibrosis-affected sib pairs maps a paternally imprinted locus to 7q34

Cited by 3 publications

References 40 publications

Genes that determine immunology and inflammation modify the basic defect of impaired ion conductance in cystic fibrosis epithelia

Genes that determine immunology and inflammation modify the basic defect of impaired ion conductance in cystic fibrosis epithelia

Gene modifiers of cystic fibrosis lung disease: A systematic review

No one left behind: review of precision medicine and cystic fibrosis—how the changing approach to cystic fibrosis treatment might lead to tailored therapies for all

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