Heritability of Respiratory Infection with Pseudomonas aeruginosa in Cystic Fibrosis

Green, Deanna M.; Collaco, Joseph M.; McDougal, Kathryn E.; Naughton, Kathleen M.; Blackman, Scott M.; Cutting, Garry R.

doi:10.1016/j.jpeds.2012.01.042

Cited by 32 publications

(20 citation statements)

References 29 publications

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“…Chronic colonization of the lungs with the bacterial pathogen Pseudomonas aeruginosa is a feature of advancing lung disease in cystic fibrosis and is associated with reduced survival 68 . Establishment of chronic P aeruginosa infection and age at establishment are highly influenced by genetic factors 69 . Poor growth is a hallmark of cystic fibrosis owing to pancreatic exocrine disease and deficiency of insulin-like growth factor 1.…”

Section: Variation In Disease Severitymentioning

confidence: 99%

Cystic fibrosis genetics: from molecular understanding to clinical application

2014

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The availability of the human genome sequence and tools for interrogating individual genomes provide an unprecedented opportunity to apply genetics to medicine. Mendelian conditions, which are caused by dysfunction of a single gene, offer powerful examples that illustrate how genetics can provide insights into disease. Cystic fibrosis, one of the more common lethalautosomal recessive Mendelian disorders, is presented here as an example. Recent progress in elucidating disease mechanism and causes of phenotypic variation, as well as in the development of treatments, demonstrates that genetics continues to play an important part in cystic fibrosis research 25 years after the d iscove1y of the disease-causing gene.

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Section: Variation In Disease Severitymentioning

confidence: 99%

Cystic fibrosis genetics: from molecular understanding to clinical application

2014

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“…The genetic architecture of phenotypic variability in cystic fibrosis (CF [MIM 219700]) is beginning to be defined, [1][2][3][4][5] but GWASs for CF are limited by numbers of subjects compared to common diseases, where tens of thousands of subjects have been used to identify pathophysiologically relevant pathways. [6][7][8] Studies of gene expression provide an alternative approach to identify gene modifiers.…”

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confidence: 99%

Gene Expression in Transformed Lymphocytes Reveals Variation in Endomembrane and HLA Pathways Modifying Cystic Fibrosis Pulmonary Phenotypes

O’Neal

Gallins

Pace

et al. 2015

The American Journal of Human Genetics

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Variation in cystic fibrosis (CF) phenotypes, including lung disease severity, age of onset of persistent Pseudomonas aeruginosa (P. aeruginosa) lung infection, and presence of meconium ileus (MI), has been partially explained by genome-wide association studies (GWASs). It is not expected that GWASs alone are sufficiently powered to uncover all heritable traits associated with CF phenotypic diversity. Therefore, we utilized gene expression association from lymphoblastoid cells lines from 754 p.Phe508del CF-affected homozygous individuals to identify genes and pathways. LPAR6, a G protein coupled receptor, associated with lung disease severity (false discovery rate q value = 0.0006). Additional pathway analyses, utilizing a stringent permutation-based approach, identified unique signals for all three phenotypes. Pathways associated with lung disease severity were annotated in three broad categories: (1) endomembrane function, containing p.Phe508del processing genes, providing evidence of the importance of p.Phe508del processing to explain lung phenotype variation; (2) HLA class I genes, extending previous GWAS findings in the HLA region; and (3) endoplasmic reticulum stress response genes. Expression pathways associated with lung disease were concordant for some endosome and HLA pathways, with pathways identified using GWAS associations from 1,978 CF-affected individuals. Pathways associated with age of onset of persistent P. aeruginosa infection were enriched for HLA class II genes, and those associated with MI were related to oxidative phosphorylation. Formal testing demonstrated that genes showing differential expression associated with lung disease severity were enriched for heritable genetic variation and expression quantitative traits. Gene expression provided a powerful tool to identify unrecognized heritable variation, complementing ongoing GWASs in this rare disease.

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“…Environmental factors are associated with approximately 50% of the population variability in lung function [ 31 ] and P. aeruginosa acquisition [ 32 ] in CF patients. Many of the CF-related pathogens are naturally occurring in the environment, although few studies have investigated specific environmental factors that may contribute to pathogen acquisition [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Air pollution exposure is associated with MRSA acquisition in young U.S. children with cystic fibrosis

et al. 2017

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BackgroundThe role of air pollution in increasing susceptibility to respiratory tract infections in the cystic fibrosis (CF) population has not been well described. We recently demonstrated that chronic PM2.5 exposure is associated with an increased risk of initial Pseudomonas aeruginosa acquisition in young children with CF. The purpose of this study was to determine whether PM2.5 exposure is a risk factor for acquisition of other respiratory pathogens in young children with CF.MethodsWe conducted a retrospective study of initial acquisition of methicillin susceptible and methicillin resistant Staphylococcus aureus (MSSA and MRSA), Stenotrophomonas maltophilia and Achromobacter xylosoxidans in U.S. children <6 years of age with CF using the CF Foundation Patient Registry, 2003–2009. Multivariable Weibull regression with interval-censored outcomes was used to evaluate the association of PM2.5 concentration in the year prior to birth and risk of acquisition of each organism.ResultsDuring follow-up 63%, 17%, 24%, and 5% of children acquired MSSA, MRSA, S. maltophilia, and A. xylosoxidans, respectively. A 10 μg/m3 increase in PM2.5 exposure was associated with a 68% increased risk of MRSA acquisition (Hazard Ratio: 1.68; 95% Confidence Interval: 1.24, 2.27). PM2.5 was not associated with acquisition of other respiratory pathogens.ConclusionsFine particulate matter is an independent risk factor for initial MRSA acquisition in young children with CF. These results support the increasing evidence that air pollution contributes to pulmonary morbidities in the CF community.

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Heritability of Respiratory Infection with Pseudomonas aeruginosa in Cystic Fibrosis

Cited by 32 publications

References 29 publications

Cystic fibrosis genetics: from molecular understanding to clinical application

Cystic fibrosis genetics: from molecular understanding to clinical application

Gene Expression in Transformed Lymphocytes Reveals Variation in Endomembrane and HLA Pathways Modifying Cystic Fibrosis Pulmonary Phenotypes

Air pollution exposure is associated with MRSA acquisition in young U.S. children with cystic fibrosis

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