Interstitial Lung Diseases: Genetic Predisposition and Inherited Interstitial Lung Diseases

Raghu, Ganesh; Hert, Richard

doi:10.1055/s-2007-1006332

Cited by 16 publications

(6 citation statements)

References 57 publications

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“…1 Interstitial lung disease has been associated with several pleiotropic genetic disorders. 2 The development of pulmonary fibrosis has been associated with private mutations in surfactant protein C, 3 surfactant protein A2, 4 and genes that maintain telomere length. 5 However, collectively these mutations account for a small proportion of the population risk of idiopathic interstitial pneumonia.…”

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confidence: 99%

A CommonMUC5BPromoter Polymorphism and Pulmonary Fibrosis

et al. 2011

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BACKGROUND The mutations that have been implicated in pulmonary fibrosis account for only a small proportion of the population risk. METHODS Using a genomewide linkage scan, we detected linkage between idiopathic interstitial pneumonia and a 3.4-Mb region of chromosome 11p15 in 82 families. We then evaluated genetic variation in this region in gel-forming mucin genes expressed in the lung among 83 subjects with familial interstitial pneumonia, 492 subjects with idiopathic pulmonary fibrosis, and 322 controls. MUC5B expression was assessed in lung tissue. RESULTS Linkage and fine mapping were used to identify a region of interest on the p-terminus of chromosome 11 that included gel-forming mucin genes. The minor-allele of the single-nucleotide polymorphism (SNP) rs35705950, located 3 kb upstream of the MUC5B transcription start site, was present at a frequency of 34% among subjects with familial interstitial pneumonia, 38% among subjects with idiopathic pulmonary fibrosis, and 9% among controls (allelic association with familial interstitial pneumonia, P = 1.2×10−15; allelic association with idiopathic pulmonary fibrosis, P = 2.5×10−37). The odds ratios for disease among subjects who were heterozygous and those who were homozygous for the minor allele of this SNP were 6.8 (95% confidence interval [CI], 3.9 to 12.0) and 20.8 (95% CI, 3.8 to 113.7), respectively, for familial interstitial pneumonia and 9.0 (95% CI, 6.2 to 13.1) and 21.8 (95% CI, 5.1 to 93.5), respectively, for idiopathic pulmonary fibrosis. MUC5B expression in the lung was 14.1 times as high in subjects who had idiopathic pulmonary fibrosis as in those who did not (P<0.001). The variant allele of rs35705950 was associated with up-regulation in MUC5B expression in the lung in unaffected subjects (expression was 37.4 times as high as in unaffected subjects homozygous for the wild-type allele, P<0.001). MUC5B protein was expressed in lesions of idiopathic pulmonary fibrosis. CONCLUSIONS A common polymorphism in the promoter of MUC5B is associated with familial interstitial pneumonia and idiopathic pulmonary fibrosis. Our findings suggest that dys-regulated MUC5B expression in the lung may be involved in the pathogenesis of pulmonary fibrosis. (Funded by the National Heart, Lung, and Blood Institute and others.)

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confidence: 99%

A CommonMUC5BPromoter Polymorphism and Pulmonary Fibrosis

et al. 2011

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“…Overall, these studies have mapped out an interesting and novel pathway linking the adaptive and natural arms of the immune system (14). These findings also highlight a practical issue that needs to be considered for future therapeutic strategies.…”

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confidence: 76%

“…While we know that excessive lung injury can result in pulmonary fibrosis (e.g., asbestosis), considerable variability in the extent of pulmonary fibrosis exists even among those individuals exposed to similar concentrations of this fibrogenic agent (12). In fact, the genetic background underlying the propensity for fibrosis can hardly be overlooked: pulmonary fibrosis clusters in families (13) and occurs in pleiotropic genetic disorders (14), and inbred strains of mice demonstrate variable susceptibility to fibrogenic agents (15)(16)(17). Some hosts, perhaps by virtue of defective repair mechanisms, simply are unable to deal with a fibrogenic insult.…”

Section: Figurementioning

confidence: 99%

Pulmonary fibrosis: thinking outside of the lung

Garantziotis

Steele²,

Schwartz³

2004

J. Clin. Invest.

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“…Familial IPF (FIPF) has been defined by the finding of histologically confirmed IPF in at least two first-degree relatives. 61 The entity was first described by Sandoz in 1907. 62 Since then, there have been several descriptions of familial clusters of IPF.…”

Section: Idiopathic Pulmonary Fibrosis (Ipf) and Familial Ipfmentioning

confidence: 99%

Genetics of Pulmonary Fibrosis

Wurfel¹,

Raghu²

2002

Seminars in Respiratory and Critical Care Medicine

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Pulmonary fibrosis is a devastating disease that occurs in association with environmental exposures, several inherited diseases, collagen vascular disease, as well as in an idiopathic form. Epithelial cell damage, excessive fibroblast proliferation, upregulation of extracellular matrix production, and attenuated matrix degradation are shared pathophysiological features of these different forms of pulmonary fibrosis. Several observations suggest that genetic predisposition plays an important role in the pathophysiology of pulmonary fibrosis. There is significant inter-individual variation in the degree of pulmonary fibrosis resulting from exposure to similar levels of an inhaled fibrogenic agent. There are several inherited diseases with known genetic mutations that have high rates of pulmonary fibrosis. Idiopathic pulmonary fibrosis can occur in multiple first-degree relatives, including those separated at an early age. Finally, recent studies have identified polymorphisms within genes for cytokines, histocompatability antigens, and extracellular matrix components that are associated with the development of pulmonary fibrosis. Identification of putative pulmonary fibrosis gene/s (PF gene/s) may result in novel diagnostic and therapeutic interventions for those at risk for development of pulmonary fibrosis.

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Interstitial Lung Diseases: Genetic Predisposition and Inherited Interstitial Lung Diseases

Cited by 16 publications

References 57 publications

A CommonMUC5BPromoter Polymorphism and Pulmonary Fibrosis

A CommonMUC5BPromoter Polymorphism and Pulmonary Fibrosis

Pulmonary fibrosis: thinking outside of the lung

Genetics of Pulmonary Fibrosis

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