Desmoplakin Variants Are Associated with Idiopathic Pulmonary Fibrosis.
Am J Respir Crit Care Med
; 193(10): 1151-60, 2016 05 15.
Article
em En
| MEDLINE
| ID: mdl-26669357
ABSTRACT
RATIONALE Sequence variation, methylation differences, and transcriptional changes in desmoplakin (DSP) have been observed in patients with idiopathic pulmonary fibrosis (IPF). OBJECTIVES:
To identify novel variants in DSP associated with IPF and to characterize the relationship of these IPF sequence variants with DSP gene expression in human lung.METHODS:
A chromosome 6 locus (7,370,061-7,606,946) was sequenced in 230 subjects with IPF and 228 control subjects. Validation genotyping of disease-associated variants was conducted in 936 subjects with IPF and 936 control subjects. DSP gene expression was measured in lung tissue from 334 subjects with IPF and 201 control subjects. MEASUREMENTS AND MAINRESULTS:
We identified 23 sequence variants in the chromosome 6 locus associated with IPF. Genotyping of selected variants in our validation cohort revealed that noncoding intron 1 variant rs2744371 (odds ratio = 0.77, 95% confidence interval [CI] = 0.66-0.91, P = 0.002) is protective for IPF, and a previously described IPF-associated intron 5 variant (rs2076295) is associated with increased risk of IPF (odds ratio = 1.36, 95% CI = 1.19-1.56, P < 0.001) after controlling for sex and age. DSP expression is 2.3-fold increased (95% CI = 1.91-2.71) in IPF lung tissue (P < 0.0001). Only the minor allele at rs2076295 is associated with decreased DSP expression (P = 0.001). Staining of fibrotic and normal human lung tissue localized DSP to airway epithelia.CONCLUSIONS:
Sequence variants in DSP are associated with IPF, and rs2076295 genotype is associated with differential expression of DSP in the lung. DSP expression is increased in IPF lung and concentrated in the airway epithelia, suggesting a potential role for DSP in the pathogenesis of IPF.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Variação Genética
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Desmoplaquinas
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Fibrose Pulmonar Idiopática
Tipo de estudo:
Etiology_studies
/
Risk_factors_studies
Limite:
Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Am J Respir Crit Care Med
Assunto da revista:
TERAPIA INTENSIVA
Ano de publicação:
2016
Tipo de documento:
Article