Desmoplakin Variants Are Associated with Idiopathic Pulmonary Fibrosis
Desmoplakin Variants Are Associated with Idiopathic Pulmonary Fibrosis
复制标题
DOI：
10.1164/rccm.201509-1863oc
复制
发表时间：
2016-05-15
影响因子：
24.7
通讯作者：
Schwartz, David A.
中科院分区：
文献类型：
--
作者：
Mathai, Susan K.;Pedersen, Brent S.;Schwartz, David A.
理由：在特发性肺纤维化（IPF）患者中观察到desmoplakin （DSP）的序列变异、甲基化差异和转录变化。目的：鉴定与IPF相关的DSP的新变异，并表征这些IPF序列变异与人肺中DSP基因表达的关系。方法：对230例IPF患者和228例对照患者的6号染色体（737,061 ~ 7606,946）进行测序。在936名IPF患者和936名对照患者中进行了疾病相关变异的基因分型验证。测定了334例IPF患者和201例对照组肺组织中DSP基因的表达。测量和主要结果：我们在6号染色体位点发现了与IPF相关的23个序列变异。在我们的验证队列中选择的变异基因分型显示，非编码内含子1变异rs2744371（优势比= 0.77,95%可信区间[CI] = 0.66-0.91, P = 0.002）对IPF具有保护作用，而先前描述的与IPF相关的内含子5变异rs2076295在控制性别和年龄后与IPF风险增加相关（优势比= 1.36,95% CI = 1.19-1.56, P < 0.001）。IPF肺组织中DSP表达增加2.3倍（95% CI = 1.91 ~ 2.71） （P < 0.0001）。只有rs2076295的次要等位基因与DSP表达降低相关（P = 0.001）。纤维化和正常人肺组织的染色将DSP定位于气道上皮。结论：DSP序列变异与IPF相关，rs2076295基因型与肺组织中DSP的差异表达相关。IPF肺组织中DSP表达升高，气道上皮组织中DSP表达集中，提示DSP可能参与IPF的发病机制。
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 Main Results: 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.