Methods and compositions for risk prediction, diagnosis, prognosis, and treatment of pulmonary disorders
a technology for pulmonary diseases and compositions, applied in drug compositions, instruments, biochemistry apparatus and processes, etc., to achieve the effect of rapid increase in muc5b expression in a short time and more rapid progression of pulmonary diseas
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example 1
Sequencing of Pulmonary, Gel-Forming Mucins and Disease Association
[0165]Study Populations:
[0166]Subjects with FIP or IPF were identified and phenotyped. The diagnosis of IIP was established according to conventional criteria. Eligible subjects were at least 38 years of age and had IIP symptoms for at least 3 months. A high resolution computerized tomography (HRCT) scan was required to show definite or probable IIP according to predefined criteria, and a surgical lung biopsy was obtained in 46% of affected subjects. FIP families were defined by the presence of two or more cases of definite or probable IIP within three degrees, with at least one case of IIP established as definite / probable IPF. Exclusion criteria included significant exposure to known fibrogenic agents or an alternative etiology for ILD. Control subjects for genetic analysis were acquired (FIG. 1).
[0167]Linkage Analysis:
[0168]A genome-wide linkage screen was completed in 82 multiplex families using a DeCode linkage p...
example 2
Single Nucleotide Polymorphism rs35705950 Results in Increased Expression of MUC5B Gene
[0179]The wildtype G allele of the rs35705950 SNP is conserved across primate species. The SNP is directly 5′ to a highly conserved region across vertebrate species, and is in the middle of sequence predicted to be involved in MUC5B gene regulation. A bioinformatic analysis of the effect of the rs35705950 SNP predicts a disruption of an E2F binding site and creation of at least two new binding sites (e.g. HOX9 and PAX-2).
[0180]Based on these analyses, the effect of rs35705950 was examined on MUC5B gene expression. In lung tissue from 33 subjects with IPF and 47 unaffected subjects, quantitative RT-PCR revealed that MUC5B gene expression was upregulated 14.1-fold among IPF subjects compared to unaffected subjects (P=0.0001, FIG. 4A). A 37.4-fold increase in MUC5B expression was observed among unaffected subjects carrying at least one copy of the variant allele compared to homozygous wildtype subjec...
example 3
Genetic Variant MUC5B Associated with Attenuated Form of Pulmonary Disease
[0187]The data described herein demonstrate that the genetic variant MUC5B rs35705950 is associated with development of pulmonary disease. We next examined whether rs35705950 genetic variant is associated with disease severity and prognosis. We found that homozygous wildtype subjects (GG), i.e., those having normal MUC5B gene sequence, displayed a steeper decline in forced vital capacity (FVC) over time as compared to subjects with at least one T allele (P=0.0006). Essentially, while FVC declines for both groups, the decline is more gradual in those carrying the G→T polymorphism. For GG subjects, the FVC absolute value fell from about 3.4 liters to about 3.1 liters over years 1-3 of the study. For GT and TT subjects, the FVC absolute value still fell, but started at over 3.5 liters and fell to about 3.4 liters over years 1-3 of the study.
[0188]Additionally, we observed an association between death with subject...
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