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March 05, 2020 – Idiopathic pulmonary fibrosis (IPF) is a type of chronic scarring lung disease characterized by a progressive and irreversible decline in lung function. Symptoms typically include gradual onset of shortness of breath and a dry cough. Other changes may include feeling tired, and abnormally large and dome shaped finger and toenails (nail clubbing). Complications may include pulmonary hypertension, heart failure, pneumonia, or pulmonary embolism. About 5 million people are affected globally. The disease newly occurs in about 12 per 100,000 people per year. Those in their 60s and 70s are most commonly affected, and males are affected more often than females.
So far, the cause is largely unknown. Risk factors include cigarette smoking, certain viral infections, and a family history of the condition. Researchers at the Universities of Leicester and Nottingham have now discovered parts of the DNA that put some people at higher risk of this incurable lung disease (i.e., IPF) and just published their work in the American Journal of Respiratory and Critical Care Medicine.
The research teams compared the DNA of 4,000 people with IPF to 20,000 people without IPF. In total they investigated over 10 million changes in the DNA. In the course of their work, identified and replicated three new genome-wide significant (P < 5 × 10−8) signals of association with IPF susceptibility (i.e., associated with altered gene expression) of the KIF15 gene, the MAD1L1 gene, and the DEPTOR gene, and confirmed associations at 11 previously reported loci. Overall, polygenic risk score analyses showed that the combined effect of many thousands of as yet unreported IPF susceptibility variants contribute to IPF susceptibility.
In conclusion, the present observation that decreased DEPTOR gene expression associates with increased susceptibility to IPF supports recent studies demonstrating the importance of mTOR signalling in lung fibrosis. New signals of association implicating the KIF15 gene and the MAD1L1 gene suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.
In addition, by combining the largest available GWAS datasets for IPF, the research team was able to confirm 11 of 17 previously reported genetic signals. Conditional analysis at the 11p15.5 region indicated that previously reported signals at the MUC2 gene and the TOLLIP gene were not independent of the association with the signals at the EHMT2 gene, the OBFC gene , and the MDGA2 gene.
The IPF susceptibility signals at the DSP gene, the FAM13A gene, position 7q22.1 (i.e., the ZKSCAN1 gene), and position 17q21.31 (i.e., the MAPT gene) have also been reported as associated with chronic obstructive pulmonary disease (COPD), although with opposite effects (i.e., the allele associated with increased risk of IPF being associated with decreased risk of COPD). Spirometric diagnosis of COPD was based on a reduced FEV1/FVC ratio. In an independent dataset of 400’102 individuals, eight of the IPF signals were associated with decreased FVC and with a comparatively weaker effect on FEV1. This is consistent with the lung function abnormalities associated with IPF, as well as the decreased risk of COPD. Of note, only around 3% of previously reported lung function signals also showed association with IPF susceptibility in the present study. This suggests that while some IPF susceptibility variants might represent genes and pathways that are important in general lung health, others are likely to represent more disease-specific processes.
Overall, IPF is a devastating disease, which accounts, for example in the United Kingdom for one percent of all deaths. To find a cure, it is vital that one understands the genetic changes associated with the process of lung fibrosis. The present work has identified three novel genes, which could lead to new treatments bringing hope to the large number of people around the world living with the disease. Genetic studies hold real promise in helping to find new treatments for IPF. Here, study was undertaken by a large international team of scientists and doctors and wouldn’t have been possible were it not for patients with IPF contributing their genetic data for research. Since IPF is a global health problem, it will also be important that genetic data from patient all around the world will wind up in the pertinent genetic research on IPF in order to also understand ethnic differences in the etiology of IPF, should there exist any.
See this short sequence on IPF: