IPF May Have Varied and Complex Genetic Roots

Genetic factors might drive at least part of the risk for idiopathic pulmonary fibrosis (IPF), particularly in familial forms of the disease, and a review from the Nanjing University School of Medicine, China, presented an updated view of genetic risk factors for IPF.

The article, “Candidate genes of idiopathic pulmonary fibrosis: current evidence and research,“ was published in the journal The Application of Clinical Genetics.

Familial IPF is thought to account for less than 5 percent of all IPF cases, but more recent estimates suggest that numbers are more likely approaching 20 percent. The only thing that differs between sporadic and familial IPF is that disease tend to appear earlier in the familial patients.

A number of genes have been identified that might be tied to the development of the disease. Today’s approaches, using next-generation sequencing techniques analyzing the sequences of whole exomes and whole genomes, as well as genome wide association studies (GWAS), are likely to identify more genes that might affect the development or outcome of IPF.

One theory of IPF pathology states that alveolar stability is affected in the disease. The idea is that the epithelial cell layer lining lung alveoli is dysfunctional. Whether this dysfunction is because of inflammatory reactions – as the classical hypothesis proposes – or due to abnormal repair of the alveolar epithelium, however, remains a point of controversy.

Defects in genetic factors affecting alveolar stability are reported to be more frequent in patients with familial IPF. Such genes, such as SFTPC — coding for the protein SP-C — may affect the surface tension at the air-water interface in lung alveoli. The epithelial cells inside alveoli are lined by a surfactant, composed of 10 percent protein and 90 percent lipids. A lack of this protective layer causes alveolar collapse. Several genes coding for various components of the surfactant layer, as well as factors processing the components, are found to be mutated in both familial and sporadic IPF.

Along with SFTPC, the related SFTPA2 gene is affected in some individuals. This gene, apart from playing a role in alveolar stability, is linked to the pro-fibrotic factor TGF-β, and patients with a mutated SFTPA2 have higher levels of TGF-β.

Another gene, called ABCA3, has been identified in a neonatal respiratory distress syndrome and childhood interstitial lung disorder. The protein transports lipids across the plasma membrane of cells, and researchers believe that it may play a role in surfactant metabolism and transport. More than 150 different mutations have been identified in this gene, of which some are believed to impact the effects of a mutation in the SPTPC gene. Recent studies also showed that, apart from inferring a risk of lung disease in children, mutations in the ABCA3 might also underly some cases of adult-onset IPF.

Telomere shortening is one of the factors most frequently associated with IPF. Telomeres are the DNA stretches at the ends of a chromosomes, protecting them from abrasion and fusion with other chromosomes. Telomeres naturally shorten with age, possibly explaining the observation of increased IPF rates in older individuals. Mutations in genes of the telomerase complex — an enzymatic machinery replenishing the telomeres during cell divisions — lead to an increased rate of telomere breakdown, and IPF is the most common clinical manifestation of short telomere syndrome.

The TERT and TERC proteins in the telomerase complex are most frequently affected, and approximately 10 percent of familial, and  1 percent to 3 percent of sporadic IPF patients carry variations in these two major telomerase components. Nonetheless, the short telomere–IPF association cannot be explained by these two genes alone, as up to 25 percent of sporadic and 40 percent of familial cases have shortened telomeres, but less than half of these patients have mutations in the TERT or TERC genes. Other telomere-associated genes are being investigated, and there is some evidence that the DKC1 gene, coding for another telomerase component, might be involved in IPF. Yet, other studies suggests PARN and, more importantly, RTEL1 as contributors to short telomeres and IPF.

A GWAS in 2011, screening patients with familial interstitial pneumonia, identified MUC5B as the gene most strongly linked to interstitial pneumonia risk. Later studies showed a risk frequency of 38 percent among subjects with IPF, 34 percent among those with familial interstitial pneumonia, and 9 percent  in controls. The gene encodes a component in airway mucus, and common mutations lead to an increased production of the protein. A specific mutation in the promoter region of the gene — controlling gene expression — is currently the most common genetic variant predisposing individuals to IPF.

How high levels of the MUC5B protein affect the development of IPF is not known, but recent studies have shown that the protein is found in alveolar epithelial cells not normally expressing mucus factors. Researchers hypothesize that increased levels of MUC5B may be tied to a defective mucus clearance and alveolar repair, and stand in the way of immune defense mechanisms. It has been suggested that this genetic variant may serve as a predictive biomarker for the development of IPF, but more research to clarify the role of this protein in IPF is needed.

The long-standing hypothesis of immune involvement in IPF may have been questioned by the lack of efficacy of immunomodulating drugs such as azathioprine, but evidence of dysfunctional immune components nevertheless remain. Mutations in immune TLR genes have frequently been linked to IPF. A mutation in the TOLLIP gene has been associated with mortality, and other studies indicate that ELMOD2 — a gene expressed in alveolar macrophages — might be linked to familial IPF. Because of a number of contrasting findings, however, the ELMOD2 gene is still under investigation as a candidate gene in IPF.

Yet other studies have indicated that genetic variations in the MHC gene locus, determining histocompatibility of tissues, contribute to IPF, but these claims are still under investigation. Evidence of alterations in cytokine genes, coding for various immune signaling molecules, are also open to debate. One interesting study found that a number of cytokine genes did not increase the risk of disease, but contributed to disease severity.

Finally, a variety of genetic factors tied to functions as disparate as cell adhesion, cytoskeleton integrity, and mitochondrial dysfunction have also been proposed to play a role in IPF disease development.

The authors stated that a more comprehensive lists of gene variants contributing to IPF might be achieved by high-throughput analysis and next-generation sequencing. However, for an understanding of pathological mechanisms that might lead the way to better treatments, it might be more important to study the interactions between genes and environmental factors.