Another building in the IPF Manhattan plot skyline
Authors: Jonathan K Alder, Daniel J Kass
Journal: The Lancet Respiratory Medicine (2017)

With ever-increasing confidence, a substantial role for genetics in idiopathic pulmonary fibrosis (IPF), or at least in so-called sporadic IPF, has been established. As a result, some people advocate that the discovery of a known susceptibility single-nucleotide polymorphism (SNP) or other genetic marker in a patient with IPF should prompt removing the term idiopathic and replacing it with a more mechanism-based molecular classification.1Merck SJ Armanios M Shall we call them “telomere-mediated”? Renaming the idiopathic after the cause is found.Eur Respir J. 2016; 48: 1556-1558Crossref PubMed Scopus (11) Google Scholar And although this change is an attractive idea, some others still suggest that molecular subphenotyping of IPF really has no effect on the clinical management of patients. In the era of IPF therapy, a patient with two copies of the rs35705950 SNP in the promoter region of mucin 5B (MUC5B)2Seibold MA Wise AL Speer MC et al.A common MUC5B promoter polymorphism and pulmonary fibrosis.N Engl J Med. 2011; 364: 1503-1512Crossref PubMed Scopus (769) Google Scholar is given the same treatment as all patients with IPF: oxygen, rehabilitation, medication, and referral for lung transplantation. People who believe in the importance of molecular subphenotyping of IPF are often reminded that despite multiple transcriptomic and genomic studies of IPF, subphenotyping is not ready to be used for clinical decision making—yet. The studies implicating genetics in the pathogenesis of IPF continue to accumulate: enter A-kinase anchoring protein 13 (AKAP13). In a study by Richard Allen and colleagues3Allen RJ Porte J Braybrooke R et al.Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study.Lancet Respir Med. 2017; (published online Oct 20.)http://dx.doi.org/10.1016/S2213-2600(17)30387-9Summary Full Text Full Text PDF PubMed Scopus (156) Google Scholar in The Lancet Respiratory Medicine, the authors report an SNP located near AKAP13 that is associated with susceptibility to IPF. The authors used a two-stage genome-wide association study (GWAS) to identify variants associated with IPF. The study included 602 individuals from the UK and 3366 controls from UK Biobank in stage 1, followed by replication in two cohorts from the USA of 2158 patients with IPF and 5195 controls in stage 2. The first stage of the study replicated findings of previous studies, and identified several SNPs that have been associated with pulmonary fibrosis.4Fingerlin TE Murphy E Zhang W et al.Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis.Nat Genet. 2013; 45: 613-620Crossref PubMed Scopus (514) Google Scholar, 5Mushiroda T Wattanapokayakit S Takahashi A et al.A genome-wide association study identifies an association of a common variant in TERT with susceptibility to idiopathic pulmonary fibrosis.J Med Genet. 2008; 45: 654-656Crossref PubMed Scopus (173) Google Scholar, 6Noth I Zhang Y Ma SF et al.Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study.Lancet Respir Med. 2013; 1: 309-317Summary Full Text Full Text PDF PubMed Scopus (386) Google Scholar Importantly, and similar to previous studies, the MUC5B promoter variant (rs35705950) showed the strongest association with IPF. SNPs within AKAP13 were previously identified during the discovery phase of other large IPF GWAS, but did not reach genome-wide significance in their meta-analysis.4Fingerlin TE Murphy E Zhang W et al.Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis.Nat Genet. 2013; 45: 613-620Crossref PubMed Scopus (514) Google Scholar The study by Allen and colleagues3Allen RJ Porte J Braybrooke R et al.Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study.Lancet Respir Med. 2017; (published online Oct 20.)http://dx.doi.org/10.1016/S2213-2600(17)30387-9Summary Full Text Full Text PDF PubMed Scopus (156) Google Scholar identified several other significant variants, but these could not be extended to other datasets because of differences in the genotyping platforms or low allele frequencies. Additional variants will probably be identified when bigger samples are available or when genotyping platforms are standardised. AKAP13 is a scaffolding protein that integrates protein kinase-A and Rho signalling pathways.7Diviani D Soderling J Scott JD AKAP-Lbc anchors protein kinase A and nucleates Galpha 12-selective Rho-mediated stress fiber formation.J Biol Chem. 2001; 276: 44247-44257Crossref PubMed Scopus (203) Google Scholar AKAP13 is essential for cardiac development, and mice deficient for AKAP13 die at embryonic day 10·5.8Mayers CM Wadell J McLean K et al.The Rho guanine nucleotide exchange factor AKAP13 (BRX) is essential for cardiac development in mice.J Biol Chem. 2010; 285: 12344-12354Crossref PubMed Scopus (47) Google Scholar But although AKAP13 has been studied primarily in the context of the heart, its expression might be even higher in the lung. Before the study by Allen and colleagues,3Allen RJ Porte J Braybrooke R et al.Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study.Lancet Respir Med. 2017; (published online Oct 20.)http://dx.doi.org/10.1016/S2213-2600(17)30387-9Summary Full Text Full Text PDF PubMed Scopus (156) Google Scholar no role for AKAP13 had been identified in lung development or disease. The association of AKAP13 with IPF susceptibility is indeed an intriguing discovery. The connection of AKAP13 with Rho signalling links this genetic observation in patients with IPF to a well studied profibrotic signalling pathway. The profibrotic signalling molecules transforming growth factor β and lysophosphatidic acid are known activators of Rho signalling. Downstream, RhoA activates the Rho-associated coiled-coil forming protein kinases (ROCKs): ROCK1 and ROCK2. ROCKs mediate actin filament bundling and contraction and have been studied extensively in animal models of pulmonary fibrosis and humans with IPF.9Knipe RS Tager AM Liao JK The Rho kinases: critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis.Pharmacol Rev. 2015; 67: 103-117Crossref PubMed Scopus (125) Google Scholar ROCK inhibition has been shown to attenuate fibrosis in animal models,10Zhou Y Huang X Hecker L et al.Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis.J Clin Invest. 2013; 123: 1096-1108Crossref PubMed Scopus (307) Google Scholar and clinical trials of ROCK inhibitors are underway for IPF (ClinicalTrials.gov identifier NCT02688647). Where (and if) AKAP13 dysregulation fits into the current Rho-ROCK signalling paradigm is unclear, but an investigation of how ROCK signalling inhibitors perform as treatment in patients stratified by AKAP13 genotype would be interesting. Immunostaining for AKAP13 in the study by Allen and colleagues3Allen RJ Porte J Braybrooke R et al.Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study.Lancet Respir Med. 2017; (published online Oct 20.)http://dx.doi.org/10.1016/S2213-2600(17)30387-9Summary Full Text Full Text PDF PubMed Scopus (156) Google Scholar suggests that AKAP13 might be widely expressed in the lung epithelium, macrophages, and lymphoid cells, further increasing the uncertainty of the role of AKAP13 in the pathogenesis of pulmonary fibrosis, since we do not know which is the relevant cell type. The remaining question is how the discovery of AKAP13 will affect the clinical subphenotyping of patients with IPF. Genetic testing for individual risk alleles such as AKAP13 is unlikely to be useful because they are common in populations of European descent. One in five individuals with European ancestry have the MUC5B risk allele and one in three have the AKAP13 risk allele. 5% of all individuals of European descent have all three of the risk alleles identified by Allen and colleagues (AKAP13, MUC5B, and desmoplakin),3Allen RJ Porte J Braybrooke R et al.Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study.Lancet Respir Med. 2017; (published online Oct 20.)http://dx.doi.org/10.1016/S2213-2600(17)30387-9Summary Full Text Full Text PDF PubMed Scopus (156) Google Scholar equating to approximately 10 million people in the USA alone. Furthermore, other genetic markers might exist. Integrating risk from each of the alleles with telomere length measurements could be useful because short telomeres are a risk factor for IPF.11Alder JK Chen JJ Lancaster L et al.Short telomeres are a risk factor for idiopathic pulmonary fibrosis.Proc Natl Acad Sci USA. 2008; 105: 13051-13056Crossref PubMed Scopus (559) Google Scholar However, these approaches are not feasible on a screening basis because of the large number of individuals who probably carry a subset of these variants and have telomeres below the age-adjusted tenth percentile. More likely, the variants identified in the study by Allen and colleagues3Allen RJ Porte J Braybrooke R et al.Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study.Lancet Respir Med. 2017; (published online Oct 20.)http://dx.doi.org/10.1016/S2213-2600(17)30387-9Summary Full Text Full Text PDF PubMed Scopus (156) Google Scholar and other IPF GWAS point to pathways that, together with time and environmental interactions, contribute to the pathogenesis of IPF. Thus, the answer to the debate about the importance of molecular subphenotyping IPF cannot be that it does not matter. The accumulating number of genetic associations with IPF cannot be random, and Allen and colleagues3Allen RJ Porte J Braybrooke R et al.Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study.Lancet Respir Med. 2017; (published online Oct 20.)http://dx.doi.org/10.1016/S2213-2600(17)30387-9Summary Full Text Full Text PDF PubMed Scopus (156) Google Scholar have made a compelling case that AKAP13 is worth studying in IPF. If personalised medicine is ever going to be applied to IPF, genetic and mechanistic studies that connect genotype to phenotype must continue. Visualising AKAP13 in a Manhattan plot—the traditional scatter plot employed to present data from GWAS—brings to mind the American short story writer, O. Henry, who once quipped about New York “It'll be a great place if they ever finish it!”. Like the Manhattan skyline, IPF and genetic subphenotyping is a constantly evolving story, which could be great if we ever finish it. The authors declare funding from the National Institutes of Health (HL113105 to JKA and HL119960 and HL126990 to DJK). DJK reports collaborative research funding from Regeneron Pharmaceuticals. Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association studyAKAP13 is a Rho guanine nucleotide exchange factor regulating activation of RhoA, which is known to be involved in profibrotic signalling pathways. The identification of AKAP13 as a susceptibility gene for IPF increases the prospect of successfully targeting RhoA pathway inhibitors in patients with IPF. Full-Text PDF Open Access