Precision Genomic Medicine in Cystic Fibrosis Eugene H. Chang, M.D.1 and Joseph Zabner, M.D.2
Abstract The successful application of precision genomic medicine requires an understanding of how a person’s genome can influence his or her disease phenotype and how medical therapies can provide personalized therapy to one’s genotype. In this review, we highlight advances in precision genomic medicine in cystic fibrosis (CF), a classic autosomal recessive genetic disorder. We discuss genotype–phenotype correlations in CF, genetic and environmental modifiers of disease, and pharmacogenetic therapies that target specific genetic mutations thereby addressing the primary defect of cystic fibrosis. Clin Trans Sci 2015; Volume 8: 606–610
Keywords: epithelium, genes, genetics
Introduction
It was only 12 years ago that the Human Genome Project (HGP) was complete, ushering in a revolution in biological research. The goal set forth by the National Institutes of Health (NIH), was to utilize genomic information to predict human health and disease while subsequently identifying targets for drug response.1 The promise of precision genomic medicine is nearing reality. Due to rapid advances in scientific technology, what took 13 years can now be completed in 1 day at considerably reduced costs, from 2.7 billion dollars to $5,000 for an individual genome. As these costs continue to decrease at four times the rate of Moore’s law,2 it is conceivable that an individual’s genome will be listed as a vital sign along with their heart rate and blood pressure in the near future. So that the biomedical community can fulfill the promise of precision genomic medicine, clinicians will be required to understand how genetics influence the phenotype of disease and the subsequent response to therapy. In this manuscript, we highlight how genomics is transforming the treatment of cystic fibrosis (CF), one of the classic autosomal recessive genetic disorders. We discuss three advances: First, how does the genetic mutation in CF correlate to human disease? Second, what modifiers can influence the CF phenotype? And third, how can targeted pharmacogenetics improve care? Genotype–Phenotype Correlations in CF
The diagnosis of CF is based on symptoms of disease and genetic abnormalities in the CF transmembrane regulator conductance gene (CFTR).3 People with CF have two CF-causing CFTR mutations and there are greater than 1,500 CFTR mutations identified and more than 100 mutations known to cause disease of varying severity. These mutations are grouped into six classes: defects in protein production (Class I), processing (Class II), regulation (Class III), conduction (Class IV), reduced number of CFTR transcripts (Class V), and accelerated turnover (Class VI).4 The five most common mutations in the United States are present in greater than 95% of people with CF: F508del (86.7% of people with CF, Class II mutation), G542X (4.6%, Class I), G551D (4.3%, Class III), R117H (2.7%, Class IV), and N1303K (2.5%, Class II).5
These mutation classes are further subdivided into severity based on residual CFTR function. Class I, II, and III mutations are classified as severe with less than 10% of residual CFTR function and Class IV, V, and VI are classified as mild/moderate with less than 20% of residual CFTR function.6 CF carriers, or CFTR heterozygotes, have one copy of a CFTR mutation and approximately 50% of total CFTR function. CF carriers do not have CF but may have a higher incidence of CF-like disease.7 In the United States, there are approximately 30,000 people with CF and 15 million people who are CF carriers.8 The classic CF phenotype involves the respiratory tract, gastrointestinal system, male reproductive tract, and the sweat glands. The CFTR2 website (cftr2.org) is a resource developed in collaboration with the CF foundation, researchers, and those affected with the disease to provide genotype–phenotype correlations between specific mutations and the symptoms of CF. The website provides information on the most common mutations, and provides a range of information, including lung function and sweat chloride levels for those carrying specific mutations.8 There have also been correlations between CFTR mutations and CF-related disorders (Figure 1 ).7 Here we review the correlation of these systems. Airway In the airway, nearly all people with two severe CFTR mutations will develop obstructive sinus and pulmonary disease. CF sinusitis presents as thick viscous mucus obstructing the sinus ostia with associated chronic infection and inflammation of the epithelia.9 Loss of CFTR function also results in abnormal sinus development with sinus hypoplasia (small sinuses) in humans and in a transgenic CFTR-null porcine model.10 Several studies have associated milder CF mutations with less severe forms of CF sinusitis and hypoplasia.11–13 CF carriers also have a three times greater risk of developing chronic sinusitis then those without CFTR mutations.14,15 In the lower airway, severe CF causes chronic infection, bronchiectasis, mucus plugging, and eventual lung destruction. However, the relationship between genotype and phenotype for the lower airway is variable between people with the same CFTR
1 Department of Otolaryngology-Head and Neck Surgery, The University of Arizona College of Medicine, Tucson, Arizona, USA ; 2Department of Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA .
Correspondence : Eugene H Chang ([email protected]) DOI: 10.1111/cts.12292
606
VOLUME 8 • ISSUE 5
WWW.CTSJOURNAL.COM
Chang and Zabner Precision Genomic Medicine ■
Figure 1. Genotype–phenotype correlations in cystic fibrosis: CFTR mutations can be divided into severe, moderate, and mild mutations based on residual CFTR function. CF carriers carry one CFTR mutation and do not have CF, but have approximately 50% of CFTR function. In multiple organ systems, the severity of the genotype can be associated with the severity of the phenotype. There may also be different variants of the disease phenotype, such as, the association of pancreatic insufficiency in severe genotypes to the increased incidence of chronic pancreatitis in CFTR heterozygotes. Dependent on the organ system, these associations can be strong or weak.
mutation, as well as members of the same family suggestive of complex genetic interactions.16 In people with mild and moderate CFTR mutations, the phenotype tends to be less severe with improved residual lung function17 and milder pancreatic disease.18 CF carriers also have increased rates of bronchiectasis, allergic bronchopulmonary aspergillosis, nontuberculous mycobacteria and chronic obstructive pulmonary disease.19–21 Gastrointestinal All people with CF will have exocrine pancreatic disease. Furthermore, the concordance of genotype to pancreatic disease is greater than 95% or greater in CF siblings with identical CFTR genotypes, suggesting that genotype strongly influences pancreatic function.22 People with CF who are homozygous for the F508del mutation produce
Abstract The successful application of precision genomic medicine requires an understanding of how a person’s genome can influence his or her disease phenotype and how medical therapies can provide personalized therapy to one’s genotype. In this review, we highlight advances in precision genomic medicine in cystic fibrosis (CF), a classic autosomal recessive genetic disorder. We discuss genotype–phenotype correlations in CF, genetic and environmental modifiers of disease, and pharmacogenetic therapies that target specific genetic mutations thereby addressing the primary defect of cystic fibrosis. Clin Trans Sci 2015; Volume 8: 606–610
Keywords: epithelium, genes, genetics
Introduction
It was only 12 years ago that the Human Genome Project (HGP) was complete, ushering in a revolution in biological research. The goal set forth by the National Institutes of Health (NIH), was to utilize genomic information to predict human health and disease while subsequently identifying targets for drug response.1 The promise of precision genomic medicine is nearing reality. Due to rapid advances in scientific technology, what took 13 years can now be completed in 1 day at considerably reduced costs, from 2.7 billion dollars to $5,000 for an individual genome. As these costs continue to decrease at four times the rate of Moore’s law,2 it is conceivable that an individual’s genome will be listed as a vital sign along with their heart rate and blood pressure in the near future. So that the biomedical community can fulfill the promise of precision genomic medicine, clinicians will be required to understand how genetics influence the phenotype of disease and the subsequent response to therapy. In this manuscript, we highlight how genomics is transforming the treatment of cystic fibrosis (CF), one of the classic autosomal recessive genetic disorders. We discuss three advances: First, how does the genetic mutation in CF correlate to human disease? Second, what modifiers can influence the CF phenotype? And third, how can targeted pharmacogenetics improve care? Genotype–Phenotype Correlations in CF
The diagnosis of CF is based on symptoms of disease and genetic abnormalities in the CF transmembrane regulator conductance gene (CFTR).3 People with CF have two CF-causing CFTR mutations and there are greater than 1,500 CFTR mutations identified and more than 100 mutations known to cause disease of varying severity. These mutations are grouped into six classes: defects in protein production (Class I), processing (Class II), regulation (Class III), conduction (Class IV), reduced number of CFTR transcripts (Class V), and accelerated turnover (Class VI).4 The five most common mutations in the United States are present in greater than 95% of people with CF: F508del (86.7% of people with CF, Class II mutation), G542X (4.6%, Class I), G551D (4.3%, Class III), R117H (2.7%, Class IV), and N1303K (2.5%, Class II).5
These mutation classes are further subdivided into severity based on residual CFTR function. Class I, II, and III mutations are classified as severe with less than 10% of residual CFTR function and Class IV, V, and VI are classified as mild/moderate with less than 20% of residual CFTR function.6 CF carriers, or CFTR heterozygotes, have one copy of a CFTR mutation and approximately 50% of total CFTR function. CF carriers do not have CF but may have a higher incidence of CF-like disease.7 In the United States, there are approximately 30,000 people with CF and 15 million people who are CF carriers.8 The classic CF phenotype involves the respiratory tract, gastrointestinal system, male reproductive tract, and the sweat glands. The CFTR2 website (cftr2.org) is a resource developed in collaboration with the CF foundation, researchers, and those affected with the disease to provide genotype–phenotype correlations between specific mutations and the symptoms of CF. The website provides information on the most common mutations, and provides a range of information, including lung function and sweat chloride levels for those carrying specific mutations.8 There have also been correlations between CFTR mutations and CF-related disorders (Figure 1 ).7 Here we review the correlation of these systems. Airway In the airway, nearly all people with two severe CFTR mutations will develop obstructive sinus and pulmonary disease. CF sinusitis presents as thick viscous mucus obstructing the sinus ostia with associated chronic infection and inflammation of the epithelia.9 Loss of CFTR function also results in abnormal sinus development with sinus hypoplasia (small sinuses) in humans and in a transgenic CFTR-null porcine model.10 Several studies have associated milder CF mutations with less severe forms of CF sinusitis and hypoplasia.11–13 CF carriers also have a three times greater risk of developing chronic sinusitis then those without CFTR mutations.14,15 In the lower airway, severe CF causes chronic infection, bronchiectasis, mucus plugging, and eventual lung destruction. However, the relationship between genotype and phenotype for the lower airway is variable between people with the same CFTR
1 Department of Otolaryngology-Head and Neck Surgery, The University of Arizona College of Medicine, Tucson, Arizona, USA ; 2Department of Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA .
Correspondence : Eugene H Chang ([email protected]) DOI: 10.1111/cts.12292
606
VOLUME 8 • ISSUE 5
WWW.CTSJOURNAL.COM
Chang and Zabner Precision Genomic Medicine ■
Figure 1. Genotype–phenotype correlations in cystic fibrosis: CFTR mutations can be divided into severe, moderate, and mild mutations based on residual CFTR function. CF carriers carry one CFTR mutation and do not have CF, but have approximately 50% of CFTR function. In multiple organ systems, the severity of the genotype can be associated with the severity of the phenotype. There may also be different variants of the disease phenotype, such as, the association of pancreatic insufficiency in severe genotypes to the increased incidence of chronic pancreatitis in CFTR heterozygotes. Dependent on the organ system, these associations can be strong or weak.
mutation, as well as members of the same family suggestive of complex genetic interactions.16 In people with mild and moderate CFTR mutations, the phenotype tends to be less severe with improved residual lung function17 and milder pancreatic disease.18 CF carriers also have increased rates of bronchiectasis, allergic bronchopulmonary aspergillosis, nontuberculous mycobacteria and chronic obstructive pulmonary disease.19–21 Gastrointestinal All people with CF will have exocrine pancreatic disease. Furthermore, the concordance of genotype to pancreatic disease is greater than 95% or greater in CF siblings with identical CFTR genotypes, suggesting that genotype strongly influences pancreatic function.22 People with CF who are homozygous for the F508del mutation produce
