Precision Genomic Medicine in Cystic Fibrosis

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.

Keywords: epithelium; genes; genetics.

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.

Figure 2

Modifier genes and environmental influences: the manifestations of CF disease are not solely dependent on genotype. Studies in humans and animals have shown heterogeneous CF phenotypes for people with identical CFTR mutations in the same family. Therefore, we need to broaden our focus from looking at the genotype alone, to CFTR modifiers including modifier genes and environmental influences that can alter CFTR function or CF phenotype.

Figure 3

Targeted molecular therapies to increase CFTR activity: the CF‐related phenotype is influenced by genotype, modifier genes, environment, organ system, and level of CFTR function. Advances in pharmacogenetics have produced therapies, such as, ivacaftor that specifically target the primary genetic defect mutations and can increase both mutant and wild‐type CFTR activity. This example of precise genomic medicine can tip the scales of CFTR function and thereby alter the progression of disease.