The influence of genetics on cystic fibrosis phenotypes

Abstract

Technological advances in genetics have made feasible and affordable large studies to identify genetic variants that cause or modify a trait. Genetic studies have been carried out to assess variants in candidate genes, as well as polymorphisms throughout the genome, for their associations with heritable clinical outcomes of cystic fibrosis (CF), such as lung disease, meconium ileus, and CF-related diabetes. The candidate gene approach has identified some predicted relationships, while genome-wide surveys have identified several genes that would not have been obvious disease-modifying candidates, such as a methionine sulfoxide transferase gene that influences intestinal obstruction, or a region on chromosome 11 proximate to genes encoding a transcription factor and an apoptosis controller that associates with lung function. These unforeseen associations thus provide novel insight into disease pathophysiology, as well as suggesting new therapeutic strategies for CF.

Figure 1.

Schematic display of the magnitude of the effect of mutant CFTR versus environmental influences and modifier genes. (Image courtesy of Peter Durie, Toronto.)

Figure 2.

Lung disease severity assessed by FEV₁ versus age in 1357 Canadian CF patients with biallelic loss-of-function (pancreatic insufficient) mutations. (Image courtesy of Peter Durie, Toronto.)

Figure 3.

A locus-zoom plot of association in the GMS and CGS F508del homozygotes at chr11p13 EHF/APIP region, showing both genotyped and HapMap-imputed SNPs. Colors represent HapMap CEU linkage disequilibrium r² with the most significant genotyped SNP (rs12793173; p = 3 × 10⁻⁸). The secondary genotyped peak (rs286873) has low r² with the primary peak. Addition of the imputed SNPs to genotyped SNPs illustrates the coverage and LD blocks across the region.