New Cystic Fibrosis Gene Modifier Loci Discovered

Cystic Fibrosis (CF) is one of the most common hereditary diseases afflicting today's global population. CF causes body-wide defects including exocrine pancreatic inefficiency, male infertility, poor digestion, and excess mucus buildup in sinuses. However, 90% of deaths caused by CF are due to the excess mucosal blockages in pulmonary air channels. Past research showed that the recessive allele mutation of the cystic fibrosis transmembrane conductance regulator protein (CFTR) is the sole culprit of causing CF when inherited from a carrier at the parental generation. Researchers concluded at the time that the recessive allele inheritance of CFTR was the sole reason of acquiring CF, yet the severity of the symptoms a patient suffers with CF can vary. This led researchers to believe that the diverse severity of CF symptoms observed from different patients attributed to secondary factors besides just the CFTR recessive mutant.

This month, researchers from the University of North Carolina, Chapel Hill have discovered two loci that could be the so called secondary factors. Using an extensive genome-wide association study (GWAS), researchers took samples from three research study groups, totaling over 3,000 patients suffering from CF, and analyzed them by their severity of their phenotype symptoms. After narrowing down to using subjects with the common homozygous CFTR variant, p.Phe508del, and eliminating any outlier cases, the study found that chromosome loci 11p13 and 20q13 heavily influenced the severity of CF symptoms expressed in various patients from the study groups. Furthermore, both genes were found to be inhibitory factors involved in apoptotic suppression pathways. Their roles as inhibitors could explain the decrease of neutrophilic-triggering apoptosis, in which inflamed neutrophils within pulmonary air channels would fail to be eradicated, and thus impair pulmonary function.

This study was not the first attempt from CF researchers in finding genetic modifiers. While three previous small-scale association studies on other loci modifiers. There modifiers could not be replicated in a genome-wide scale by both this study and a previous one conducted in 2009. Nevertheless, the discovery of two possible modifiers from this GWAS study has shed new light and potential opportunities in creating better or possibly more individualized therapies to CF sufferers. For instance, a new therapy treatment could be created to suppress the activation of these modifiers as a method to reduce the severity of the symptoms CF patients exhibit or bring a new perspective road map for scientists to now tackle the disease by also integrating these modifiers in the equation. Therefore, this discovery of CF-modifying genes could completely change the methods we could use against this devastating disease.

Witt, Heiko. Nature Genetics 43, 508–509 (2011).

Wright, Fred A. et al. Nature Genetics 43, 539–549 (2011).