Editors' ChoiceCystic Fibrosis

Inheriting Disease Severity

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Science Translational Medicine  15 Jun 2011:
Vol. 3, Issue 87, pp. 87ec91
DOI: 10.1126/scitranslmed.3002753

Many vexing questions arise in clinical medicine, not the least of which is the following: Why do two people with the same condition display different levels of disease severity? Physicians can rarely provide a meaningful answer to this question—even when some information about molecular pathogenesis is available. Understanding the roots of heterogeneous severity for myriad diseases represents a major frontier in translational medicine. In a recent study, Wright et al. begin to identify genetic factors that correlate with disease severity in patients with cystic fibrosis (CF).

A severe inherited secretory condition, CF is characterized by pancreatic insufficiency, frequent respiratory infections, a disruption in lung function caused by an accumulation of thick mucus, and early mortality. CF is caused by recessive inheritance of a loss-of-function change in the CFTR gene, which encodes a chloride channel called cystic fibrosis transmembrane conductance regulator (CFTR). The most common mutation in the CFTR gene (Phe508del) accounts for more than two-thirds of CF cases. Despite this seeming genetic homogeneity, large differences in disease severity exist among individual patients. Previous studies suggest that severity of lung disease runs in families and that this familial correlation in severity is not dependent on CFTR genotype, suggesting that additional genetic modifiers of severity may be present.

Wright et al. performed a genome-wide association study to hunt for these putative genetic modifiers of severity in an unbiased manner. To limit the genetic heterogeneity among test subjects, the authors studied 2535 CF patients who were all homozygous for the common Phe508del mutation, including 557 subjects from a twins and siblings cohort. The authors identified a significant association between the EHF-APIP locus and disease severity, which was consistent in both the sibling and unrelated CF cohorts. EHF encodes a transcriptional repressor that is expressed in bronchial epithelial cells, and APIP encodes the APAF1 interacting protein, which regulates apoptosis. The sib-pair study also identified a significant associated region on chromosome 20, which includes some interesting candidates such as melanocortin-3 receptor, Cas scaffolding protein family member 4, and Aurora kinase A. More work will be required to define the precise causal alleles that underlie these associations, but this study demonstrates the ability to pinpoint genes and pathways related to CF disease severity. Mapping the genetics of severity should improve our predictive capacity in the clinic.

F. A. Wright et al., Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2. Nat. Genet. 43, 539–546 (2011). [Full Text]

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