EDNRA – Cystic fibrosis

In a single multi-cohort study of 1,577 cystic fibrosis (CF) patients homozygous for ΔF508, polymorphisms in the endothelin receptor A gene EDNRA were uniquely associated with pulmonary function. An initial cohort of 808 patients showed a significant link for EDNRA 3′-UTR variant rs5335 with worse lung function (P = 0.04) (PMID:20028935), a finding replicated in three additional cohorts (n=769) with P = 0.002 across groups (PMID:20028935). No other endothelin pathway genes reached significance.

Functional assays demonstrated that the deleterious rs5335 allele drives higher EDNRA mRNA levels in cultured primary tracheal smooth muscle cells and accelerates proliferation of homozygous cells, providing a quantitative gain-of-function mechanism that likely exacerbates CF pulmonary disease severity. While these data support a modifier role for EDNRA in Cystic fibrosis, the evidence is limited to association and in vitro studies without familial segregation, and further replication is required.

Key take-home: EDNRA 3′-UTR variant rs5335 is a potential pulmonary severity modifier in CF, meriting additional validation before clinical application.

References

• Physiological genomics • 2010 • EDNRA variants associate with smooth muscle mRNA levels, cell proliferation rates, and cystic fibrosis pulmonary disease severity. PMID:20028935

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