| MUC4/20 |
Lung function |
(89) |
Encode cell surface-associated airway cell mucin 4 and 20, respectively Important for creating an osmotic barrier at the periciliary layer, and ciliary motility Mucins are over-abundant in patients with CF, leading to osmotic compression of the periciliary layer, and consequently mucociliary stasis and susceptibility to infection (reviewed in 106) |
|
SLC9A3 (a.k.a. NHE3) |
Lung function, Meconium ileus |
(40,89) |
Major absorptive Na+/H+ exchanger, and mice lacking Slc9a3 have impaired acid-base balance and Na+-fluid volume homeostasis (107) Deletion of Slc9a3 rescues the intestinal phenotype in Cftr-/- mice and significantly improves their survival (104) Regulation of SLC9A3 and CFTR by SLC9A3R1, SLC9A3R2 and ezrin (EZR), which bind via PDZ domains, has been extensively reviewed in (108) Gene variation affecting the SLC9A3/SLC9A3R2/EZR complex may influence lung disease severity in CF (88) |
| HLA-DRA |
Lung function |
(89) |
Class II HLA (human leukocyte antigen) regulates immune response via antigen presentation to T lymphocytes Expression variation of HLA genes and HLA immune response pathways associate with lung disease severity in patients with CF (109,110) |
| EHF |
Lung function |
(89) |
Ets family transcription factor expressed in epithelial cells GWAS locus lies in an intergenic region between EHF and APIP genes, but physical interactions of regulatory elements confirm enhancer–promoter interactions of the GWAS locus with the EHF promoter (111) EHF allele variation alters regulation of genes responsible for protein glycosylation and trafficking, processes that may be important for the folding and trafficking of F508del-CFTR, in rectal biopsies of F508del patients (112) EHF expression variation regulates genes involved in wound closure, transepithelial resistance, inflammation and goblet cell hyperplasia (113,114) EHF represses CFTR expression, with EHF knockdown improving CFTR production and function in cultured Calu-3 airway epithelial cells (29) |
| AGTR2 |
Lung function |
(89) |
Encodes angiotensin II receptor type 2 GWAS locus lies in between AGTR2 and SLC6A14, and GTEx data (100) suggest associated variants are eQTLs for both genes Deletion of Agtr2 in Cftr-/- mice restores airway compliance, elastance, and airway damping (115,116) |
|
SLC6A14 (a.k.a. ATB0,+) |
Lung function, Meconium ileus |
(40,89) |
Sodium- and chloride-dependent neutral and cationic amino acid transporter shown to have a role in maintaining low luminal amino acid levels Regulator of Pseudomonas aeruginosa (PsA) attachment to bronchial epithelial cells (42,117) |
| SLC26A9 |
Meconium ileus, CF-related diabetes |
(38,40) |
Anion channel in epithelial cells (118,119), with STAS domain that interacts with the CFTR R domain (120) Interaction enhances the functional expression of CFTR (90,121,122) Slc26a9-/-/CFTR-/- DKO mice have a much lower rate of survival post-birth than Cftr-/- or Slc26a9-/- mice (93) |
| DCTN4 |
PsA infection |
(85) |
Encodes dynactin 4 (p62), a subunit of the 20S dynactin complex, involved in microtubule organization through processing of dynein, acting as an adapter between dynein and the cargo (123) Has a role in ciliary beat via dynein processing (124,125) |
| CAV2 |
PsA infection |
(86,126) |
|
| TMC6 |
PsA infection |
(86,126) |
|
| ATP12A |
Meconium ileus |
(39) |
The α subunit of the nongastric H+/K+ adenosine triphosphate (ATPase) Responsible for the acidification of ASL pH in pigs and humans, resulting in an increased susceptibility to bacterial infections and compromised host defenses (105) Chronic inflammation in the lungs (via IL-13) increases ATP12A expression and function, which leads to increased ASL viscosity and impaired mucociliary clearance (129) In the pancreatic ducts, ATP12A is co-expressed with CFTR, carbonic anhydrase, and aquaporins where it may regulate the /H+ transport for the alkalinization of pancreatic fluid (130) |
