What is the role of genetic modifiers in the etiology of cystic fibrosis (CF)?

Updated: Oct 22, 2019
  • Author: Girish D Sharma, MD, FCCP, FAAP; Chief Editor: Kenan Haver, MD  more...
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Studies in murine CF models have shown an increase in mast cells and neutrophils as part of the immune response. For example, the KITL gene plays a vital role in the differentiation of mast cells, as demonstrated by a decreased expression of MCPT2. Another focus includes the proteins selectin and intercellular adhesion molecule–1 (ICAM-1), which facilitate neutrophil extravasation. Neutrophils and mast cells release proteases, prostaglandins, and histamine, influencing mucus production.

A research model found in CFTR- knockout gene mice highlighted the importance of MCLCA3 expression in goblet cells. This gene influences mucus production, among other activities, and its expression was noted to be diminished in these mice. Correction of this deficiency increased survival and decreased intestinal disease. In humans, this finding may translate to applications such as correcting modifier genes (eg, HCLCA1) in order to improve outcomes in patients with CF. [17]

Additional genetic modifiers include a 129/Sv allelic contribution in mice that yields a milder inflammatory response in CF and is potentially linked to chromosomes 1, 9, and 10. The regulation of these genes and processes helps explain the range of phenotypic variability in similar genetic mutations.

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