THE GENETIC ADVANTAGE HYPOTHESIS IN CYSTIC-FIBROSIS HETEROZYGOTES - AMURINE STUDY

1. The Delta F508 mutation of the cystic fibrosis (CF) gene is of high frequency in man (1 in 25) and in homozygotes causes cystic fibrosis. It is suggested that cystic fibrosis heterozygotes withstand secretor y diarrhoea better than normal individuals and so a-re genetically adv antaged. This hypothesis has been examined by measuring electrogenic c hloride secretion in gut epithelia of normal and heterozygous CF mice. 2. Chloride secretory responses of normal and heterozygous colonic ep ithelia to forskolin, vasoactive intestinal polypeptide (VIP), isopren aline, cholera toxin, heat-stable enterotoxin (STa), guanylin, carbach ol and lysylbradykinin were examined. Mo significant differences in re sponses of tissues of the two genotypes were found. 3. Responses of no rmal and heterozygous ileal epithelia to forskolin and glucose were in vestigated. Heterozygous tissues responded as well as normal tissues. 4. Frusemide (furosemide) caused virtually identical inhibition of the chloride secretory responses to forskolin in colonic epithelia of bot h genotypes. 5. No evidence to support the genetic advantage hypothesi s in ileal or colonic epithelia of the null CF mouse has been found, a t least for acute responses. If the hypothesis is true then either (a) other non-cystic fibrosis transmembrane conductance regulator (non-CF TR) transport processes are involved, (b) prolonged exposure to secret agogues is required, or (c) Delta F508 CFTR is responsible for the pro tective effect.