Of Genes and Men: The Alternative View of Sex Differences in Cystic Fibrosis

Response to Creus et al.

We thank Creus et al. (1) for their interesting comments on our proposal that female subjects with cystic fibrosis–related diabetes develop worse lung function compared with age- and genotype-matched male peers. They ask whether these differences are a result of “evolutionary, sex-specific selective pressures.” They then make the assertion that cystic fibrosis heterozygosity must “simultaneously place an enormous selective pressure against men carrying these same ‘infertility’ alleles even in heterozygosity.” The difficulty we face in accepting this notion of selective negative pressure on the Y chromosome is that most heterozygote males are perfectly fertile, but for reasons unknown, more males are diagnosed with cystic fibrosis than females (1.1 to 1.0). The latter ratio is higher than the accepted male preponderance at birth in the population as a whole (1.05 to 1.0), which is offset back toward unity by a higher male mortality in childhood (2).

We accept that it is not fully understood why some patients with apparently “severe genotypes” do not develop classical cystic fibrosis, although intronic/exonic boundary structure, modifier genes, and environmental factors have all been implicated (3). However, although Rodman et al. (3) reported that females outnumbered males by three to one in their late-diagnosed cohort, females formed a smaller proportion of their early-diagnosed cohort. But, Rodman et al.’s results contradict the recognized excess of female cystic fibrosis mortality (4). Indeed, we have recently submitted a manuscript responding to Rodman et al.’s findings and report that for a national population of 135 patients aged >40 years, comparable male-to-female ratios were found in pediatric- and adult-diagnosed cohorts (J.M., personal communication). The different findings between our work and that of Rodman et al. could indicate a possible unknown bias in a single-center approach (3).

Finally, Creus et al. (1) also suggest that “rather than decreased lung function and survival in women, we should view the published results as better survival and lung function in men.” We suggest that the imminent imposition of neonatal screening across the U.K. and France provides an opportunity to test the ideas proposed by the correspondents, but we feel it is premature to envisage a change in the title of our report (5).