Female subjects with cystic fibrosis–related diabetes have a worse prognosis than male subjects according to two independent studies recently published in Diabetes Care (1, 2). It has been known for some time that females with cystic fibrosis generally have a significantly higher mortality than males from age 1 to 20 years (3), a sex difference that remains despite radical improvement in survival rates through the years (4). Are these differences a result of evolutionary, sex-specific selective pressures? We propose an evolutionary explanation for the observed sex differences in cystic fibrosis.
Congenital bilateral absence of the vas deferens (CBAVD), a cause of infertility in 1–2% of European men, is a clinical sign of cystic fibrosis. Conversely, mutations in the cystic fibrosis transmembrane regulator (CFTR), the cause of cystic fibrosis, are also found in 80% of patients with isolated CBAVD (5, 6). Indeed, the observation that the vas deferens is abnormal in almost all male cystic fibrosis patients led to the suggestion that CBAVD is an incomplete form of cystic fibrosis (7).
To account for the high incidence of CFTR mutations in the population, it is generally assumed that there are selective advantages in being a heterozygous carrier, perhaps in the form of resistance against typhoid fever (8); such CFTR mutations must, however, simultaneously place an enormous selective pressure against men carrying these same “infertility” alleles even in heterozygosity. This selective pressure is much less pronounced in female carriers.
We postulate that compensatory mutations in the Y chromosome have arisen to ensure that CFTR mutations do not lead to sterility in men; such mutations will preserve the selective advantage of CFTR mutations. As an evolutionary consequence, the phenotype of cystic fibrosis will be skewed toward less severe manifestations of the disease in men. Furthermore, these protective effects of alleles in the Y chromosome may be reflected in the extreme cases of CBAVD patients lacking clinical evidence of cystic fibrosis who harbor “serious,” homozygous CFTR mutations (5).
Our postulate could help explain epidemiological findings such as unequal sex distribution among diagnosed cystic fibrosis patients and prevalence of women diagnosed later in life (9). What is our suggested explanation for this observation? Simply, females homozygous for mutations in the CFTR gene diagnosed as adults still have penetrant cystic fibrosis, whereas age-matched males do not, and are therefore never diagnosed, except, perhaps, if these males have CBAVD or pancreatitis (10).
In view of the recent findings reported by Sims et al. and Milla et al., we believe that searching for alleles in the Y chromosome that confer resistance to CBAVD, cystic fibrosis, and cystic fibrosis–related diabetes may be of considerable scientific value. In conclusion, rather than decreased lung function and survival in women, we should view the published results as better survival and lung function in men.