Cystic fibrosis (CF) is a common genetic disorder, caused by mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR gene encodes a transmembrane chloride channel, which is important for key physiological functions, such as production of sweat and mucus, as well as mucociliary clearance in the lungs (1). Affected individuals are homozygous for mutated copies of CFTR and are at elevated risk for a variety of diseases, including bronchiectasis and repeated pulmonary infection; gastrointestinal disorders, including malabsorption and nutritional deficiency states; and pancreatitis and diseases of the hepatobiliary system (1). While management of CF has improved drastically in recent decades, individuals with CF experience reduced life expectancy relative to the general population (2). The prevalence of carrier state of mutated CFTR genes is high [greater than 3% in some subpopulations (3)], leading to the suggestion that the carrier state must be positively selected for due to positive health effects, analogous to protection against malaria conferred by carrier states in sickle cell anemia (4, 5). CF has been regarded as a classical autosomal recessive disorder, with no adverse health effects associated with the carrier state. I use the past tense, because in PNAS Miller et al.(6) provide convincing evidence that CF heterozygosity may represent a haploinsufficiency state, analogous to that seen with thalassemia, where individuals with a single copy of the disease-causing allele do suffer adverse health effects, presumably due to production of the gene’s product at lower levels than would be seen in noncarriers. Beta-thalassemia is an autosomal recessive disorder of hemoglobin, but the carrier state is often characterized as “thalassemia minor” with individuals experiencing anemia that is less severe than homozygotes (who experience thalassemia major or thalassemia intermedia)(7). The contrast with CF relates to the multisystemic nature of CF, and the numerous disease states linked to CF, compared to beta-thalassemia as a hematological disease. Miller et al.(6) were able to link genetic testing information to diagnostic codes using a very large, commercial health analytics database built on insurance claims data [the Truven Marketscan Database (8)]. They evaluated the risk of 59 diseases that occur with higher frequency in individuals with cystic fibrosis in a cohort of 19,802 CF carriers matched by age, gender, and duration of enrollment to 99,010 controls. Remarkably, they found that individuals with the CF carrier state were at significantly increased risk of nearly all of the diseases evaluated (57/59). In a second analysis, they calculated odds ratios for the same 59 diseases in individuals with CF compared to matched controls and found strong correlation in odds ratios (OR) for disease states between CF carriers and individuals with CF. In other words, the higher the OR of the disease in individuals with CF, the higher the OR in CF carriers. Their results were robust when restricted to individuals who might be presumed not to have undergone CF genetic testing (mothers of CF cases during the time period prior to the pregnancy) and also when they removed individuals in whom CF genetic testing might have been performed due to occurrence of a disease that suggested underlying CF. They also performed simulations to determine whether false discovery might explain their results and found this unlikely to be the case. Their results have important implications not only for how CF is conceptualized, but also for the potential burden of disease associated with the CF gene at the population level. The study also raises …