Cystic fibrosis carriers are at increased risk for a wide range of cystic fibrosis-related conditions

Abstract

Autosomal recessive diseases, such as cystic fibrosis (CF), require inheritance of 2 mutated genes. However, some studies indicate that CF carriers are at increased risk for some conditions associated with CF. These investigations focused on single conditions and included small numbers of subjects. Our goal was to determine whether CF carriers are at increased risk for a range of CF-related conditions. Using the Truven Health MarketScan Commercial Claims database (2001-2017), we performed a population-based retrospective matched-cohort study. We identified 19,802 CF carriers and matched each carrier with 5 controls. The prevalence of 59 CF-related diagnostic conditions was evaluated in each cohort. Odds ratios for each condition were computed for CF carriers relative to controls. All 59 CF-related conditions were more prevalent among carriers compared with controls, with significantly increased risk (P < 0.05) for 57 conditions. Risk was increased for some conditions previously linked to CF carriers (e.g., pancreatitis, male infertility, bronchiectasis), as well as some conditions not previously reported (e.g., diabetes, constipation, cholelithiasis, short stature, failure to thrive). We compared our results with 23,557 subjects with CF, who were also matched with controls; as the relative odds of a given condition increased among subjects with CF, so did the corresponding relative odds for carriers (P < 0.001). Although individual-level risk remained low for most conditions, because there are more than 10 million carriers in the US, population-level morbidity attributable to the CF carrier state is likely substantial. Genetic testing may inform prevention, diagnosis, and treatment for a broad range of CF carrier-related conditions.

Keywords: CF carrier; CFTR; carrier; cystic fibrosis; heterozygote.

Fig. 1.

Study cohort identification and sample size. *Note that genetic screening is typically performed at birth or during the course of prenatal counseling. Thus, we were able to identify only a small proportion of enrollees who are CF carriers, and some of the subjects in the control population are very likely to be actual CF carriers.

Fig. 2.

CF carriers are at greater risk for a wide range of CF-related conditions. For each CF-related health condition, the figure compares the prevalence between CF carriers and matched controls in terms of percent prevalence, OR and associated 95% CI, and P value for a test of the hypothesis that prevalence is greater among CF carriers. In addition, each natural log OR and its associated 95% CI are graphically depicted. The prevalence of CF-related conditions was greater in CF carriers compared with matched controls for all 59 conditions. The natural log OR for carriers was significantly greater than that for controls (P < 0.05) for 57 of the 59 conditions. A similar analysis between subjects with CF and matched controls is provided in SI Appendix, Fig. S1.

Fig. 3.

The prevalence of CF-related conditions is correlated between CF carriers and subjects with CF relative to control subjects. In the main figure, natural log ORs and corresponding 95% CIs are plotted for the various conditions for CF carriers (red) and subjects with CF (blue), ordered by the natural log OR for subjects with CF. The inset at the upper right shows a scatterplot of these values. The slope of the trend line (green) between conditions in CF carriers and subjects with CF is 0.22 (P < 0.001); the natural log OR of a given condition in CF carriers is ∼22% of the natural log OR in subjects with CF. The Pearson correlation between natural log ORs in the 2 cohorts across the conditions is 0.67 (P < 0.001).