Diseases Common in Persons With Cystic Fibrosis Among CFTR Heterozygotes

Area of Science:

• Genetics
• Population Health
• Genomic Medicine

Background:

• Cystic fibrosis (CF) is a common autosomal recessive disorder.
• Millions of individuals are heterozygous for CFTR gene variants, but their disease risk is unclear, especially in non-European populations.
• Understanding CFTR heterozygote risk is crucial for improving management strategies across diverse groups.

Purpose of the Study:

• To investigate the association between carrying a single pathogenic CFTR gene variant and the risk of various diseases across the phenome.
• To analyze these associations in different genetic ancestral groups.

Main Methods:

• A genetic association study using whole-genome sequencing data from the All of Us Research Program linked to electronic health records (EHRs).
• Inferred genetic ancestry using reference datasets (1000 Genomes Project, Human Genome Diversity Project).
• Performed multivariable-adjusted phenome-wide association studies (PheWAS) to calculate odds ratios (ORs) for disease risk.

Main Results:

• Analyzed 317,964 adult participants, identifying 7,957 CFTR heterozygotes.
• No statistically significant associations between CFTR heterozygosity and disease risk were found overall or within specific ancestral groups.
• While some CF-associated diseases showed slightly elevated risks in certain heterozygotes (e.g., allergic bronchopulmonary aspergillosis, bronchiectasis), the effect sizes were very small compared to homozygotes.

Conclusions:

• CFTR heterozygotes, in general, do not exhibit a substantially increased risk for CF-associated diseases in adulthood.
• Elevated risks for specific respiratory and infectious diseases in some heterozygotes warrant further investigation into underlying factors.
• These findings highlight the importance of considering genetic ancestry in population health research.