Biology subjects

Quon, B. S.

Publications and source records attributed to Quon, B. S..

2 recordsLinked to original sources

bioRxiv2026

Elexacaftor/tezacaftor/ivacaftor treatment is associated with epigenetic age deceleration in cystic fibrosis

Background: Cystic fibrosis (CF) is associated with chronic inflammation and progressive multisystem disease, which may contribute to accelerated biological aging. Elexacaftor/tezacaftor/ivacaftor (ETI) substantially improves clinical outcomes in people with CF (pwCF), but its effects on epigenetic aging and their relationship with inflammation remain poorly understood. Methods: We performed a pilot longitudinal study of 8 modulator-naive pwCF. Blood DNA methylation was profiled before ETI initiation and after 1 year of treatment. DNAmGrimAge2 age acceleration was calculated adjusting for chronological age and blood cell composition. Associations with inflammatory biomarkers and clinical measures were assessed using repeated measures correlation. Results: DNAmGrimAge2 was strongly correlated with chronological age at baseline and follow-up. DNAmGrimAge2 age acceleration decreased after ETI treatment, from a median of 1.92 years before treatment to -1.70 years after 1 year (p=0.008). Greater age acceleration was associated with higher IL-6, IL-1{beta}, and calprotectin concentrations. Higher FEV1pp was associated with lower age acceleration, whereas higher sweat chloride was associated with greater age acceleration. Conclusions: DNAmGrimAge2 age acceleration decreased following ETI initiation and was associated with markers of innate and neutrophilic inflammation and CF disease activity. These findings suggest that epigenetic aging in CF may be dynamic and responsive to improvements in CFTR function and inflammatory disease burden. Larger longitudinal studies are needed to validate these findings and determine their relationship with long-term clinical outcomes.

genetics↗

bioRxiv2022

High Quality Phasing Using Linked-Read Whole Genome Sequencing of Patient Cohorts Informs Genetic Understanding of Complex Traits

Phasing of heterozygous alleles is critical for interpretation of cis-effects of disease-relevant variation. For population studies, phase is often inferred from external data but read-based phasing approaches that span long genomic distances would be more accurate because they enable both genotype and phase to be obtained from a single dataset. To demonstrate how read-based phasing can provide functional insights, we sequenced 477 individuals with Cystic Fibrosis (CF) using linked-read sequencing. We benchmark read-based phasing with different short- and long-read sequencing technologies, prioritize linked-read technology as the most informative and produce a benchmark phase call set from reference sample HG002 for the community. The 477 samples display an average phase block N50 of 4.39 Mb. We use these samples to construct a graph representation of CFTR haplotypes, which facilitates understanding of complex CF alleles. Fine-mapping and phasing of the chr7q35 trypsinogen locus associated with CF meconium ileus demonstrates a 20 kb deletion and a PRSS2 missense variant p.Thr8Ile (rs62473563) independently contribute to meconium ileus risk (p=0.0028, p=0.011, respectively) and are PRSS2 pancreas eQTLs (p=9.5e-7 and p=1.4e-4, respectively), explaining the mechanism by which these polymorphisms contribute to CF. Phase enables access to haplotypes that can be used for genome graph or reference panel construction, identification of cis-effects, and for understanding disease associated loci. The phase information from linked-reads provides a causal explanation for variation at a CF-relevant locus which also has implications for the genetic basis of non-CF pancreatitis to which this locus has been reported to contribute.

genetics↗