Enrichment of CYP21A2 Promoter Variant rs150223621 in Congenital Adrenal Hyperplasia Cohorts from the 100 000 Genomes Project
Year: 2026
Type: article
Study design: Observational Study
Abstract: Objective To determine whether non‑coding variation in the CYP21A2 promoter contributes to congenital adrenal hyperplasia (CAH) and to test the functional impact of any enriched variant. Results Whole-genome data from the 100,000 Genomes Project (100k GP) were filtered to produce a case cohort of seven participants with recorded CAH diagnoses and a control cohort of 33,412 individuals. Bioinformatic screening of the 1 kb region upstream of CYP21A2 identified 3 promoter variants in the case cohort. Fisher’s exact testing showed significant enrichment of rs150223621 (NC_000006.12:g.32037495G > A) in confirmed cases versus controls ( p = 2.6 × 10⁻⁵, odds ratio 30.4, 95% CI 6.95–105.5) and versus gnomAD v4.1 ( p = 5.3 × 10⁻⁵, OR 25.2, 95% CI 5.77–87.7). No other variant reached significance. A 1 kb wild-type or rs150223621 promoter fragment was cloned upstream of firefly luciferase and transfected into zebrafish PAC2 cells (9 replicate wells per construct). Two-way repeated-measures ANOVA found no interaction between promoter genotype and luminescence over 30 time points ( p = 0.654); Wilcoxon testing of total luminescence also suggested equivalence ( p = 0.863). Thus, rs150223621 is statistically associated with CAH but did not measurably alter transcript output in this cell model, highlighting the need for additional context-specific assays.
Source: Current Genetic Medicine Reports
Authors: Harrison Gee, Timothy J. Hearn
Institution: University of Cambridge
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,090
OpenAlex ID: W7155978960