Abstract Rationale Primary ciliary dyskinesia (PCD) pathogenic gene variants disrupt motile cilia, leading to both PCD and asthma through epithelial dysfunction. Asthma shows sex differences, and progesterone regulates ciliary beat frequency, indicating that genetic defects in ciliary proteins may exert sex-dependent effects. Therefore, we hypothesize that rare, pathogenic variants in PCD genes contribute to asthma risk in a sex-specific manner. Methods We performed a rare-variant aggregation analysis of the DNAH11 gene using UK Biobank OQFE exome dosages, with sex-stratified analyses. Within each sex, genotype dosages were coded as individual-level minor allele counts (0-2) and filtered to include variants with a minor allele frequency (MAF) ≤1% and a minor allele count (MAC) ≥5 across the cohort. Asthma phenotypes were defined from a curated dataset (N = 452, 927), excluding COPD and other lung diseases. For each sex, logistic null models adjusted for age were fitted, and gene-level associations for binary outcomes were tested using SKAT, Burden, and SKAT-O. To assess variant-specific influences, we performed leave-one-out (LOO) analyses, sequentially omitting each variant and recalculating p-values. The effect size across the cohort was calculated by fitting a Firth logistic regression comparing carriers to non-carriers, adjusted for age by sex. Finally, sex modification was tested using a Firth model including carrier-by-sex interaction term. Results After filtering, DNAH11 included two rare variants; 7: 21564185-GT and 7: 21591370-GA in each sex (MAF≈1-2x10-5). Among females (N = 245, 718; 28, 649 with asthma), 16 carriers were observed (MAC≈16). Gene-based tests showed a significant association with asthma (Burdenₚ=0. 004; SKAT-Oₚ=0. 005; SKATₚ=0. 013). Firth carrier model OR was 4. 58 (95% CI 1. 62-11. 98, p = 0. 0055) (Figure 1A). LOO analyses (Figure 1B) showed both variants contributed to the signal; removing 7: 21591370-GA increased SKAT-O p to 0. 075 (Δ-log10p≈+1. 15), while removing 7: 21564185-GT increased p to 0. 014 (Δ-log10p≈+0. 41, with the association remaining significant after removing the latter. Among males (N = 207, 209; 20, 777 with asthma), 10 carriers were observed (MAC≈10) with no significant association (Burdenₚ=0. 926; SKAT-Oₚ=0. 797; SKATₚ=0. 668; Firthₚ=0. 781). The carrier-by-sex interaction term in the combined Firth model was not significant (p = 0. 190), suggesting the female-specific signal could not be detected in the males due to limited power. Conclusions This analysis provides primary evidence that these rare, pathogenic variants in the DNAH11 PCD gene may contribute to asthma susceptibility in a sex-specific manner, with a significant association observed only in females. The signal was predominantly driven by 7: 21591370-GA. This suggests that genetic disruption of ciliary function may interact with female-specific hormonal factors (i. e. , progesterone) to influence asthma risk. This abstract is funded by: NIH
Kyriakidou et al. (Fri,) studied this question.