AbstractBackground: Recurrent wheeze in early childhood imposes substantial clinical and public-health burden and may presage later asthma. Observational and trial evidence on vitamin D and early wheeze has been suggestive but inconclusive due to confounding, reverse causation, and phenotype heterogeneity.
Objective: To estimate the causal effect of circulating 25-hydroxyvitamin D (25(OH)D) on risk of early-childhood recurrent wheeze using Mendelian randomization (MR).
Methods: We conducted a two-sample MR study using genome-wide significant, linkage-disequilibrium-clumped variants for 25(OH)D from contemporary large GWAS as instruments and harmonized GWAS summary statistics for preschool recurrent wheeze as the outcome. The primary analysis used inverse-variance-weighted (IVW) MR under a multiplicative random-effects model. Robustness was assessed using MR-Egger and weighted-median estimators, heterogeneity (Cochran’s Q), leave-one-out analyses, MR-PRESSO outlier removal, and Steiger directionality tests. Prespecified exploratory analyses examined effect modification by sex and season of birth.
Results: Across 102 independent instruments (mean F≈45; R²≈6.1%), higher genetically proxied 25(OH)D was associated with lower odds of recurrent wheeze. Per 10 ng/mL (~25 nmol/L) higher 25(OH)D, the IVW odds ratio (OR) was 0.88 (95% CI 0.80-0.97; p=0.010); the weighted-median estimator was directionally concordant (OR 0.90, 95% CI 0.81-1.01) and MR-Egger was attenuated with wider uncertainty (OR 0.94, 95% CI 0.76-1.17). Modest heterogeneity was observed without evidence of directional pleiotropy; outlier removal strengthened estimates (IVW OR 0.86, 95% CI 0.78-0.95). Exploratory subgroup patterns suggested larger protective effects among boys and winter births, though interactions were not statistically definitive.
Conclusions: Genetic evidence supports a modest, likely causal protective effect of higher vitamin D status on early-childhood recurrent wheeze. Translational implications include integrating vitamin D sufficiency into maternal-child health strategies, emphasizing safe, guideline-consistent approaches in pregnancy and infancy, and focusing seasonal and high-risk subgroups. Future work should refine pediatric wheeze endotypes, optimize intervention timing and dosing, and expand multi-ancestry analyses to enhance generalizability.
