Relationship of serum vitamin D levels with atrial fibrillation incidence: The HUNT Study

Abstract Background Evidence on the association between serum vitamin D levels and incidence of atrial fibrillation (AF) was inconclusive. To elucidate the nature of the association, we studied the relationship between serum 25-hydroxyvitamin D (25(OH)D) levels and AF incidence in the Norwegian Trøndelag Health (HUNT) Study using both conventional observational and Mendelian Randomization (MR) approaches. Methods 3394 adult participants without AF diagnoses were followed up from HUNT3 (2006-2008) to 2021 in a prospective cohort. Average serum 25(OH)D levels over ten years between HUNT2 (1995-1997) and HUNT3 were calculated and categorized into <50 and ≥50 nmol/L as exposure. AF diagnoses were retrieved from hospital registers and validated by medical doctors. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI). Furthermore, a one-sample MR was conducted among 36,554 adults who participated in both HUNT2 and HUNT3. An externally weighted genetic risk score based on 19 vitamin D-related genetic variants, chosen for their clear biological functions in serum vitamin D transport, synthesis and metabolism, was used as instrument. We applied the Wald ratio method to assess the causal effect. Results During a median 13-year follow-up, 303 AF cases were diagnosed in the prospective cohort. Serum 25(OH)D level <50.0 nmol/L was associated with a 26% reduced incidence of AF (HR 0.74, 95% CI 0.58 to 0.95), compared to serum 25(OH)D ≥50 nmol/L after adjustment for confounders. Genetically determined 10 nmol/L decrease in serum 25(OH)D level was associated with a 7% reduced incidence of AF (HR 0.93, 95% CI 0.86 to 1.00) in the MR analysis. Sensitivity analyses supported this positive association. Conclusions We found a consistent positive association between serum 25(OH)D level and AF incidence in the Norwegian HUNT population using both observational and MR approaches. Key messages • Serum vitamin D levels appeared to be positively associated with the incidence of AF. • Vitamin D supplementation should be prescribed with caution, especially for people at high risk for AF.