General and sex-specific effects of vitamin D against atrial fibrillation and young-onset ischemic stroke: a Mendelian randomization series.

Whether vitamin D deficiency causes atrial fibrillation and ischemic stroke of young onset was unknown. We derived a Genetic Risk Score for vitamin D from 3,922 subjects in Hong Kong and applied it in an independent sample (n = 1,297) for clinical outcomes. Primary endpoint was a composite of atrial fibrillation and/or ischemic stroke. A second study was performed in the UK Biobank (n = 392,010; 46% men; 14,878 atrial fibrillation and 4,050 ischemic stroke cases, vs 374,102 controls). After 76 ± 46 months, 240 primary endpoints (18.5%) were adjudicated. Higher genetically-predicted vitamin D independently predicted reduced primary endpoint [odds ratio = 0.83 (0.72 to 0.95), p = 0.008]. Mendelian randomization analyses indicated vitamin D was causally protective against the primary endpoint [odds ratio = 0.81 (95% CI: 0.65 to 0.98)]. Independent analyses in the UK Biobank revealed that vitamin D was protective against young-onset ischemic stroke <50 years and atrial fibrillation combined [odds ratio = 0.36 (95% CI 0.14 to 0.94)], with predominant effect amongst men [odds ratio = 0.28 (95% CI 0.09 to 0.91)] compared to women [odds ratio = 0.60 (95% CI: 0.11 to 3.22)]. In conclusion, vitamin D may protect against young-onset ischemic stroke through preventing atrial fibrillation. Investigating the sex-specifc effects of vitamin D deficiency may elucidate sex disparities of atrial fibrillation in the young.