General and Sex-Specific Effects of Vitamin D Against Atrial Fibrillation and Young-Onset Ischemic Stroke: A Mendelian Randomization Series

Background: Whether vitamin D deficiency causes atrial fibrillation and ischemic stroke of young onset <50 years was unknown. Methods: We derived a Genetic Risk Score for vitamin D by high-throughput exome chip analysis from 3922 subjects in the University of Hong Kong-Theme Based Research Cohort (rs2060793, rs4588, rs7041, [F-statistic=50.5, P<0.001]), and applied it in an independent sample of 1297 Chinese subjects (age: 67.0 +/- 10.6 years, 73% male) on clinical outcomes. Primary endpoint was a composite of atrial fibrillation and/ or ischemic stroke. A second study was performed to investigate generalisability and sex-specific effects in the UK Biobank (n=392,010; 46% men; 14,878 atrial fibrillation and 4,050 ischemic stroke cases, versus 374,102 controls). Results: After follow-up over 76 +/- 46 months, 240 primary endpoints (18.5%) were adjudicated. Higher genetically-predicted vitamin D independently predicted reduced odds of atrial fibrillation and/or ischemic stroke (OR=0.83 [0.72 to 0.95], P=0.008). Mendelian randomization analyses indicated vitamin D was causally protective against primary endpoint in Chinese (OR=0.81 [95%CI: 0.65 to 0.98]). An independent analysis in the UK Biobank revealed that vitamin D was generally protective against pre-specified 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]). Conclusions: Vitamin D may protect against young-onset ischemic stroke through preventing atrial fibrillation. Investigating the sex-specifc effects of vitamin D deficiency may potentially elucidate sex disparities of atrial fibrillation in the young.