Basic/Translational Science -> Genomics: Translational D-AB03 - Inherited arrhythmic disorders: new approaches for understanding of mechanisms and experimental therapies (ID 5) Abstract

D-AB03-06 - Mendelian Randomisation Via An Exome Chip-derived Multi-loci Genetic Instrument Unveiled Role Of Lifelong Vitamin D Deficiency In Atrial Fibrillation And Ischemic Stroke Sequelae (ID 1405)


Background: Vitamin D (Vit-D) deficiency has been linked to Atrial Fibrillation (AF).
Objective: We dissect the role of lifetime Vit-D deficiency in AF-related cardiovascular (CV) sequelae using Mendelian Randomization (MR).
Methods: We used high-throughput exome chip in the Hong Kong TBRS Cohort (n=5180), deriving a 16-alleles Genetic Risk Score (GRS) for prediction of serum Vit-D [(rs4646536, rs10877012, rs1993116, rs2060793, rs2282679, rs4588, rs7041, rs1155563 [F=74,P<0.001])]. We applied GRS in 1297 subjects (age: 67±11 years, 73%M) for prospective analysis. Primary outcome was combined incident ischemic stroke/ CV death. Findings were verified in the UK Biobank as replicating cohort.
Results: Over 77±46 months, 56 primary endpoints (4.3%) occurred. Serum Vit-D negatively predicted primary endpoint (B=0.95 [95%CI 0.91 to 0.99], P=0.018). In K-M analyses, GRS predicted improved event-free survival (GRS≥10 vs 0-5: 190±2 vs 180±3 mths, Log-rank X2=9.1,P=0.011, Fig.). Multi-variable cox regression showed GRS independently predicted reduced primary endpoint (HR=0.84 [95%CI 0.74 to 0.96], P=0.011), with such effect abolished by pre-existed AF (interaction P=0.015). MR analyses revealed lifelong Vitamin D exposure is causally protective against primary endpoint (Wald’s est: OR=0.68 [95%CI: 0.47 to 0.93]). Using UK Biobank as replicating cohort of 392,010 subjects (46%M) that included 14,878 AF cases and 4,050 ischemic stroke, MR revealed that Vit-D was causally protective against young-onset ischemic stroke <50 years and AF combined (OR=0.36 [95%CI 0.14 to 0.94]).
Conclusion: Vit-D may protect against young-onset ischemic stroke and CV death through preventing AF.