SUN-271 The VITamin D and OmegA-3 TriaL (VITAL): Genetics and Incident Fractures

Abstract M.S. LeBoff: Stock Owner; Self; Johnson &Johnson, Amgen Inc. S.H. Chou: None. D.M. Ratnarajah: None. N.R. Cook: None. F. Giulianini: None. J.E. Buring: None. J.E. Manson: None. D.I. Chasman: None. An estimated 37% of U.S. adults aged ≥60 use vitamin D supplements.1 In an ancillary study to the VITamin D and OmegA-3 TriaL (VITAL) we recently reported that supplemental vitamin D3 (2000 IU/d) vs. placebo did not lower the risk of total, nonvertebral, and hip fractures in 25,871 generally healthy U.S. men (aged ≥50) and women (aged ≥55).2 The aim of this ancillary study in VITAL was to investigate whether any of 128 genetic variants related to 25(OH)D levels identified among 417,580 UK Biobank participants with European ancestry3 modify effects of supplemental vitamin D vs. placebo on incident total fracture outcomes. Genotyping using the Global Screening Array was performed by Erasmus Medical Center Rotterdam (Netherlands), with imputation to the TOPMed reference panel. Incident fractures were self-reported on annual VITAL questionnaires and confirmed by medical record review. The sample for this study was restricted to individuals of European ancestry (verified by genetics) and comprised of nested incident cases of fracture (N= 834) and an age/sex-matched subcohort (N= 847) selected at random from ∼72% of VITAL participants who consented to genetic analysis. This case/subcohort was 68% female with mean (±SD) age of 70.4±6.8 years and BMI of 26.8±5.1 kg/m2. We tested for significant interaction between an additive encoding of genetic variants and randomized vitamin D vs. placebo allocation in association with incident total fractures. We found a variant on chr20, rs2207132 (minor allele frequency 0.04) that interacted statistically with randomized vitamin D allocation to offset a significant risk for fracture in the placebo group from the major allele, in a model adjusted for age, sex, randomized omega-3 supplementation, and eigenvectors of population sub-stratification (main effect: β±SE 1.268±0.169, p=0.0005, p interaction=0.0135). The clinical relevance of this association is currently unknown as this intergenic region has many GWAS hits with an emphasis on liver function. In VITAL, genetic differences in vitamin D-related pathways revealed a genetic profile that may confer a benefit of vitamin D supplementation on fracture risk. Future VITAL studies will focus on an expanded set of pharmacogenetic hypotheses involving effects of supplemental vitamin D on bone and musculoskeletal outcomes. 1.Mishra S, et al. NCHS Data Brief. 2021 2.LeBoff MS, et al. NEJM. 2022 3.Revez JA, et al. Nat Commun. 2020 Sunday, June 2, 2024