Abstract
BACKGROUND: Antioxidants can prevent osteoporosis, but the association between serum antioxidants and the cause of osteoporosis remains unknown. We aimed to utilize Mendelian randomization (MR) to determine whether genetically predicted serum levels of diet-derived antioxidants can affect the risk of osteoporosis, to determine the effect of dietary supplementation of antioxidants. METHODS: Genetic variants associated with diet-derived antioxidants were selected from the genome-wide association studies. A total of 12,946 osteoporosis cases and 506,624 healthy controls were obtained from UK Biobank (UKB) and Genetic Factors of Osteoporosis (GEFOS) consortia. We implemented a two-sample MR design and performed several sensitivity analyses to evaluate the causal relationship. RESULTS: In UKB, the genetically predicted higher β-carotene (OR = 0.863, p = 7.37 × 10-6, power = 100%) and γ-tocopherol (OR = 0.701, p = 0.021, power = 5%) had an inverse relationship with osteoporosis. However, only the association of serum β-carotene passed FDR correction. In GEFOS, there were no significant diet-derived antioxidants. The direction of the association of β-carotene with osteoporosis (OR = 0.844, p = 0.106, power = 87%) was consistent with that in the UKB dataset. A fixed-effects meta-analysis confirmed that β-carotene (OR = 0.862, p = 2.21 × 10-6) and γ-tocopherol (OR = 0.701, p = 2.31 × 10-2) could decrease the risk of osteoporosis. To reduce exclusion limit bias, we used total body bone mineral density, lumbar spine bone mineral density and femoral neck bone mineral density as surrogates and found that the genetically elevated circulating β-carotene level could increase total body BMD (beta = 0.043, p-value = 8.26 x 10-5, power = 100%), lumbar spine BMD (beta = 0.226, p-value = 0.001, power = 100%) and femoral neck BMD(beta = 0.118, p-value = 0.016, power = 100%). CONCLUSIONS: We observed that genetically predicted serum β-carotene could elevate BMD and prevent osteoporosis.