Abstract
Background & aims:Available epidemiological evidence on the associations of individual fatty acids (FAs) with bone mineral density and fracture risk is inconsistent and scarce. We conducted a two-sample Mendelian randomization study to explore these relationships. Methods: Summary-level data from up to 426 824 individuals in UK Biobank for estimated bone mineral density (eBMD) derived from heel quantitative ultrasound and bone fractures were used in this study. Single-nucleotide polymorphisms associated with plasma phospholipid FA levels at genome-wide significance were exploited as instrumental variables. Analyses were conducted using the inverse-variance weighted method. Results:Eight of ten FAs were associated with eBMD and fracture risk. Specifically, genetic predisposition to higher plasma α-linolenic acid, linoleic acid, palmitoleic acid, and oleic acid levels was positively associated with eBMD and inversely associated with the odds of fracture, whereas the opposite directions were observed for plasma arachidonic acid, eicosapentaenoic acid, docosapentanenoic acid, and stearic acid levels. Most of the associations were driven by single-nucleotide polymorphisms within or nearby the FADS1 and FADS2 genes, which explained the largest proportion of variance in FA levels. The associations of arachidonic acid and palmitoleic acid with eBMD remained after exclusion of the variants in the FADS1-FADS2 gene regions. FADS encodes fatty acid desaturases, which have a major role in FA metabolism. Conclusions:Genetic variations in plasma levels of several FAs were associated with eBMD and fracture risk. Variants in FADS1-FADS2 were the major determinants of the observed associations, except the associations of arachidonic acid and palmitoleic acid with eBMD.
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Key Points
Utilizing genetic variants as instrumental variables of exposures in Mendelian randomization (MR) studies can strengthen causal inference on an exposure outcome relationship. The MR
design attenuates confounding because genetic variants are randomly assorted at conception, thereby having no connections to self-adapted lifestyle factors and behaviors. Additionally, reverse causality can be eliminated as allelic randomization precedes the development of disease. Estimated bone mineral density (eBMD) derived from heel quantitative ultrasound is a reliable proxy of BMD and an efficient predictive of fracture. A two-sample MR study to
investigate the association of plasma phospholipid levels of ten individual FAs with eBMD and fracture risk was conducted. In this MR study, genetically higher plasma levels of ALA, LA,
POA, and OA were associated with higher eBMD and lower fracture risk, while higher plasma AA, EPA, DPA and SA levels had opposite effects. All associations except the associations of plasma AA and POA levels with eBMD were driven by SNPs within or nearby the FADS1 and FADS2 genes. No previous study has examined the association of FADS1 or FADS2 genetic
variants with bone mineral density and fracture. In previous work, high red blood cell levels of total n-3 PUFAs, ALA, and EPA were associated with reduced hip fracture risk. The Framingham Osteoporosis Study including 904 older adults also found that ALA intake was significantly
inversely associated with risk of hip fracture. In conclusion, genetic variations in plasma levels of several FAs were associated with eBMD and fracture risk. Variants in or nearby the FADS1 and FADS2 genes were the major determinants of plasma FA levels and of most associations.