Plasma phospholipid fatty acids, bone mineral density and fracture risk: Evidence from a Mendelian randomization study

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.

Keywords: Bone mineral density; Diet; Fatty acids; Fracture; Mendelian randomization.