Polygenic predisposition modifies the associations of fish oil supplementation with circulating omega-3 fatty acids: A cross-sectional gene-diet interaction study.

BACKGROUND AND AIMS: Several genetic variants have been identified to modify the effects of fish oil supplementation (FOS) on increasing circulating omega-3 fatty acids, but it remains unexplored whether polygenic predisposition to low circulating omega-3 fatty acids modifies these effects. This study aims to test if polygenic scores (PGS) for circulating omega-3 fatty acids modify the associations of FOS with corresponding circulating concentrations. METHODS: We developed PGS models for absolute circulating concentrations of total omega-3 fatty acids (Omega-3), docosahexaenoic acid (DHA), and their relative percentages in total fatty acids (Omega-3% and DHA%), using a multi-ethnic genome-wide association study (N = 136,016). PGS models were validated in 437,803 participants of European (EUR), Central/South Asian (CSA), African, and East Asian genetic ancestries. Linear models tested PGS-by-FOS interactions on corresponding observed circulating concentrations. Discovery analysis was performed separately in 237,380 EUR participants and each non-EUR group. Replication analyses were performed using two secondary exposures (i.e., oily fish intake and dietary omega-3 intake) and in another 178,935 EUR participants. RESULTS: In EUR participants, PGS explained 5.3-11.1% of the phenotypic variance, and significant PGS-by-FOS interactions were detected across all four circulating omega-3 traits. Among participants in the bottom 5% of the PGS distribution, FOS was significantly associated with a 0.40 SD (95% CI: 0.39-0.44) increase in Omega-3. This association effect was 11.1% larger than the population average (β = 0.36; 95% CI: 0.35-0.37; PInt = 0.016) and 42.8% larger than that in participants in the top 5% of the PGS distribution (β = 0.28 SD; 95% CI: 0.25-0.32; PInt = 4.03 × 10-10). These interaction patterns were consistently observed in the CSA ancestry and confirmed in replication and sensitivity analyses. CONCLUSIONS: PGS modify the associations of FOS with circulating omega-3 fatty acids in EUR and CSA populations, with larger FOS effects in participants with lower PGS. These findings support the development of genome-informed precision nutrition.