Abstract P494: Gene-Level Gene-Environment Interaction Testing Reveals Rare Variants With Large Impacts on the Omega-3 Fatty Acid-Inflammation Relationship

Dietary omega-3 fatty acid (dN3FA) intake affects plasma N3FA (pN3FA) concentrations, circulating biomarkers of chronic inflammation such as high-sensitivity C-reactive protein (hsCRP), and ultimately cardiometabolic disease risk. Genetic variation may modify the N3FA-inflammation relationship, facilitating applications in precision medicine and possibly explaining variable intervention trial responses. Here, we explored the dual hypothesis that pN3FA mediates the dN3FA-hsCRP relationship and that genetic variants across the frequency spectrum modify this association. Regression models in the UK Biobank (N = 342,120) tested main effects of oily fish intake (a primary dietary source of N3FA; measured by food frequency questionnaire) on hsCRP and its mediation by pN3FA (measured by nuclear magnetic resonance; N = 188,701). Three genome-wide interaction studies tested modification of the dN3FA-hsCRP (“full”), dN3FA-pN3FA (“upstream”), and pN3FA-hsCRP (“downstream”) associations. Regression covariates included demographics, lifestyle indicators, socioeconomic measures, and genetic principal components. Variant-specific GWIS were followed by gene-level enrichment testing using the MAGMA tool. Replication of gene-based signals was conducted in the Women’s Genome Health Study (WGHS; N = 23,294) by testing the interaction of the top variant in each gene with total dN3FA impacting hsCRP. Oily fish intake associated most strongly with hsCRP compared to other questionnaire-based estimates of fish or fish oil intake, with statistical evidence that plasma N3FA mediated approximately 100% of this diet-inflammation relationship. While the “full” genetic interaction analysis did not produce any FDR-significant gene-level interactions, the “upstream” analysis uncovered nine genes, including a cluster containing the biologically-relevant fatty acid desaturases FADS1 and FADS2 , and the “downstream” analysis uncovered four genes. Primary variant interaction effect sizes were small (e.g., -0.02 std. dev. bN3FA / std. dev. fish / allele for the top FADS1 variant rs174560), but in-depth follow-up at these genes revealed allelic spectra including rare variants with substantially larger effects (e.g., -0.11 for a FADS1 missense variant with allele frequency of 0.14%, after conditioning on rs174560). WGHS results supported the overall robustness of the findings (consistent interaction effect signs at 8/10 loci), replicated specific signals (p = 0.04 for FADS1 rs174560), and implicated additional inflammatory biomarkers (e.g., fibrinogen and ICAM-1 for the top GLTSCR1 variant). In conclusion, we report (1) the novel epidemiological finding that pN3FA fully mediates the dN3FA-hsCRP relationship, and (2) specific genes with large-effect rare variants that modify the upstream (absorption) and downstream (inflammatory pathways) components of this relationship.