(P10-001-23) Circulating Omega-3 Fatty Acids Mediate and Moderate the Effect of FADS on Cardiovascular Biomarkers

Objectives: To determine if the FADS-associated risk for cardiovascular disease (CVD) depends on circulating omega-3 fatty acids (N3FA).

Methods: White UK Biobank participants with circulating FA and outcome data at baseline (N = 96,892) were analyzed cross-sectionally. Linear regression models were used to predict six CVD measures: total cholesterol (TC), log(HDL-c), LDL-c, log(CRP), log(HbA1c), and total triglycerides (log(TG)). Health markers were modeled using an individual’s fatty acid desaturase complex (FADS) genotype (DD, Da, aa), with the addition of N3FA measures as additive or interaction (with FADS) terms to test mediation and moderation hypotheses, respectively. Models were adjusted for demographic and medical history variables.

Results: Across 36 tests, we found 6 mediation and 10 moderation effects of the FADS-health relationship. All tests were statistically significant (p < 0.0001), except where noted. For example, individuals with the recessive haplotype (a) have lower HDL-c (mmol/l) compared to common homozygotes (Adjusted diff (95% CI) HDL: DD vs Da -0.014 [-0.017, -0.011]; DD vs. aa -0.027 [-0.031, -0.023]). After adjusting for circulating DHA levels as a mediator, the association of the genotype with HDL-c substantially lessened for both Da (vs. DD: -0.0032 [-0.0058, -0.0006], p = 0.02) and genotype aa (vs. DD: -0.0031 [-0.0073, 0.00097], p = 0.1). Thus, DHA mediates 77% (Da) to 88% (aa) of the relationships between the minor allele of FADS and HDL-c. Additionally, an individual’s N3FAs can act as a moderator. For example, there is an interaction between total N3FAs and FADS genotypes on TG. With increasing N3FA, DD individuals switch from having the lowest TG to having the highest and aa individuals switch from having the highest TG to having the lowest (Q1: DD vs Da: 0.070 [0.058, 0.081]; DD vs aa: 0.13 [0.11, 0.14]; Q4: DD vs Da: -0.028 [-0.038, -0.018]; DD vs aa: -0.06 [-0.081, -0.039]).

Conclusions: An individual’s N3FA profile may partially ablate the genetic component of disease biomarkers. Cross-sectional evidence suggests individuals with the recessive FADS haplotype benefit most from higher N3FAs and, in some cases, individuals with higher N3FAs appear to benefit more when they have the rare FADS haplotype.

Funding Sources: NIGMS, NHLBI