Do FADS1 rs174537 and FADS2 rs174575 variants alter desaturase activity and omega fatty acid levels?

The FADS1 and FADS2 genes encode delta-5 (D5D) and delta-6 (D6D) desaturases, the rate-limiting enzymes responsible for converting plant-derived precursor fatty acids into long-chain polyunsaturated fatty acids (LC-PUFAs). Genetic variations in this cluster, specifically the FADS1 rs174537 and FADS2 rs174575 polymorphisms, are major determinants of individual lipid profiles and metabolic efficiency.

Impact on enzyme activity and lipid profiles

• Carrying the minor T allele of FADS1 rs174537 or minor alleles of FADS2 rs174575 results in significantly reduced D5D and D6D enzymatic activities.
• This diminished activity shifts metabolic conversion rates, resulting in an accumulation of precursor plant oils (such as linoleic acid) and lower circulating levels of long-chain omega-6 and omega-3 fatty acids, including arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). This is highly reflected in altered precursor-to-product desaturase indices, such as a decreased AA to dihomo-gamma-linolenic acid (AA/DGLA) ratio.

Molecular and inflammatory mechanisms

• At the genomic level, the rs174537 variant is strongly associated with allele-specific DNA methylation in a putative enhancer region located between FADS1 and FADS2, directly linking genetic variation to epigenetic regulation of gene expression.
• These shifted LC-PUFA profiles directly modulate downstream inflammatory pathways. Specifically, altered availability of arachidonic acid changes the production of eicosanoids and key mediators, affecting the synthesis of 5-lipoxygenase products like leukotriene B4 and 5-HETE.

Bottom line

• Bottom line: Strong scientific evidence confirms that FADS1 rs174537 and FADS2 rs174575 variants alter fatty acid desaturase activity through epigenetic modifications, directly reducing circulating long-chain omega-3 and omega-6 levels and shifting downstream inflammatory mediator profiles.