Genetically predicted gene expression effects on changes in red blood cell and plasma polyunsaturated fatty acids

Area of Science:

• Human Genetics
• Nutritional Genomics
• Biomarker Discovery

Background:

• Polyunsaturated fatty acids (PUFAs), including omega-3 and omega-6, are essential dietary fats.
• PUFAs can be measured as biomarkers in plasma and red blood cells (RBCs), reflecting different dietary intake periods.
• In vivo conversion of PUFAs involves shared metabolic pathways regulated by FADS and ELOVL genes.

Purpose of the Study:

• To investigate the tissue-specific genetic effects on RBC and plasma PUFA levels.
• To utilize genome-wide association study (GWAS) and expression quantitative trait loci (eQTL) data for gene expression analysis.
• To identify genetic variants influencing the metabolism of omega-3 and omega-6 PUFAs.

Main Methods:

• Leveraged GWAS summary statistics for RBC and plasma PUFAs.
• Employed eQTL analysis to estimate genetically predicted gene expression effects for FADS1, FADS2, and ELOVL2.
• Used colocalization analysis to identify shared variants associated with gene expression and PUFA levels in relevant tissues.

Main Results:

• Identified shared genetic variants influencing both gene expression and RBC PUFA levels in adipose, liver, muscle, and whole blood tissues.
• Observed distinct differences in RBC versus plasma PUFA levels associated with genetically predicted FADS1 and FADS2 expression, especially for omega-6 PUFAs (linoleic acid and arachidonic acid).
• The variant rs102275 was significantly associated with a 0.69% increase in total RBC membrane-bound linoleic acid (P=5.4×10^-12).

Conclusions:

• Genetic regulation of PUFA metabolism differs between RBC membrane and plasma biomarkers.
• Specific genetic variants in FADS genes significantly impact omega-6 PUFA levels, particularly linoleic acid, in RBCs.
• Further genetic studies on long-term PUFA biomarkers are warranted to validate these findings.