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 components.
• PUFAs are measurable in plasma and red blood cell (RBC) membranes, reflecting different dietary exposure times.
• In vivo conversion of short-chain to long-chain PUFAs involves shared metabolic pathways regulated by FADS1, FADS2, and ELOVL2.

Purpose of the Study:

• To investigate the genetically predicted effects of FADS1, FADS2, and ELOVL2 gene expression on RBC and plasma PUFA levels.
• To identify shared genetic variants influencing both gene expression and PUFA biomarker levels using colocalization analysis.

Main Methods:

• Leveraged genome-wide association study (GWAS) summary statistics for RBC and plasma PUFAs.
• Utilized expression quantitative trait loci (eQTL) data to estimate tissue-specific genetically predicted gene expression.
• Employed colocalization analysis to identify shared variants associated with gene expression and PUFA levels in relevant tissues.

Main Results:

• Identified shared genetic variants associated with increased gene expression and altered RBC PUFA levels in adipose, liver, muscle, and whole blood.
• Observed differences in RBC versus plasma PUFA responses to genetically predicted FADS1 and FADS2 expression, particularly for omega-6 PUFAs (linoleic acid and arachidonic acid).
• The variant rs102275 was significantly associated with a 0.69% increase in RBC membrane-bound linoleic acid levels.

Conclusions:

• Genetic factors significantly influence the levels of specific PUFAs in RBC membranes and plasma.
• FADS1 and FADS2 gene expression variations have distinct impacts on omega-6 PUFA levels in RBCs compared to plasma.
• Further genetic studies focusing on long-term PUFA biomarkers are warranted to validate these findings.