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Genome-wide association study of fish oil supplementation on lipid traits in 81,246 individuals reveals new gene-diet interaction loci
- Source :
- PLoS Genetics, PLoS Genetics, Vol 17, Iss 3, p e1009431 (2021)
- Publication Year :
- 2021
- Publisher :
- Public Library of Science (PLoS), 2021.
-
Abstract
- Fish oil supplementation is widely used for reducing serum triglycerides (TAGs) but has mixed effects on other circulating cardiovascular biomarkers. Many genetic polymorphisms have been associated with blood lipids, including high- and low-density-lipoprotein cholesterol (HDL-C, LDL-C), total cholesterol, and TAGs. Here, the gene-diet interaction effects of fish oil supplementation on these lipids were analyzed in a discovery cohort of up to 73,962 UK Biobank participants, using a 1-degree-of-freedom (1df) test for interaction effects and a 2-degrees-of-freedom (2df) test to jointly analyze interaction and main effects. Associations with P < 1×10−6 in either test (26,157; 18,300 unique variants) were advanced to replication in up to 7,284 participants from the Atherosclerosis Risk in Communities (ARIC) Study. Replicated associations reaching 1df P < 0.05 (2,175; 1,763 unique variants) were used in meta-analyses. We found 13 replicated and 159 non-replicated (UK Biobank only) loci with significant 2df joint tests that were predominantly driven by main effects and have been previously reported. Four novel interaction loci were identified with 1df P < 5×10−8 in meta-analysis. The lead variant in the GJB6-GJB2-GJA3 gene cluster, rs112803755 (A>G; minor allele frequency = 0.041), shows exclusively interaction effects. The minor allele is significantly associated with decreased TAGs in individuals with fish oil supplementation, but with increased TAGs in those without supplementation. This locus is significantly associated with higher GJB2 expression of connexin 26 in adipose tissue; connexin activity is known to change upon exposure to omega-3 fatty acids. Significant interaction effects were also found in three other loci in the genes SLC12A3 (HDL-C), ABCA6 (LDL-C), and MLXIPL (LDL-C), but highly significant main effects are also present. Our study identifies novel gene-diet interaction effects for four genetic loci, whose effects on blood lipids are modified by fish oil supplementation. These findings highlight the need and possibility for personalized nutrition.<br />Author summary We utilized the unprecedentedly large genotype and phenotype dataset in the UK Biobank to perform a genome-wide association study (GWAS) which accounts for the interplay between genotype and dietary intake. We examined the interaction effects of fish oil supplementation on levels of blood lipids (LDL-C, HDL-C, TAGs, and total cholesterol). Our findings were replicated in the Atherosclerosis Risk in Communities (ARIC) Study. We found that at the genetic variant rs112803755 (A>G), the minor allele (G) is associated with a decrease in TAGs among individuals with fish oil supplementation, but is associated with an increase in TAGs among those without supplementation. In other words, only individuals carrying the minor allele benefit from fish oil supplementation in reducing TAG levels. We further analyzed rs112803755 with functional genomics data from the Genotype-Tissue Expression (GTEx) project to identify potential target genes, and found a connexin coding gene which has been previously reported to respond to cellular omega-3 levels. This research suggests that inter-personal variation in TAG response to fish oil supplementation is in part explained by genotype, and that fish oil dose adjustment based on genotype should be investigated as a means to protect against cardiovascular disease risk.
- Subjects :
- Cancer Research
Physiology
Single Nucleotide Polymorphisms
Adipose tissue
Blood lipids
Genome-wide association study
QH426-470
030204 cardiovascular system & hematology
Biochemistry
chemistry.chemical_compound
Mathematical and Statistical Techniques
0302 clinical medicine
Medicine and Health Sciences
Genetics (clinical)
0303 health sciences
Statistics
Chromosome Mapping
Genomics
Metaanalysis
Fish oil
Lipids
Body Fluids
Blood
Cholesterol
Physical Sciences
Anatomy
Research Article
medicine.medical_specialty
Quantitative Trait Loci
Locus (genetics)
Single-nucleotide polymorphism
Biology
Research and Analysis Methods
Polymorphism, Single Nucleotide
03 medical and health sciences
Fish Oils
Quantitative Trait, Heritable
Internal medicine
Genome-Wide Association Studies
Genetics
medicine
Humans
Statistical Methods
Molecular Biology
Alleles
Ecology, Evolution, Behavior and Systematics
030304 developmental biology
Biology and Life Sciences
Computational Biology
Human Genetics
Lipid Metabolism
Genome Analysis
United Kingdom
Minor allele frequency
Endocrinology
chemistry
Genetic Loci
Dietary Supplements
Oils
Mathematics
Genome-Wide Association Study
Subjects
Details
- ISSN :
- 15537404
- Volume :
- 17
- Database :
- OpenAIRE
- Journal :
- PLOS Genetics
- Accession number :
- edsair.doi.dedup.....18e41e29114418a285b602968e13c130