Genomics of Postprandial Lipidomics in the Genetics of Lipid-Lowering Drugs and Diet Network Study

Abstract

Postprandial lipemia (PPL) is an important risk factor for cardiovascular disease. Inter-individual variation in the dietary response to a meal is known to be influenced by genetic factors, yet genes that dictate variation in postprandial lipids are not completely characterized. Genetic studies of the plasma lipidome can help to better understand postprandial metabolism by isolating lipid molecular species which are more closely related to the genome. We measured the plasma lipidome at fasting and 6 h after a standardized high-fat meal in 668 participants from the Genetics of Lipid-Lowering Drugs and Diet Network study (GOLDN) using ultra-performance liquid chromatography coupled to (quadrupole) time-of-flight mass spectrometry. A total of 413 unique lipids were identified. Heritable and responsive lipid species were examined for association with single-nucleotide polymorphisms (SNPs) genotyped on the Affymetrix 6.0 array. The most statistically significant SNP findings were replicated in the Amish Heredity and Phenotype Intervention (HAPI) Heart Study. We further followed up findings from GOLDN with a regional analysis of cytosine-phosphate-guanine (CpGs) sites measured on the Illumina HumanMethylation450 array. A total of 132 lipids were both responsive to the meal challenge and heritable in the GOLDN study. After correction for multiple testing of 132 lipids (α = 5 × 10−8/132 = 4 × 10−10), no SNP was statistically significantly associated with any lipid response. Four SNPs in the region of a known lipid locus (fatty acid desaturase 1 and 2/FADS1 and FADS2) on chromosome 11 had p < 8.0 × 10−7 for arachidonic acid FA(20:4). Those SNPs replicated in HAPI Heart with p < 3.3 × 10−3. CpGs around the FADS1/2 region were associated with arachidonic acid and the relationship of one SNP was partially mediated by a CpG (p = 0.005). Both SNPs and CpGs from the fatty acid desaturase region on chromosome 11 contribute jointly and independently to the diet response to a high-fat meal.

Holistic Integration of Omics Tools for Precision Nutrition in Health and Disease

“…Similarly, a meta-analysis revealed that higher ABCA1 promoter cg14019050 methylation correlated with lower ABCA1 expression and was concomitantly associated with the C allele of the ABCA1 rs2246293 variant and lower circulating eicosapentaenoic acid [ 17 ]. Genomic, epigenomic, and lipidomic analyses also showed that polymorphisms and methylation sites within the FADS1/2 region influenced the plasma levels of arachidonic acid in response to a high-fat meal in humans [ 18 ]. Of note, genomic assays of post-prandial lipidomic features after dietary fat intake identified potential biomarkers of cardiovascular risk including two polymorphisms in the SORBS1 gene (rs12247017 and rs12240292) affecting b-Sitosterol plasma concentrations [ 19 ].…”