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.
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This research was funded by NIH National Heart, Lung and Blood Institute grants U01HL072524 (GOLDN recruitment and interventions), R01HL091357 (GOLDN GWAS and lipidomics), R01HL104135 (GOLDN epigenetics), U01HL072515 (HAPI Heart), U01HL084756 (HAPI Heart methods) and U01HL137181 (HAPI Heart computing resources), T32HL007457 (Nicole A Davis) and American Heart Association AHA 15SDG25760020.
Data available on request due to restrictions.
The following are available online at https://www.mdpi.com/article/10.3390/nu13114000/s1, Figure S1. Arachidonic acid, FA (20:4) Manhattan and QQ plot. Figure S2. LPE (16:0) Manhattan and QQ plot; Figure S3. LPE (18:0) Manhattan and QQ plot; Figure S4. LPE (22:6) Manhattan and QQ plot; Figure S5. PC (36:5)A Manhattan and QQ plot; Table S1. GOLDN responsive and heritable lipid species Table S2. Expanded replication on chromosome 9 in HAPI Heart; Table S3. Results of the GOLDN sensitivity analysis; Table S4. Regional epigenetic analysis of GWAS findings from Table 2.
The above materials are also available for download as the additional file listed at the end of this record.
Irvin, Marguerite R.; Montasser, May E.; Kind, Tobias; Fan, Sili; Barupal, Dinesh K.; Patki, Amit; Tanner, Rikki M.; Armstrong, Nicole D.; Ryan, Kathleen A.; Claas, Steven A.; O’Connell, Jeffrey R.; Tiwari, Hemant K.; and Arnett, Donna K., "Genomics of Postprandial Lipidomics in the Genetics of Lipid-Lowering Drugs and Diet Network Study" (2021). Epidemiology and Environmental Health Faculty Publications. 85.