scholarly journals An exome-wide sequencing study of lipid response to high-fat meal and fenofibrate in Caucasians from the GOLDN cohort

2018 ◽  
Vol 59 (4) ◽  
pp. 722-729 ◽  
Author(s):  
Xin Geng ◽  
Marguerite R. Irvin ◽  
Bertha Hidalgo ◽  
Stella Aslibekyan ◽  
Vinodh Srinivasasainagendra ◽  
...  
Keyword(s):  
Rare Variants ◽  
Transcript Level ◽  
Lipid Lowering ◽  
Gene Transcript ◽  
High Fat ◽  
Heart Study ◽  
Lipid Response ◽  
Coding Variants ◽  
Fat Meal ◽  
Meal Challenge

Our understanding of genetic influences on the response of lipids to specific interventions is limited. In this study, we sought to elucidate effects of rare genetic variants on lipid response to a high-fat meal challenge and fenofibrate (FFB) therapy in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) cohort using an exome-wide sequencing-based association study. Our results showed that the rare coding variants in ITGA7, SIPA1L2, and CEP72 are significantly associated with fasting LDL cholesterol response to FFB (P = 1.24E-07), triglyceride postprandial area under the increase (AUI) (P = 2.31E-06), and triglyceride postprandial AUI response to FFB (P = 1.88E-06), respectively. We sought to replicate the association for SIPA1L2 in the Heredity and Phenotype Intervention (HAPI) Heart Study, which included a high-fat meal challenge but not FFB treatment. The associated rare variants in GOLDN were not observed in the HAPI Heart study, and thus the gene-based result was not replicated. For functional validation, we found that gene transcript level of SIPA1L2 is associated with triglyceride postprandial AUI (P < 0.05) in GOLDN. Our study suggests unique genetic mechanisms contributing to the lipid response to the high-fat meal challenge and FFB therapy.

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

Nutrients ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 4000
Author(s):  
Marguerite R. Irvin ◽  
May E. Montasser ◽  
Tobias Kind ◽  
Sili Fan ◽  
Dinesh K. Barupal ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Fatty Acid ◽  
Fatty Acid Desaturase ◽  
Lipid Lowering ◽  
Chromosome 11 ◽  
High Fat ◽  
Lipid Lowering Drugs ◽  
Lipid Species ◽  
Lipid Response ◽  
Fat Meal

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.

scholarly journals Genome-wide association study of triglyceride response to a high-fat meal among participants of the NHLBI Genetics of Lipid Lowering Drugs and Diet Network (GOLDN)

Metabolism ◽  
2015 ◽  
Vol 64 (10) ◽  
pp. 1359-1371 ◽  
Author(s):  
Mary K. Wojczynski ◽  
Laurence D. Parnell ◽  
Toni I. Pollin ◽  
Chao Q. Lai ◽  
Mary F. Feitosa ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Lipid Lowering ◽  
High Fat ◽  
Lipid Lowering Drugs ◽  
Genome Wide ◽  
Fat Meal

scholarly journals High-fat meal effect on LDL, HDL, and VLDL particle size and number in the Genetics of Lipid-Lowering drugs and diet network (GOLDN): an interventional study

2011 ◽  
Vol 10 (1) ◽  
pp. 181 ◽  
Author(s):  
Mary K Wojczynski ◽  
Stephen P Glasser ◽  
Albert Oberman ◽  
Edmond K Kabagambe ◽  
Paul N Hopkins ◽  
...  
Keyword(s):  
Particle Size ◽  
Lipid Lowering ◽  
High Fat ◽  
Interventional Study ◽  
Lipid Lowering Drugs ◽  
Vldl Particle ◽  
Meal Effect ◽  
Fat Meal

Postprandial Lipid Response Following a High Fat Meal in Rats Adapted to Dietary Fiber

1992 ◽  
Vol 122 (2) ◽  
pp. 219-228 ◽  
Author(s):  
Carol L. Redard ◽  
Paul A. Davis ◽  
Suzette J. Middleton ◽  
Barbara O. Schneeman
Keyword(s):  
Dietary Fiber ◽  
High Fat ◽  
Lipid Response ◽  
Postprandial Lipid ◽  
Fat Meal

scholarly journals Effects of a High Fat Meal Challenge with Different Doses of Spice Blend on Postprandial Fatty Acid Suppression (P08-094-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Jessica Anto ◽  
Rachel Walker ◽  
Ester Oh ◽  
Connie Rogers ◽  
Kristina Petersen ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Unsaturated Fatty Acids ◽  
Saturated Fatty Acids ◽  
Saturated Fat ◽  
High Fat ◽  
Insulin Resistant ◽  
Funding Sources ◽  
Penn State ◽  
Fat Meal ◽  
Meal Challenge

Abstract Objectives High fat meals can increase inflammation and plasma triglycerides. Poor suppression of postprandial adipocyte lipolysis results in higher levels of non-esterified fatty acids (NEFA) in insulin resistant subjects. This impaired suppression of NEFA may exacerbate hypertriglyceridemia following a high fat meal by increasing available fatty acids. We have shown myristic acid (MA) and stearic acid (SA) are less suppressed than other fatty acids 1 hour following a glucose challenge, and this pattern may indicate optimal adipocyte insulin sensitivity. It is unknown if the same pattern occurs in other contexts, such as high fat meal. Methods Plasma samples were collected from 12 obese male subjects at baseline and 4 time points following a high fat meal (1076 kcal, 39% kcal from saturated fat) on three visits. Meals contained either 0, 2, or 6 grams of a spice blend. Plasma was analyzed by GC-MS to measure multiple fatty acids, including MA, SA, palmitic acid (PA), oleic acid (OA), and linoleic acid (LA). Results At 1 hour following the high fat meal, MA and SA were less suppressed than OA, PA, and LA (P < 0.0001). Total NEFA concentrations were most suppressed (61%; CI: 46%, 76%) at 2 hours following the meal and remained suppressed until 4 hours. PA (59%, P < 0.0001), SA (43%, P < 0.001), OA (68%, P < 0.0001), and LA (71%, P < 0.0001) also achieved maximal suppression at 2 hours and remained suppressed. MA was suppressed (34%, P = 0.0002) at 1 hour, then returned to baseline. Compared to baseline, all saturated fatty acids increased as % of total NEFA at 2 hours (MA: 0 hr, 1.8%, 2 hr, 3.7%, P < 0.0001; PA: 0 hr, 24%, 2 hr, 26%, P = 0.009; SA: 0 hr, 8%, 2 hr, 12%, P < 0.0001), while the unsaturated fatty acids decreased (OA: 0 hr, 33%, 2 hr, 25%, P < 0.0001; LA: 0 hr, 24%, 2 hr, 19%, P < 0.0001). There was no significant effect of spice. Conclusions NEFA was most suppressed at 2 hours following a high fat meal challenge, but MA and SA were suppressed less than all other fatty acids. Saturated fatty acids increased as a % of total NEFA following the meal challenge, while unsaturated fatty acids decreased. These data support our previous findings that MA and SA are less suppressed by insulin than other fatty acids. Funding Sources McCormick Science Institute; Penn State Department of Nutritional Sciences; National Center for Advancing Translational Sciences, NIH, (UL1 TR002014).

Abstract P328: Genetic Variants Involved in Postprandial Triglyceride Metabolism are Modified by Fenofibrate Treatment in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study

Circulation ◽  
2012 ◽  
Vol 125 (suppl_10) ◽  
Author(s):  
Mary K Wojczynski ◽  
Laurence D Parnell ◽  
M R Irvin ◽  
Robert J Straka ◽  
Jose M Ordovas ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Repeated Measures ◽  
Linkage Disequilibrium Block ◽  
Dietary Factors ◽  
Lipid Lowering ◽  
High Fat ◽  
Gene Effects ◽  
Postprandial Triglyceride ◽  
Before And After ◽  
Fat Meal

Genetic variants associated with fasting plasma triglycerides (TG) have been reported in the literature. Less is known about genetic variants influencing TG response to dietary factors, specifically a fat challenge (postprandial lipemia, PPL). Additionally, little is known about genetic variants associated with response to pharmacologic agents, such as fenofibrate (FFB), which are used to reduce plasma levels of TG. Preliminary genome-wide association (GWA) analyses on three interventions: 1) FFB; 2) PPL before FFB; and 3) PPL after FFB, implicated different genetic variants associated with the TG response. Therefore, we hypothesized that FFB treatment modifies gene effects on TG response to a dietary postprandial fat challenge. We analyzed participants (N=693) from the GOLDN study who ingested a standardized high-fat meal containing 83% fat and 700 calories/m2 both before and after 3 weeks of daily FFB treatment, thereby having two postprandial plasma TG assessments. Plasma TG was measured at baseline, 3.5 hrs, and 6 hrs after each high-fat meal. The area under the curve (AUC) describing the change in plasma TG concentration over the PPL period was calculated using the trapezoid method. Standardized TG AUC residuals were obtained by using a growth curve method and a stepwise regression approach, retaining covariate terms (age, age2, age3, sex, field center, baseline TG, and principle components (EIGENSTRAT)) that were significant at 5% level. A GWA scan of ∼2.5 million typed or imputed single nucleotide polymorphisms (SNPs) was undertaken to identify gene by FFB treatment interaction effects on the TG AUC PPL response using a repeated measures mixed model with a random effect to adjust for family relatedness. The GWA model included a SNP effect, FFB effect (before or after treatment), and an interaction term (SNP*FFB). For TG AUC residuals, we found GWA significant associations with 8 variants in LDLRAD3 (11p13) for the SNP*FFB term (p<5E-08), and the accompanying main effect terms had suggestive (p<1E-05) associations. These 8 variants are in one linkage disequilibrium block, and indicate that FFB interacts with these variants to decrease their independent effects on TG AUC. In analyses using only the SNP, these 8 variants had p-values <0.005 for TG response to PPL both before and after FFB. SNPs in this group associate with expression of CD44, a molecule which binds osteopontin which is an activator of human adipose tissue macrophages and adipocyte function. This analysis highlights a new gene implicated in TG metabolism whose effect on dietary TG responses to fat ingestion is modified by FFB, possibly by acting through CD44. Further investigation into this gene region is needed in order to enhance our understanding of the underlying mechanistic processes involved in TG metabolism during the postprandial state and the effect of FFB treatment.

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