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

Geng, Xin; Irvin, Marguerite R.; Hidalgo, Bertha; Aslibekyan, Stella; Srinivasasainagendra, Vinodh; An, Ping; Frazier‐Wood, Alexis C.; Tiwari, Hemant K.; Dave, Tushar; Ryan, Kathleen A.; Ordovás, José M.; Straka, Robert J.; Feitosa, Mary F.; Hopkins, Paul N.; Borecki, Ingrid B.; Province, Michael A.; Mitchell, Braxton D.; Arnett, Donna K.; Zhi, Degui

doi:10.1194/jlr.p080333

Cited by 9 publications

(8 citation statements)

References 36 publications

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“…ITGA2 , an ITGA7 homolog, was reported to be associated with coronary atherosclerosis in the Chinese Han population (Wang Y. et al, 2010), drawing attention to the ITGA gene family in the cardiovascular context. We also observed associations between ITGA7 and LDL-C response to fenofibrate in another GOLDN study (Geng et al, 2018). In the conditional analysis after including LDL-C response to fenofibrate as a covariate, ITGA7 is still significantly associated with fasting TG ( P < 0.05).…”

Section: Discussionsupporting

confidence: 69%

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An Exome-Wide Sequencing Study of the GOLDN Cohort Reveals Novel Associations of Coding Variants and Fasting Plasma Lipids

et al. 2019

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Background: Associations of both common and rare genetic variants with fasting blood lipids have been extensively studied. However, most of the rare coding variants associated with lipids are population-specific, and exploration of genetic data from diverse population samples may enhance the identification of novel associations with rare variants. Results: We searched for novel coding genetic variants associated with fasting lipid levels in 894 samples from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) with exome-wide sequencing-based genotype data. In single variant tests, one variant (rs11171663 in ITGA7 ) was associated with fasting triglyceride levels ( P = 7.66E-08), explaining approximately 3.2% of the total trait variance. In gene-based tests, we found statistically significant associations between ITGA7 ( P = 1.77E-07) and SLCO2A1 ( P = 7.18E-07) and triglycerides, as well as between POT1 ( P = 3.00E-07) and low-density lipoprotein cholesterol. In another independent replication cohort consisting of 3,183 African American samples from Hypertension Genetic Epidemiology Network (HyperGEN) and the Genetic Epidemiology Network of Arteriopathy (GENOA), the top genes achieved P -values of 0.04 ( ITGA7 ), 0.08 ( SLCO2A1 ), and 0.02 ( POT1 ). In GOLDN, gene transcript levels of ITGA7 and SLCO2A1 were associated with fasting triglycerides ( P = 0.07 and P = 0.02), highlighting functional relevance of our findings. Conclusion: In this study, we present preliminary evidence of novel rare variant determinants of fasting lipids, and reveal potential underlying molecular mechanisms. Moreover, these results were replicated in an independent cohort. Our findings may inform novel biomarkers of disease risk and treatment targets.

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Section: Discussionsupporting

confidence: 69%

“…The sequencing, genotyping, and quality control procedures were described in a prior study (Geng et al, 2018). Briefly, genomic DNA from peripheral blood nucleated cells was extracted using QIAmp 96 DNA Blood Kits (Qiagen, Hilden, Germany).…”

Section: Methodsmentioning

confidence: 99%

An Exome-Wide Sequencing Study of the GOLDN Cohort Reveals Novel Associations of Coding Variants and Fasting Plasma Lipids

et al. 2019

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“…This study included 422 GOLDN participants who were in the extreme tertiles of the lipid response to the high fat diet intervention and had lipidomics data available. The diet intervention has been described [20].…”

Section: Methodsmentioning

confidence: 99%

The circulating lipidome is largely defined by sex descriptors in the GOLDN, GeneBank and the ADNI studies

Barupal

Zhang

Fan

et al. 2019

Preprint

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Biological sex is one of the major anthropometric factors which influences 21 physiology, metabolism and health status. We have investigated the effect of sexual 22 dimorphism on the blood lipidome profile in three large population level studies -the 23 Alzheimer's disease neuroimaging initiative -ADNI (n =806), the GeneBank 24 Functional Cardio-Metabolomics cohort (n= 1015) and the Genetics of Lipid lowering 25Drugs and Diet Network -GOLDN (n=422). In total, 355 unique lipids from 15 lipid 26 classes were detected across all three studies using LC-MS. Sixty percent of these 27 lipids differed between men and women in all three cohorts, and up to 87% of all 28 lipids demonstrated sex differences in at least one cohort. ChemRICH enrichment 29 statistics on lipid classes showed that phosphatidylcholines, 30 phosphatidylethanolamines, phosphatidylinositols, ceramides, sphingomyelins and 31 cholesterol esters were found at higher levels in female subjects while 32 triacylglycerols and lysophosphatidylcholines were found at higher levels in male 33 participants across the three cohorts. This strong sex effect on the blood lipidome 34suggests that specific regulatory mechanisms may exist that regulate lipid 35 metabolism in a different manner between men and women. Cohort studies involving 36 blood lipidomics should consider separate analyses for male and female participants 37 instead of combined analyses treating sex as a confounding factor. 38 39 phospholipids, triacylglycerol 40 41 Introduction 42Differences between the sexes are one of the fundamental variations in biology [1]. 43Sex disparities in research can ignore discoveries of the biological mechanisms that 44 are specific to particular sex, leading to missing opportunities in developing new sex-45 specific therapeutic strategies[2]. Sex differences have been observed for gut 46 microbiota[3] and transcriptome [4], suggesting that sex-specific strategies for health 47 improvement are needed. 48Metabolomics has been validated for molecular epidemiology to discover risk factors 49 and biological mechanisms for diseases. Several epidemiological studies have 50 investigated biological sex as a main factor to define a person's metabolome. 51Differential network analysis of metabolomics data for 844 healthy subjects 52 suggested a sex-related variability in branched chain amino acids, ketone bodies, All lipid classes were found to be significantly different between men and women in 131 at least one cohort. The most drastic effects were observed for sphingomyelins, 132 triacylglycerol and phosphatidylcholines in the GOLDN and the GeneBank cohorts. 133Triacylglycerols and lysophosphatidylcholines were consistently higher in men 134 across the three cohorts. Ceramides were higher in men in the GOLDN study but 135 not in the ADNI cohort.

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“…The next study to evaluate rare variants at the genome-wide level was performed with the GOLDN cohort [76]. Exome-wide sequencing was used to evaluate associations with fibrate response and interactions with high-fat diets.…”

Section: Candidate Gene Studiesmentioning

confidence: 99%

“…Irvin et al examined the impact of a high-fat diet on drug response in a candidate gene study but did not detect a direct gene-environment-environment interaction [94]. A previous study established that high-fat meals modify fibrate response [76,94], and genetic data from the GOLDN cohort was used to determine the impact of fibrate treatment on the association of APOE genotype differences and association with baseline lipids. The researchers found that while APOE was not directly associated with drug response (change in lipid levels), the association of overall lipid levels with APOE were conserved even after fibrate treatment, with slight mediation of effect sizes.…”

Section: Epistasis Modelingmentioning

confidence: 99%

Fibrate Pharmacogenomics: Expanding Past the Genome

House

Motsinger‐Reif

2020

Pharmacogenomics

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Fibrates are a medication class prescribed for decades as ‘broad-spectrum’ lipid-modifying agents used to lower blood triglyceride levels and raise high-density lipoprotein cholesterol levels. Such lipid changes are associated with a decrease in cardiovascular disease, and fibrates are commonly used to reduce risk of dangerous cardiovascular outcomes. As with most drugs, it is well established that response to fibrate treatment is variable, and this variation is heritable. This has motivated the investigation of pharmacogenomic determinants of response, and multiple studies have discovered a number of genes associated with fibrate response. Similar to other complex traits, the interrogation of single nucleotide polymorphisms using candidate gene or genome-wide approaches has not revealed a substantial portion of response variation. However, recent innovations in technological platforms and advances in statistical methodologies are revolutionizing the use and integration of other ‘omes’ in pharmacogenomics studies. Here, we detail successes, challenges, and recent advances in fibrate pharmacogenomics.

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

Cited by 9 publications

References 36 publications

An Exome-Wide Sequencing Study of the GOLDN Cohort Reveals Novel Associations of Coding Variants and Fasting Plasma Lipids

An Exome-Wide Sequencing Study of the GOLDN Cohort Reveals Novel Associations of Coding Variants and Fasting Plasma Lipids

The circulating lipidome is largely defined by sex descriptors in the GOLDN, GeneBank and the ADNI studies

Fibrate Pharmacogenomics: Expanding Past the Genome

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