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Genomics of post-prandial lipidomic phenotypes in the Genetics of Lipid lowering Drugs and Diet Network (GOLDN) study.

Irvin MR, Zhi D, Aslibekyan S, Claas SA, Absher DM, Ordovas JM, Tiwari HK, Watkins S, Arnett DK - PLoS ONE (2014)

Bottom Line: After the PPL challenge, fatty acids increased as well as sterols associated with cholesterol absorption, while sterols associated with cholesterol synthesis decreased.Two SNPs (rs12247017 and rs12240292) in the sorbin and SH3 domain containing 1 (SORBS1) gene were associated with b-Sitosterol after correction for multiple testing (P≤4.5*10(-10)).Integration of lipidomic and genomic data has the potential to identify new biomarkers of CVD risk.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.

ABSTRACT

Background: Increased postprandial lipid (PPL) response to dietary fat intake is a heritable risk factor for cardiovascular disease (CVD). Variability in postprandial lipids results from the complex interplay of dietary and genetic factors. We hypothesized that detailed lipid profiles (eg, sterols and fatty acids) may help elucidate specific genetic and dietary pathways contributing to the PPL response.

Methods and results: We used gas chromatography mass spectrometry to quantify the change in plasma concentration of 35 fatty acids and 11 sterols between fasting and 3.5 hours after the consumption of a high-fat meal (PPL challenge) among 40 participants from the GOLDN study. Correlations between sterols, fatty acids and clinical measures were calculated. Mixed linear regression was used to evaluate associations between lipidomic profiles and genomic markers including single nucleotide polymorphisms (SNPs) and methylation markers derived from the Affymetrix 6.0 array and the Illumina Methyl450 array, respectively. After the PPL challenge, fatty acids increased as well as sterols associated with cholesterol absorption, while sterols associated with cholesterol synthesis decreased. PPL saturated fatty acids strongly correlated with triglycerides, very low-density lipoprotein, and chylomicrons. Two SNPs (rs12247017 and rs12240292) in the sorbin and SH3 domain containing 1 (SORBS1) gene were associated with b-Sitosterol after correction for multiple testing (P≤4.5*10(-10)). SORBS1 has been linked to obesity and insulin signaling. No other markers reached the genome-wide significance threshold, yet several other biologically relevant loci are highlighted (eg, PRIC285, a co-activator of PPARa).

Conclusions: Integration of lipidomic and genomic data has the potential to identify new biomarkers of CVD risk.

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Related in: MedlinePlus

Manhattan plots for markers with P< 0.0001 from epigenome-wide association study and genome-wide association study.Phenotypes include 11 postprandial sterols and 35 postprandial fatty acids after adjustment for fasting concentration.
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pone-0099509-g003: Manhattan plots for markers with P< 0.0001 from epigenome-wide association study and genome-wide association study.Phenotypes include 11 postprandial sterols and 35 postprandial fatty acids after adjustment for fasting concentration.

Mentions: Manhattan plots of association signals with P<1.0*10−4 from EWAS and GWAS of postprandial sterols and fatty acids (adjusted for fasting concentrations) are presented in Figure 3. For a complete list of all CpGs and SNPs (including annotations) shown in Figure 3, see Spreadsheet S2. Table 3 highlights GWAS and EWAS results from the postprandial analysis of sterols and fatty acids with P<1.0*10−7. No marker in EWAS or GWAS was statistically significantly associated with any PPL sterol or fatty acid after correction for multiple testing. Marginally significant sterol GWAS signals included 5 markers on chromosome 14 associated with coprostanol that were not near (within 200kb up or downstream) any characterized gene. Four SNPs on chromosome 5 were also associated with postprandial coprostanol concentration after adjustment for fasting concentration. The region is gene rich and the 4 SNPs lie in intron 1 of an alternate transcript of the Kv channel interacting protein 1 (KCNIP1) gene in addition to intron 1 of a smaller overlapping gene known as potassium large conductance calcium-activated channel, subfamily M, beta member 1 (KCNMB1). No CpGs were associated with any postprandial sterol with P<1.0*10−7 and, thus, are not represented in Table 3. The SNP rs666566 in the microtubule-associated protein 6 (MAP6) gene associated with docosahexaenoic acid (DHA) was the top hit for the fatty acid GWAS. The same SNP was also associated with 7a-hydroxycholesterol. Another SNP (rs685448) in MAP6 was associated with DHA with P = 1.5*10−7 and with 7a-hydroxycholesterol with P = 9.5*10−5. A group of SNPs (rs16843235, rs2759275, rs16843150) upstream of ATPase, H+ transporting, lysosomal 13kDa, V1 subunit G3 (ATP6V1G3) were associated with palmitelaidic acid. Finally, two CpGs are highlighted in Table 3 for fatty acids, the first (cg15718583) with DGLA in the EPH receptor B3 (EPHB3) gene and another (cg03758021) with mead acid in the PPARA interacting complex 285 (PRIC285) gene.


Genomics of post-prandial lipidomic phenotypes in the Genetics of Lipid lowering Drugs and Diet Network (GOLDN) study.

Irvin MR, Zhi D, Aslibekyan S, Claas SA, Absher DM, Ordovas JM, Tiwari HK, Watkins S, Arnett DK - PLoS ONE (2014)

Manhattan plots for markers with P< 0.0001 from epigenome-wide association study and genome-wide association study.Phenotypes include 11 postprandial sterols and 35 postprandial fatty acids after adjustment for fasting concentration.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4048279&req=5

pone-0099509-g003: Manhattan plots for markers with P< 0.0001 from epigenome-wide association study and genome-wide association study.Phenotypes include 11 postprandial sterols and 35 postprandial fatty acids after adjustment for fasting concentration.
Mentions: Manhattan plots of association signals with P<1.0*10−4 from EWAS and GWAS of postprandial sterols and fatty acids (adjusted for fasting concentrations) are presented in Figure 3. For a complete list of all CpGs and SNPs (including annotations) shown in Figure 3, see Spreadsheet S2. Table 3 highlights GWAS and EWAS results from the postprandial analysis of sterols and fatty acids with P<1.0*10−7. No marker in EWAS or GWAS was statistically significantly associated with any PPL sterol or fatty acid after correction for multiple testing. Marginally significant sterol GWAS signals included 5 markers on chromosome 14 associated with coprostanol that were not near (within 200kb up or downstream) any characterized gene. Four SNPs on chromosome 5 were also associated with postprandial coprostanol concentration after adjustment for fasting concentration. The region is gene rich and the 4 SNPs lie in intron 1 of an alternate transcript of the Kv channel interacting protein 1 (KCNIP1) gene in addition to intron 1 of a smaller overlapping gene known as potassium large conductance calcium-activated channel, subfamily M, beta member 1 (KCNMB1). No CpGs were associated with any postprandial sterol with P<1.0*10−7 and, thus, are not represented in Table 3. The SNP rs666566 in the microtubule-associated protein 6 (MAP6) gene associated with docosahexaenoic acid (DHA) was the top hit for the fatty acid GWAS. The same SNP was also associated with 7a-hydroxycholesterol. Another SNP (rs685448) in MAP6 was associated with DHA with P = 1.5*10−7 and with 7a-hydroxycholesterol with P = 9.5*10−5. A group of SNPs (rs16843235, rs2759275, rs16843150) upstream of ATPase, H+ transporting, lysosomal 13kDa, V1 subunit G3 (ATP6V1G3) were associated with palmitelaidic acid. Finally, two CpGs are highlighted in Table 3 for fatty acids, the first (cg15718583) with DGLA in the EPH receptor B3 (EPHB3) gene and another (cg03758021) with mead acid in the PPARA interacting complex 285 (PRIC285) gene.

Bottom Line: After the PPL challenge, fatty acids increased as well as sterols associated with cholesterol absorption, while sterols associated with cholesterol synthesis decreased.Two SNPs (rs12247017 and rs12240292) in the sorbin and SH3 domain containing 1 (SORBS1) gene were associated with b-Sitosterol after correction for multiple testing (P≤4.5*10(-10)).Integration of lipidomic and genomic data has the potential to identify new biomarkers of CVD risk.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.

ABSTRACT

Background: Increased postprandial lipid (PPL) response to dietary fat intake is a heritable risk factor for cardiovascular disease (CVD). Variability in postprandial lipids results from the complex interplay of dietary and genetic factors. We hypothesized that detailed lipid profiles (eg, sterols and fatty acids) may help elucidate specific genetic and dietary pathways contributing to the PPL response.

Methods and results: We used gas chromatography mass spectrometry to quantify the change in plasma concentration of 35 fatty acids and 11 sterols between fasting and 3.5 hours after the consumption of a high-fat meal (PPL challenge) among 40 participants from the GOLDN study. Correlations between sterols, fatty acids and clinical measures were calculated. Mixed linear regression was used to evaluate associations between lipidomic profiles and genomic markers including single nucleotide polymorphisms (SNPs) and methylation markers derived from the Affymetrix 6.0 array and the Illumina Methyl450 array, respectively. After the PPL challenge, fatty acids increased as well as sterols associated with cholesterol absorption, while sterols associated with cholesterol synthesis decreased. PPL saturated fatty acids strongly correlated with triglycerides, very low-density lipoprotein, and chylomicrons. Two SNPs (rs12247017 and rs12240292) in the sorbin and SH3 domain containing 1 (SORBS1) gene were associated with b-Sitosterol after correction for multiple testing (P≤4.5*10(-10)). SORBS1 has been linked to obesity and insulin signaling. No other markers reached the genome-wide significance threshold, yet several other biologically relevant loci are highlighted (eg, PRIC285, a co-activator of PPARa).

Conclusions: Integration of lipidomic and genomic data has the potential to identify new biomarkers of CVD risk.

Show MeSH
Related in: MedlinePlus