Ignite Creation Date:
2024-05-06 @ 11:12 AM
Last Modification Date:
2024-10-26 @ 12:41 PM
Study NCT ID:
NCT03452787
Status:
COMPLETED
Last Update Posted:
2018-03-02
First Post:
2018-01-29
Brief Title:
Epigenomic and Metabolomic Signatures of APOA2 Gene by Saturated Fat Interaction
Sponsor:
Tufts University
Organization:
Tufts University
Study Overview
Official Title:
Meta Analysis of Epigenomic and Metabolomic Signatures of APOA2 Gene by Saturated Fat
Status:
COMPLETED
Status Verified Date:
2018-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Obesity is driven by genetic and environmental factors Among the latter diet is a most important one The investigators refer to these combinations of genetic and dietary factors as gene-diet interactions Higher consumption of saturated fats found mostly in foods of animal origin has been associated with higher weight in people who were homozygotes for the minor allele at a genetic variant known as APOA2 -265 TC rs5082 In the current study the investigators will seek to gain an understanding of the biological mechanisms driving this interaction The investigators will select participants in three cohorts according to this genetic factor and conduct a series of molecular analyses epigenetics transcriptomics and metabolomics The analyses will identify epigenetic marks that are associated with saturated fat intake exclusively in subjects who carry this genetic factor Moreover the investigators will examine the association between epigenetic status and genotype at APOA2 and mRNA expression of the gene and concentrations of metabolites in the blood This study will increase the understanding of how genetics and diet act together to promote weight gain and may eventually have implications for dietary recommendations that make use of genetic information
Detailed Description:
Background Apolipoprotein A-II APOA2 is a significant constituent of high-density lipoproteins HDL with an undefined biological role A putative functional variant -265 TC rs5082 within the APOA2 promoter has been shown consistently to interact with saturated fat SFA intake to influence the risk of obesity
Objective This study will implement an integrative approach to characterize the molecular basis of this interaction
Design The investigators will conduct an epigenome-wide scan on 80 participants carrying either the rs5082 less common genotype CC or the most common genotype TT and consuming either a low 22 gd or high 22 gd SFA diet matched for age sex BMI and diabetes status in the Boston Puerto Rican Health Study BPRHS The investigators then will validate the findings in selected participants in the Genetics of Lipid Lowering Drugs and Diet Network GOLDN n379 and the Framingham Heart Study FHS n243 Transcription and metabolomics analyses will be conducted to determine the relationship between epigenetic status APOA2 mRNA expression and blood metabolites
Data sources The Boston Puerto Rican Health Study BPRHS the Genetics of Lipid Lowering Drugs and Diet Network GOLDN and the Framingham Heart Study FHS Study selection In BPRHS 40 participants with CC genotype at APOA2 -265TC rs5082 will be selected with 20 reporting a low SFA intake 22 gd and 20 indicating a high SFA intake 22 gd By matching age sex SFA intake type 2 diabetes status and BMI for the 40 participants with CC genotype the second set of 40 participants with TT genotype of APOA2 -265TC will be selected from the same population In GOLDN 107 participants with CC genotype and 272 with TT genotype for APOA2 -265TC who were not taking medication for hypertension dyslipidemia or diabetes will be selected to validate the findings from BPRHS In FHS the investigators will include 73 unrelated participants with CC genotype and 170 with TT genotype at APOA2 -265TC who did not take medication for hypertension dyslipidemia or diabetes Participants of each genotype will be further divided into two subgroups based on SFA intake low 22 gramsday high 22 gramsday
Data Extraction Genome-wide DNA methylation of isolated DNA samples in BPRHS and GOLDN was quantified using Illumina Infinium human methylation 450K arrays Illumina San Diego CA USA The methylation signal at each methylation site will be estimated as a β score the proportion of total methylation-specific signal and the detection P-value as the probability that total intensity for a given probe falls within the background signal intensity after normalization and quantity control check FHS methylome data from dbGaP accessionphg000492v2 where methylation statuses of 2741 participants were measured in samples taken from participants attending their exam 8 visit between 2005 and 2008 using Illumina Infinium human methylation 450K array Methylation signals will be processed and normalized as for BPRHS and GOLDN The investigators will obtain FHS transcriptome data from dbGaP under accession phe00002v6 Metabolic profiling of plasma samples from those 80 participants of BPRHS for whom the methylome analysis will be performed by Metabolon Inc Durham NC USA Outcomes Body mass index will be the only outcome Data Synthesis 1 Epigenome-wide analysis of APOA2 genotype by high and low SFA intake will be conducted in 80 matched casecontrol participants of BPRHS replicated in selected participants of GOLDN and FHS using linear mixed models 2 A meta-analysis of the results from the three populations will be conducted using the meta R packageThe comparison of allelic effect beta of APOA2 -265TC from the meta-analysis between low and high SFA intake will be conducted with SAS 94 using a t-test 3 Associations between epigenetic variants and APOA2 genotypes with APOA2 mRNA expression will be tested in FHS 4 Metabolome analysis will be conducted in the same 80 matched casecontrol participants of BPRHS and metabolites will be correlated with epigenetic variants at APOA2 locus 5 Enriched metabolic pathways will be examined in relation to identified epigenetic variants at APOA2 region
Knowledge translation plan The results will be disseminated through interactive presentations at local national and international scientific meetings and publication in high impact factor journals Target audiences will include the public health and scientific communities with interest in nutrition diabetes obesity and cardiovascular disease Feedback will be incorporated and used to improve the public health message and key areas for future research will be defined ApplicantCo-applicant Decision Makers will network among opinion leaders to increase awareness and participate directly as committee members in the development of future guidelines
Preliminary findings In BPRHS the investigators identified methylation site cg04436964 as exhibiting significant differences between CC and TT participants consuming a high SFA diet but not among those consuming low SFA Similar results were observed in GOLDN and FHS Additionally in FHS cg04436964 methylation was negatively correlated with APOA2 expression in participants consuming a high SFA diet Furthermore when consuming a high SFA diet CC carriers had lower APOA2 expression compared to those with the TT genotype but expression levels were similar when consuming a low SFA diet Lastly the metabolomic analysis identified four pathways as overrepresented by metabolite differences between CC and TT genotypes with high SFA intake
Significance The investigators will apply multi-omics approaches to investigate the mechanistic foundations of the APOA2 -265TC genotype by SFA interaction linked to the disruptive condition of obesity the investigators may uncover plausible dysregulation of several metabolic pathways This study will illustrate the effectiveness of multiple omics approaches to well-established gene-diet interactions and contribute new evidence to ongoing explorations of the impact of saturated fat on human health
Objective This study will implement an integrative approach to characterize the molecular basis of this interaction
Design The investigators will conduct an epigenome-wide scan on 80 participants carrying either the rs5082 less common genotype CC or the most common genotype TT and consuming either a low 22 gd or high 22 gd SFA diet matched for age sex BMI and diabetes status in the Boston Puerto Rican Health Study BPRHS The investigators then will validate the findings in selected participants in the Genetics of Lipid Lowering Drugs and Diet Network GOLDN n379 and the Framingham Heart Study FHS n243 Transcription and metabolomics analyses will be conducted to determine the relationship between epigenetic status APOA2 mRNA expression and blood metabolites
Data sources The Boston Puerto Rican Health Study BPRHS the Genetics of Lipid Lowering Drugs and Diet Network GOLDN and the Framingham Heart Study FHS Study selection In BPRHS 40 participants with CC genotype at APOA2 -265TC rs5082 will be selected with 20 reporting a low SFA intake 22 gd and 20 indicating a high SFA intake 22 gd By matching age sex SFA intake type 2 diabetes status and BMI for the 40 participants with CC genotype the second set of 40 participants with TT genotype of APOA2 -265TC will be selected from the same population In GOLDN 107 participants with CC genotype and 272 with TT genotype for APOA2 -265TC who were not taking medication for hypertension dyslipidemia or diabetes will be selected to validate the findings from BPRHS In FHS the investigators will include 73 unrelated participants with CC genotype and 170 with TT genotype at APOA2 -265TC who did not take medication for hypertension dyslipidemia or diabetes Participants of each genotype will be further divided into two subgroups based on SFA intake low 22 gramsday high 22 gramsday
Data Extraction Genome-wide DNA methylation of isolated DNA samples in BPRHS and GOLDN was quantified using Illumina Infinium human methylation 450K arrays Illumina San Diego CA USA The methylation signal at each methylation site will be estimated as a β score the proportion of total methylation-specific signal and the detection P-value as the probability that total intensity for a given probe falls within the background signal intensity after normalization and quantity control check FHS methylome data from dbGaP accessionphg000492v2 where methylation statuses of 2741 participants were measured in samples taken from participants attending their exam 8 visit between 2005 and 2008 using Illumina Infinium human methylation 450K array Methylation signals will be processed and normalized as for BPRHS and GOLDN The investigators will obtain FHS transcriptome data from dbGaP under accession phe00002v6 Metabolic profiling of plasma samples from those 80 participants of BPRHS for whom the methylome analysis will be performed by Metabolon Inc Durham NC USA Outcomes Body mass index will be the only outcome Data Synthesis 1 Epigenome-wide analysis of APOA2 genotype by high and low SFA intake will be conducted in 80 matched casecontrol participants of BPRHS replicated in selected participants of GOLDN and FHS using linear mixed models 2 A meta-analysis of the results from the three populations will be conducted using the meta R packageThe comparison of allelic effect beta of APOA2 -265TC from the meta-analysis between low and high SFA intake will be conducted with SAS 94 using a t-test 3 Associations between epigenetic variants and APOA2 genotypes with APOA2 mRNA expression will be tested in FHS 4 Metabolome analysis will be conducted in the same 80 matched casecontrol participants of BPRHS and metabolites will be correlated with epigenetic variants at APOA2 locus 5 Enriched metabolic pathways will be examined in relation to identified epigenetic variants at APOA2 region
Knowledge translation plan The results will be disseminated through interactive presentations at local national and international scientific meetings and publication in high impact factor journals Target audiences will include the public health and scientific communities with interest in nutrition diabetes obesity and cardiovascular disease Feedback will be incorporated and used to improve the public health message and key areas for future research will be defined ApplicantCo-applicant Decision Makers will network among opinion leaders to increase awareness and participate directly as committee members in the development of future guidelines
Preliminary findings In BPRHS the investigators identified methylation site cg04436964 as exhibiting significant differences between CC and TT participants consuming a high SFA diet but not among those consuming low SFA Similar results were observed in GOLDN and FHS Additionally in FHS cg04436964 methylation was negatively correlated with APOA2 expression in participants consuming a high SFA diet Furthermore when consuming a high SFA diet CC carriers had lower APOA2 expression compared to those with the TT genotype but expression levels were similar when consuming a low SFA diet Lastly the metabolomic analysis identified four pathways as overrepresented by metabolite differences between CC and TT genotypes with high SFA intake
Significance The investigators will apply multi-omics approaches to investigate the mechanistic foundations of the APOA2 -265TC genotype by SFA interaction linked to the disruptive condition of obesity the investigators may uncover plausible dysregulation of several metabolic pathways This study will illustrate the effectiveness of multiple omics approaches to well-established gene-diet interactions and contribute new evidence to ongoing explorations of the impact of saturated fat on human health
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None