Epigenomic and Metabolomic Signatures of APOA2 Gene by Saturated Fat Interaction

March 1, 2018 updated by: Jose Ordovas, Tufts University

Meta Analysis of Epigenomic and Metabolomic Signatures of APOA2 Gene by Saturated Fat

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 T>C (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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 T>C (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 g/d) or high (≥22 g/d) 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) (n=379) and the Framingham Heart Study (FHS) (n=243). 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 -265T>C (rs5082) will be selected, with 20 reporting a low SFA intake (<22 g/d) and 20 indicating a high SFA intake (≥22 g/d). 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 -265T>C will be selected from the same population. In GOLDN, 107 participants with CC genotype and 272 with TT genotype for APOA2 -265T>C, 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 -265T>C, 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 grams/day, high, ≥22 grams/day.

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, accession#:phg000492.v2, where methylation statuses of 2,741 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 phe00002.v6. 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 case/control 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 package.The comparison of allelic effect (beta) of APOA2 -265T>C from the meta-analysis between low and high SFA intake will be conducted with SAS 9.4 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 case/control 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. Applicant/Co-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 -265T>C 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 Type

Observational

Enrollment (Actual)

602

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Massachusetts
      • Boston, Massachusetts, United States, 02111
        • JM-USDA-HNRCA at Tufts University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 90 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

Individuals extracted from the BPRHS, GOLDN and Framingham Studies

Description

Inclusion Criteria:

  • subjects with the apoA2 genotype TT or CC

Exclusion Criteria:

  • all other genotypes

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Boston Puerto Rican Health Study (NCT01231958)
40 with CC and 40 with TT genotypes at APOA2 rs5082. Participants of each genotype will be further divided into two subgroups based on SFA intake: low, <22 grams/day, high, ≥22 grams/day.
Other: None, cohort studies
this is a metanalysis of previously obtained observational data. there is not intervention on any of the cohorts.
GOLDN (NCT00083369)
107 participants with CC genotype and 272 with TT genotype for APOA2 rs5082.
Other: None, cohort studies
this is a metanalysis of previously obtained observational data. there is not intervention on any of the cohorts.
Framingham Heart Study (NCT00005121)
73 with CC and 170 with TT genotypes at APOA2 rs5082. Participants of each genotype will be further divided into two subgroups based on SFA intake: low, <22 grams/day, high, ≥22 grams/day.
Other: None, cohort studies
this is a metanalysis of previously obtained observational data. there is not intervention on any of the cohorts.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Body mass index (BMI)
Time Frame: One time point taken during the first visit of the participants to the studies used for the meta-analyses.
BMI calculated based on weight (kg) and height (meters) information from each participant using the equation BMI=kg/m2
One time point taken during the first visit of the participants to the studies used for the meta-analyses.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Tufts University

Investigators

  • Principal Investigator: Jose M Ordovas, PHD, JM-USDA-HNRCA at Tufts University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

January 1, 2017

Primary Completion (ACTUAL)

December 1, 2017

Study Completion (ACTUAL)

December 31, 2017

Study Registration Dates

First Submitted

January 29, 2018

First Submitted That Met QC Criteria

March 1, 2018

First Posted (ACTUAL)

March 2, 2018

Study Record Updates

Last Update Posted (ACTUAL)

March 2, 2018

Last Update Submitted That Met QC Criteria

March 1, 2018

Last Verified

March 1, 2018

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • APOA2_SATFAT_META_ANALYSIS

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

we are getting deidentified data from dbGAP and we cannot shared with any other group

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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