Epigenomic and Metabolomic Signatures of APOA2 Gene by Saturated Fat Interaction

Body Mass Index Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03452787
• Other study ID #: APOA2_SATFAT_META_ANALYSIS
• Status: Completed
• Phase: N/A
• First received: January 29, 2018
• Last updated: March 1, 2018
• Start date: January 1, 2017
• Est. completion date: December 31, 2017

Study information

• Verified date: March 2018
• Source: Tufts University
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 602
• Est. completion date: December 31, 2017
• Est. primary completion date: December 1, 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

Inclusion Criteria:

• subjects with the apoA2 genotype TT or CC

Exclusion Criteria:

• all other genotypes

Related Conditions & MeSH terms

• Body Mass Index

Intervention

Other:
• None, cohort studies
this is a metanalysis of previously obtained observational data. there is not intervention on any of the cohorts.

Locations

Country	Name	City	State
United States	JM-USDA-HNRCA at Tufts University	Boston	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Tufts University

Country where clinical trial is conducted

United States, 

References & Publications (8)

Corella D, Arnett DK, Tsai MY, Kabagambe EK, Peacock JM, Hixson JE, Straka RJ, Province M, Lai CQ, Parnell LD, Borecki I, Ordovas JM. The -256T>C polymorphism in the apolipoprotein A-II gene promoter is associated with body mass index and food intake in the genetics of lipid lowering drugs and diet network study. Clin Chem. 2007 Jun;53(6):1144-52. Epub 2007 Apr 19. — View Citation

Corella D, Peloso G, Arnett DK, Demissie S, Cupples LA, Tucker K, Lai CQ, Parnell LD, Coltell O, Lee YC, Ordovas JM. APOA2, dietary fat, and body mass index: replication of a gene-diet interaction in 3 independent populations. Arch Intern Med. 2009 Nov 9;169(20):1897-906. doi: 10.1001/archinternmed.2009.343. — View Citation

Corella D, Tai ES, Sorlí JV, Chew SK, Coltell O, Sotos-Prieto M, García-Rios A, Estruch R, Ordovas JM. Association between the APOA2 promoter polymorphism and body weight in Mediterranean and Asian populations: replication of a gene-saturated fat interaction. Int J Obes (Lond). 2011 May;35(5):666-75. doi: 10.1038/ijo.2010.187. Epub 2010 Oct 26. — View Citation

DAWBER TR, MEADORS GF, MOORE FE Jr. Epidemiological approaches to heart disease: the Framingham Study. Am J Public Health Nations Health. 1951 Mar;41(3):279-81. — View Citation

Delgado-Lista J, Perez-Jimenez F, Tanaka T, Perez-Martinez P, Jimenez-Gomez Y, Marin C, Ruano J, Parnell L, Ordovas JM, Lopez-Miranda J. An apolipoprotein A-II polymorphism (-265T/C, rs5082) regulates postprandial response to a saturated fat overload in healthy men. J Nutr. 2007 Sep;137(9):2024-8. — View Citation

Lai CQ, Wojczynski MK, Parnell LD, Hidalgo BA, Irvin MR, Aslibekyan S, Province MA, Absher DM, Arnett DK, Ordovás JM. Epigenome-wide association study of triglyceride postprandial responses to a high-fat dietary challenge. J Lipid Res. 2016 Dec;57(12):2200-2207. Epub 2016 Oct 24. — View Citation

Smith CE, Ordovás JM, Sánchez-Moreno C, Lee YC, Garaulet M. Apolipoprotein A-II polymorphism: relationships to behavioural and hormonal mediators of obesity. Int J Obes (Lond). 2012 Jan;36(1):130-6. doi: 10.1038/ijo.2011.24. Epub 2011 Mar 8. — View Citation

Tucker KL, Mattei J, Noel SE, Collado BM, Mendez J, Nelson J, Griffith J, Ordovas JM, Falcon LM. The Boston Puerto Rican Health Study, a longitudinal cohort study on health disparities in Puerto Rican adults: challenges and opportunities. BMC Public Health. 2010 Mar 1;10:107. doi: 10.1186/1471-2458-10-107. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Body mass index (BMI)	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.