Roles of Functional Genetic Variants and Dietary Factors on MicroRNA-Mediated Gene Regulation of Cardiometabolic Traits
Lee, Yu-Chi.
2018
-
Abstract: Background:
Dysregulation of metabolic traits and obesity are risk factors for cardiovascular
disease (CVD) and other chronic diseases that accompany unhealthy aging. MicroRNAs
(miRNAs) regulate gene expression via targeting mRNAs and represent an epigenetic
mechanism that underlies human biology and diseases, including metabolic function and
CVD. Previous research has identified ... read morefunctional genetic variants involved in
miRNA-based gene regulation, suggesting that such genetic polymorphisms also modulate
cardiometabolic traits through miRNAs. This leads to our interest in investigating the
roles of genetic variants in miRNA-mediated regulation of blood lipids and their
interactions with diet (gene × environment interactions). It has also been
demonstrated that dietary factors can modulate miRNA levels. The underlying miRNA-based
mechanisms related to the effect of dietary factors on cardiometabolic traits are not
well-understood. Aims: To create a genome-wide miRNA-related single nucleotide
polymorphism (SNP) database with a particular focus on genetic variants which
potentially modulate miRNA-mediate gene regulation and affect blood lipids (Aim 1a) and
to identify miRNA-related genetic associations and their interactions with diet for
blood lipid concentrations (Aim 1b). Then to investigate the effect of virgin olive oil
intervention on miRNA profiles in the context of cardiovascular disease biomarkers (Aim
2). We hypothesize that miRNAs affect the activity of genes regulating blood lipids, and
miRNA function can be further modulated by genetic variants and dietary factors.
Methods: We used miRNA target prediction algorithms, publicly available databases and
bioinformatics tools to create a genome-wide miRNA-related SNP database (Aim 1a). We
then performed functional genome-wide association studies (fGWAS) and genome-wide
interaction studies (fGWIS) and meta-analyzed association and interaction data in 9
population-based cohort studies (n = ~21,000, European origin participants) from the
CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium for
blood lipids using SNPs predicted to be functional via miRNA-related mechanisms. We
evaluated interactions for dietary carbohydrate and saturated, monounsaturated and
polyunsaturated fats (Aim 1b). We conducted a two-armed, 3-month randomized controlled
trial (RCT): 41 overweight/obese older participants (age: 72.0 ± 5.6 y; BMI: 28.8
± 2.6 kg/m2) were given virgin olive oil or control (soy oil/corn oil/butter) oil
to replace substitutable oils/fats commonly used in participants' typical American diet.
We quantified blood miRNAs using miRNA microarray and quantitative RT-PCR and used
bioinformatics analyses to assess the effects of olive oil on cardiometabolic traits
(Aim 2). Results: We created a miRNA-related SNP database, including 914,515
miRNA-related SNPs (Aim 1a). Using miRNA fGWAS and fGWIS approaches, we identified 19
loci associated with blood lipids and 17 novel loci potentially interacted with diet in
determining blood lipids. Several of these key results such as miRNA-related SNPs in
CELSR2, NECTIN2 (also known as PVRL2), FADS1, SH3YL1, ONECUT2 and PPIL2 were supported
by multiple functional annotation databases (Aim 1b). In the olive oil RCT, following a
3-month intervention, systolic blood pressure (SBP) was significantly reduced in the
olive oil group (P = 0.004) but not in the control group. Individuals in the olive oil
group had a significantly lower SBP (P = 0.04) compared with the control group at month
3. Change in hsa-miR-96-5p was correlated with changes in serum glucose and insulin
levels in the olive oil group after 3 months. Furthermore, participants with impaired
fasting glucose appeared to benefit from the olive oil intervention by improving fasting
glucose and insulin (Aim 2). Conclusions: The comprehensive miRNA-related SNP database
can be used to assess the genetic contribution of miRNA-mediated regulation on any
traits of interest (Aim 1a). Our study of fGWAS and fGWIS generated miRNA-based
hypotheses for previously known lipid-associated loci and identified novel genetic
variants in response to dietary macronutrients for blood lipids. Replication, different
analytic methods and follow-up functional studies are recommended for further
investigation (Aim 1b). Our findings from the olive oil RCT suggested that hsa-miR-96-5p
may be induced by olive oil intervention to regulate glycemic homeostasis. The
regulation of miRNAs related to olive oil consumption contributing to health benefits
requires further research (Aim 2). Further mechanistic examination and larger dietary
intervention studies are needed to validate our findings, to advance the general field
of miRNA regulation of blood lipids and to eventually develop personalized
strategies/recommendations to reduce CVD
risk.
Thesis (Ph.D.)--Tufts University, 2018.
Submitted to the Dept. of Biochemical and Molecular Nutrition.
Advisor: José Ordovás.
Committee: Stefania Lamon-Fava, Paul Jacques, and Carlos Fernández-Hernando.
Keywords: Epidemiology, Genetics, and Nutrition.read less - ID:
- 6h441522f
- Component ID:
- tufts:24322
- To Cite:
- TARC Citation Guide EndNote
