Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04279704 |
| Other study ID # |
H 37359 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
September 2016 |
| Est. completion date |
March 1, 2020 |
Study information
| Verified date |
October 2020 |
| Source |
Baylor College of Medicine |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Background Cardiovascular disease is the leading cause of death in the U.S., however
scientists have failed to learn fully what are the causes of this disease. A promising lead
in understanding the origins of cardiovascular disease may be in gene expression changes
occurring in utero in response to environmental (non-genetic) factors. Such changes govern
whether a gene is turned on or turned off during an individual's lifetime. Twin pregnancies
and twin infants help researchers to have a better understanding of whether the gene
expression changes are genetic or environmental in origin. Therefore, the purpose of this
project is to examine which body tissues (such as hair, fingernails, urine or blood) are
needed to accurately study how gene activity is affected by prenatal factors.
Description:
Cardiovascular disease (CVD) is the leading cause of death in the US, emphasizing an
incomplete understanding of its pathology and translation into effective interventions. The
fetal origins hypothesis posits that the risk of CVD is partially set in utero. Individual
differences in epigenetic DNA methylation are a leading candidate mechanism to explain the
association between CVD risk and the fetal environment. Indeed, differences in DNA
methylation have been implicated in the pathogenesis of CVD and its risk factors. Previous
studies in rats have been characterizing a specific class of epigenetic loci known as
metastable epialleles (MEs). Methylation of DNA in utero can be in response to non-genetic
factors and the degree of hypo- or hyper- methylation remains stable throughout the lifespan.
Studies in mice further have shown that methylation has dramatic and permanent phenotypic
effects. In recent studies over 100 human MEs have been identified. Several of these loci
have been associated with phenotypes related to CVD risk.
Investigators now need to determine the phenotypic consequences of interindividual variation
in DNA methylation at human MEs. Studies in inbred mice have been instrumental in showing
that there are non-genetic influences on the establishment of methylation at MEs. Twin
studies, typically using saliva or peripheral blood cells (PBCs), have been used to assess
whether individual epigenetic variation in humans is influenced by non-genetic factors.
Indeed, in translating epigenetic findings from mice to humans, monozygotic (MZ;
genetically-identical) twins are commonly viewed as the human equivalent of isogenic mice.
However, there is an important difference between MZ twins and isogenic mice. Whereas each
inbred mouse littermate has its own placenta, about 75% of MZ twins share a single placenta
(monochorionicity) and therefore have intermingled circulation during fetal development. It
is therefore essential to determine whether the resulting "cross pollination" of
hematopoietic stem cells (HSCs) results in peripheral blood (and salivary) DNA of two
monochorionic MZ twins being more epigenetically similar than that of other somatic tissues.
Accurately quantifying epigenetic effects of periconceptional nutrition in twin studies, and
thereby providing future intervention targets to reduce CVD risk in offspring, will likely
require analyses of DNA methylation in tissues other than saliva or peripheral blood cells.
Investigators need to examine whether Monozygotic:Dizygotic twin comparisons, without regard
to placental sharing in utero (chorionicity), are a suitable model for future work which will
characterize ME loci and establish their associations with phenotypic consequences. Infancy
is the ideal time to examine the association between MEs and CVD factors, since it provides
the earliest time for risk prediction and intervention. Therefore, for this study
investigators plan to recruit 40 twins pairs under 4 months of age to identify more easily
available tissues for epigenetic analyses than hair follicles (which has been previously used
as an alternative to PBCs or saliva). The plucking of hair follicles from infants is too
burdensome on participants to accrue the large samples intended for future analyses.
Summary: Studies in rats provide evidence that maternal nutrition around the time of
conception can alter epigenetic mechanisms affecting obesity, and obesity itself is a strong
CVD risk factor. This relationship is mediated by the early embryonic methylation at
metastable alleles. Following the identification of over 100 MEs in humans many of which are
associated with obesity or other CVD risk factors, investigators are now ready to implement
studies to examine whether periconceptional nutrition influences CVD risk via methylation.
Investigators seek to translate this work on MEs into human populations since it suggests an
important CVD risk. Further, investigators want to establish the importance of chorionicity
as a factor in epigenetic analyses of MZ twins, and to validate a new tissue for such
studies.
Aim 1: Validate nail clippings as an acceptable DNA source for the study for human MEs
Hypothesis 1: At MEs, DNA methylation in infant nail clippings (which can be easily
collected) is highly correlated with that in hair follicles, urine and buccal swabs.
Aim 2: Compare epigenetic discordance at MEs in monochorionic vs. dichorionic MZ twins
Hypothesis 2: At MEs, dichorionic MZ twin pairs (with separate placentae) will show greater
epigenetic dissimilarity in PBCs than monochorionic MZ twin pairs (which share a placenta),
but not in other tissues.
