Result
In total, 63 articles were included (details in appendix). Half of all
studies (n=32) were cohort study of population. The number of studies
increased with years. Included studies were limited to observational
studies, and exploratory experiment studies were rare. The frequency of
genes studied was counted in the literature, and the genes were listed
with frequencies more than once(Fig.2). ABCG1, involved in the
transportation of lipid elements, was ranked first with as many as 11
studies. These 11 articles were all population cohort studies, and some
researched the same CpG sites. Individual factors were classified into
six categories, which were listed below.
Mother during pregnancy
There were 13 studies showed that mother’s behavior would leave an
epigenetic mark on offspring’s DNA(Table.1). Mothers’ smoking would lead
to lighter baby birth weight and DNA methylation played an important
role in this process. CYP1A1 CpG sites was significantly associated with
birthweight (P= 4.76×10-5) and had significant
mediation effect together with GFI1 and AHRR
genes[13].
Correlation differed in gender and race. CYP1A1 was considered to
detoxification of the components of tobacco smoke in phase I metabolism.
CYP1A1 methylation may be one of the signal paths that how smoking
affects babies. Trace metals exposure also affected fetal gene
methylation levels. Cadmium (Cd), lead (Pb), total mercury (Hg),
manganese (Mn) and selenium (Se) were associated with CpG
sites[14].
Especially, Pd was associated with CYP24A1(cg01243877)
(P<0.001) and Arsenic(As) was associated with CYP2A4 and
CYP7B1[15]. CYP24A1
CpG sites, involved in vitamin D3 metabolism and cellular calcium
homoeostasis, provided an evidence supporting Pb as a neurotoxicant.
Maternal hormone affected the fetus’ ABCA1 and CYP11A1 methylation
during pregnancy[16,
17]. Maternal gestational weight gain
was related to offspring ABCA1 methylation (β = -1.1% per quartile;
95% CI: -2.0,
-0.3)[18]. Poor
nutrition or food deprivation during fetal development was related to
PPARγ and ABCA1
methylation[19,
20]. ABCA1 may play a role in the
efflux of intracellular cholesterol to apoliproteins and the formation
of nascent high density lipoproteins (HDLs). These factors may influence
baby HDL through DNA methylation. These studies suggested that parental
generation affects DNA methylation in offspring, a reminder to be more
careful during pregnancy to protect the fetus.
Environmental pollutants exposure
There were 11 studies exploring environment affects(Table.2).
Environmental pollution has been attached great importance, and
scientists are studying its impact on people. Smoking was one of
well-known risk factors. Studies showed that smoking led to CYP1A1,
CYP1A2, CYP2A6, CYP11B2 and PARβ methylation
alteration[13,
21-26]. Polycyclic aromatic
hydrocarbons (PAHs), one kind of carcinogens of cigarette, were
metabolized by phase I (e.g. CYP1A1) and detoxified by phase II (e.g.
GSTM1) before targeting
DNA[27]. Epigenetic
differences in CYP1A1 may explain individual metabolic differences and
lung cancer risk in smokers. CYP2A6 was involved in 90% nicotine
metabolism and its expression differed in gender and age. Men had lower
nicotine clearance than women, and older people also had lower nicotine
clearance than younger
people[24]. DNA
methylation explained some of the variation. Other common environmental
pollutants, like PM2.5, dust mite and chemicals, were related to
aberrant methylation. Shang Y et al. employed the mouse model to prove
that the reprogramming of lung or airways by dust mite can be mediated
through
epigenetic[28].
Polycyclic aromatic hydrocarbons including dioxin affected CYP1A1
demethylation via aryl hydrocarbon receptor
(Ahr)[29]. The
change was tissue specific and may account for their carcinogenicity.
These results suggested that our genes were sensitive to environmental
pollutants, and we should minimize environmental pollution exposure.
Obesity and Diet
There were 18 studies showed that body mass index (BMI) and blood lipids
affected the DNA methylation(Table.3). Obesity or high BMI had wide
effects on gene methylation, including ABCG1,ABCC1, CYP27B1,
SLC45A3,SLC1A5,and SLCO3A1. ABCG1 was an important part of lipid
metabolism and also the most researched and conclusive gene. ABCG1 was
believed that responsible for macrophage cholesterol and phospholipid
transport[30].
Downregulation of ABCG1 led to reduce cholesterol efflux, which was
associated with cardiovascular disease risk, obesity and dyslipidemia.
High-risk groups of these diseases were often found hypermethylation of
ABCG1[31-33].
Exactly, the results correspond to its function. However, we were not
sure whether the methylation changes occur before or after the disease.
Studies on ABCG1 were population cohort studies or case-control studies,
while none of the studies explored specific mechanisms. These studies
suggested that changes in epigenetics was one of the reasons for
individual differences in obesity.
The ratio of different nutrients in the diet affected LMAO2, MnSOD,
GSTM1, GSTT1, CYP1A1 and CYP2E1
methylation[34-36].
High fat diet led to CYP2R1,CYP27A1,CYP27B1,CYP24A1 and PPAR-α
methylation alteration, but had no significant effect on PPAR-γ
methylation[37-39].
These genes were involved in the metabolism of adipocytes, and studies
shown that the body’s response to the stimulation of high-fat diet.
However, the specific mechanism was still unclear. Specially, lack of
folic acid led to demethylation of
ABCG2[40], lack of
Vitamin D led to hypermethylation of CYP24A1 and
CYP27B1[41,
42]. The folic acid excretion cells
increased or decreased when folic acid was excessive or deficient. This
process was transported by ABCG2 and the expression of ABCG2 was
regulated by methylation. Finally, the total folic acid maintain
stable[40].
24-hydroxylase encoded by the CYP24A1 gene was a catabolic enzyme and
both 25(OH)D and 125(OH)2D were catabolized by the 24-hydroxylase into
inactive metabolites, thereby lowering the vitamin D
levels[41].
Drugs
There were 7 studies showed that some drugs can also influence the DNA
methylation (Table.4). Although most studies did not display the
magnitude of the effect, the genes drugs affected were important
metabolic genes. Berberine can lead to hypermethylation of CYP2B6 and
CYP3A4[43]. Aspirin
can induce hypermethylation of
ABCB1[44].
Methadone can cause hypermethylation of ABCB1 and CYP2D6, and the
influence can be transmitted to the
fetus[45].
Therefore we need pay more attention to drug combination and may have
deeper understandings of drug interactions. However, there were another
results that attracted our attention. García-Calzón, S. et al. found
that metformin can influence methylation degree of SLC22A1, SLC22A3 and
SLC47A1[46]. At the
same time, metformin was their metabolic substrate. Additionally, Wang,
X. K. et al. found that afatinib can effectively resist to the multidrug
resistance (MDR) by hypermethylation in promoter and downregulating the
expression of
ABCG2[47].
Meanwhile, afatinib was also the transporter substrate of BCRP, coded by
ABCG2.These findings may help us better understand the process of drug
metabolism in the human body.
Gender
There were 6 studies showed that DNA methylation alteration was
different in gender groups (Table.5). Study showed that CYP1A1, CYP2E1
and CYP7B1 methylation was different among
genders[48].
Moreover, the same exposure affected different genders differently.
Smoking showed significant methylation alternation of CYP11B2 and ABCG1
in different
gender[22,
26]. Lead exposure influenced GPX1,
CYP1A1 and SOD3 methylation differently in gender
groups[49].
Polycyclic aromatic hydrocarbons exposure caused different PPARγ
methylation in gender
groups[50]. LDL-C
and TG had different association with ABCG1 DNA methylation in different
gender groups[33].
These studies reminded us that gender needed to be considered in
personalized medicine.
Other factors
Besides above factors, other studies reported some meaningful experiment
(Table.6). Some factors that often taken into account, like race, age
and inflammation, also been shown to affect gene
methylation[51-53].
Nano-SiO2, not often mentioned, led to hypomethylation
of PARP and decreased expression on mRNA and protein
level[54]. ABCA1
promoter methylation level was an independent risk factors for premature
coronary artery disease along with traditional risk factors, like high
BMI and HbA1c[55].
Worthy of attention, 2 studies explored the correlation of methylation
changes with time and
periodicity[56,
57]. CYP27B1 methylation was weakly
association with season and CYP17A1 promoter was hypomethylated after
circadian rhythm was disrupted. These findings provided evidence for the
new idea to explain the relationship between the affecting factors and
individualized medicine that time affected methylation periodically.