SINGLE-NUCLEOTIDE POLYMORPHISMS IN EXONIC
AND PROMOTER REGIONS OF TRANSCRIPTION
FACTORS OF SECOND HEART FIELD ASSOCIATED
WITH SPORADIC CONGENITAL CARDIAC ANOMALIES
Wang E, Fan X, Nie Y, Zheng Z, Hu S,
*Corresponding Author: Shengshou Hu M. D., Cardiac Surgery Department, Fuwai Hospital, Chinese
Academy of Medical Sciences, Peking Union Medical College, Xicheng District, Beijing, 100037,
China, Tel & Fax: 86-010-88322325 E-mail: shengshouh@sina.cn
page: 39
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RESULTS
Ten SNPs located in exon
and promoter regions were genotyped
There were seven SNPs in exons and three SNPs in
promoters (Table S3). Among the seven exonic SNPs,
SMYD1: rs88387557 T>G was a nonsynonymous mutation,
while the remaining six SNPs were all synonymous
mutations (Table S3). The bioinformatics analysis suggested
that the other three SNPs located in promoters caused
promoter loss, which might influence MEF2C and TBX20
mRNA transcription (Table S3). The polymorphism rates
of genotyping were 98-100%. The genotype frequencies
of the controls were in accordance with Hardy-Weinberg
equilibrium (p>0.05) (Table S4).
The risk of CHD was increased by minor alleles
of rs6061243 and rs336283
The minor alleles of two SNPs, including the C allele
of GATA5: rs6061243 G>C and the G allele of TBX20:
rs336283 A>G, significantly increased the risk of CHD.
Subjects carrying GATA5: rs6061243 GC had a 4.31-fold
increased risk of CHD (OR=4.31, 95% CI 3.03-6.13,
p=1.03×10‑16); additionally, compared with patients with
wild-type TBX20: rs336283 AA, AG increased the risk of
CHD by 1.54-fold (OR=1.54; 95% CI 1.08-2.19, p<0.05)
(Table 2). The subjects with TBX20: rs336283 GG were
associated with a 1.91-fold increased risk of CHD in comparison
with patients carrying AA (OR=1.91; 95% CI 1.27-
2.87, p=0.002). The remaining minor alleles of the 8 polymorphisms
were not associated with CHD risk (Table 2).
Subgroup analyses were then implemented to assess
the impacts of GATA5: rs6061243 G>C and TBX20:
rs336283 A>G polymorphisms on CHD subtypes. The
minor C allele of GATA5 rs6061243 G>C increased the risk
of different CHD subtypes (p<0.05) (Table S5). However,
GG in TBX20: rs336283 A>G increased the risk of various
CHD subtypes but not simple CHD (p<0.05) (Table S6).
The minor alleles of SMYD1: rs1542088 T>G,
MEF2C: rs80043958 A>G and GATA5: rs6587239
T>C increase the risk of simple CHD
The minor alleles in SMYD1: rs1542088 T>G, MEF2C:
rs80043958 A>G and GATA5: rs6587239 T>C had
no associations with the risk of CHD but were associated
with the risk of simple CHD, including VSD, ASD,
and PDA. Additionally, these three SNPs did not change
the RVOTO or SV risk. For MEF2C: rs80043958 A>G,
subjects carrying GG+GA had an increased simple CHD
risk in comparison with patients carrying AA homozy- gotes (OR=1.59, 95% CI 1.02-2.48, p=0.04) (Table 3).
For SMYD1: rs1542088 T>G, subjects carrying GT were
associated with an increased risk of simple CHD compared
with TT subjects (OR=1.62, 95% CI 1.01-2.60, p=0.043)
(Table S7). GG+GT increased the risk of simple CHD compared
with TT (OR = 1.72, 95% CI 1.08-2.73, p=0.021)
(Table S7). GATA5: rs6587239 CC was associated with
an increased risk of simple CHD compared with TT+TC
(OR=1.59, 95% CI 1.02-2.48, p=0.042) (Table S8).
The minor A allele of GATA5: rs41305803 G>A and
the minor G allele of MEF2C: rs304154 A>G
increase the risk of RVOTO or TOF
The minor G allele of MEF2C: rs304154 A>G only
increased TOF risk. GA increased the TOF risk by 1.67-
fold in comparison with AA (OR=1.67, 95% CI = 1.03-
2.69, p = 0.036) (Table 4). The minor A allele of GATA5:
rs41305803 G>A increased the risk of RVOTO. The RVOTO
group was then divided into three subgroups: TOF,
PA or PS with VSD and PA or PS with IVS. The minor A
allele of GATA5: rs41305803 G>A only increased the risk
of TOF (Table S9).
The minor alleles of TBX20: rs336284 A>G,
SMYD1: rs2919881 A>G, and SMYD1: rs88387557
T>G increase the risk of other CHD types
Among patients harboring TBX20: rs336284 A>G,
GG subjects were significantly associated with an increased
risk of SV compared with AA subjects (OR =2.26,
95% CI 1.05-4.86, p=0.033) (Table 5). However, among
patients harboring SMYD1: rs2919881 A>G, the risk of PA
or PS with IVS was increased significantly in GG subjects
compared with AA patients (OR =3.19, 95% CI 1.19-8.59,
p= 0.039) (Table S10). For SMYD1: rs88387557 T>G,
the SV risk was increased by 2.66-fold in the G allele
compared with the T allele (OR=2.66, 95% CI 1.06-6.70,
p=0.03) (Table S11).
Luciferase assays of MEF2C: rs80043958 A>G,
MEF2C: rs304154 A>G,
and TBX20: rs336284 A>G.
For rs80043958, the G allele plasmid showed nonsignificant
luciferase expression compared with the A
allele counterparts in HEK 293T cells (p>0.05) (Figure
3A). When combined with HLTF, the G promoter showed
a higher expression level than the A promoter (p<0.01)
(Figure 3A). No such increase occurred when CEBPA
or CEBPA+HLTF were added to the MEF2C promoter
(Figure 3A).
For rs304154, the G promoter displayed a significantly
lower luciferase expression than the A promoter
(p<0.01) (Figure 3B). When the MEF2C promoter was
combined with GATA1, FOXC1, or GATA1+FOXC1, the
two groups still exhibited a significant difference (p<0.01)
(Figure 3B).
For rs336284, the G promoter exhibited a significantly
lower level of luciferase expression than the A promoter
(p<0.01) (Figure 3C). The promoter in the (G)+ZFX group
showed a lower expression level (p<0.01).
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