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Single-Nucleotide Polymorphisms in Exonic and Promoter Regions of Transcription Factors of Second Heart Field Associated with Sporadic Congenital Cardiac Anomalies

E Wang
E Wang
, 
X Fan
X Fan
, 
Y Nie
Y Nie
, 
Z Zheng
Z Zheng
 y 
S Hu
S Hu
   | 05 jun 2022
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Article Category: Original Article
Publicado en línea: 05 jun 2022
Páginas: 39 - 47
DOI: https://doi.org/10.2478/bjmg-2021-0028
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© 2021 E Wang et al., published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Figure 1

Genotyping of five exonic and promoter SNPs located in GATA5, TBX20, SMYD1 and MEF2C.Genotyping of (A) GATA5: rs6061243 G>C, (B) TBX20: rs336283 A>G, (C) SMYD1: rs1542088 T>G, (D) MEF2C: rs80043958 A>G and (E) GATA5: rs6587239 T>C SNPs by MALDI-TOF-MS.
Genotyping of five exonic and promoter SNPs located in GATA5, TBX20, SMYD1 and MEF2C.Genotyping of (A) GATA5: rs6061243 G>C, (B) TBX20: rs336283 A>G, (C) SMYD1: rs1542088 T>G, (D) MEF2C: rs80043958 A>G and (E) GATA5: rs6587239 T>C SNPs by MALDI-TOF-MS.

Figure 2

Genotyping of the other five SNPs located in GATA5, TBX20, SMYD1 and MEF2C exons and promoters.Genotyping of (A) GATA5: rs41305803 G>A, (B) MEF2C: rs304154 A>G, (C) SMYD1: rs2919881 A>G, (D) TBX20: rs336284 A>G and (E) SMYD1: rs88387557 T>G SNPs by MALDI-TOF-MS.
Genotyping of the other five SNPs located in GATA5, TBX20, SMYD1 and MEF2C exons and promoters.Genotyping of (A) GATA5: rs41305803 G>A, (B) MEF2C: rs304154 A>G, (C) SMYD1: rs2919881 A>G, (D) TBX20: rs336284 A>G and (E) SMYD1: rs88387557 T>G SNPs by MALDI-TOF-MS.

Figure 3

Luciferase assays of MEF2C: rs80043958 A>G, MEF2C: rs304154 A>G, and TBX20: rs336284 A>GFigure 3A, For rs80043958, the plasmid containing the G allele displayed nonsignificant luciferase expression compared with the wild-type A allele (p>0.05). When combined with HLTF, the (G) promoter showed a higher expression level than the (A) promoter (#, p<0.01);Figure 3B, For rs304154, the (G) promoter displayed significant lower luciferase expression than the (A) promoter (π, p<0.01). When the MEF2C promoter was combined with GATA1, FOXC1, or GATA1+FOXC1, the difference was still significant between the two groups ($, λ, †, p<0.01);Figure 3C, For rs336284, the (G) promoter exhibited a significantly lower luciferase expression level than the (A) promoter (§, p<0.01). The promoter (G)+ZFX group also showed a lower expression level (*, p<0.01).
Luciferase assays of MEF2C: rs80043958 A>G, MEF2C: rs304154 A>G, and TBX20: rs336284 A>GFigure 3A, For rs80043958, the plasmid containing the G allele displayed nonsignificant luciferase expression compared with the wild-type A allele (p>0.05). When combined with HLTF, the (G) promoter showed a higher expression level than the (A) promoter (#, p<0.01);Figure 3B, For rs304154, the (G) promoter displayed significant lower luciferase expression than the (A) promoter (π, p<0.01). When the MEF2C promoter was combined with GATA1, FOXC1, or GATA1+FOXC1, the difference was still significant between the two groups ($, λ, †, p<0.01);Figure 3C, For rs336284, the (G) promoter exhibited a significantly lower luciferase expression level than the (A) promoter (§, p<0.01). The promoter (G)+ZFX group also showed a lower expression level (*, p<0.01).

MEF2C: rs304154 A>G

Genotype TOF (n=105) Control (n=382) OR (95%CI) p value
No (%) No. (%)
AA 33 31 151 40 1
GA 59 56 162 42 1.67(1.03–2.69) 0.036
GG 13 12 69 18 0.86(0.43–1.74) 0.68
GG+GA 72 69 231 60 1.43(0.90–2.26) 0.13
AA+GA 92 88 313 82 1
GG 13 10 69 4 0.64(0.34–1.21) 0.17
A allele 125 60 464 61 1
G allele 85 40 300 39 1.05(0.77–1.44) 0.75

MEF2C: rs80043958 A>G

Genotype simple CHD (n=125) Control (n=381) OR (95%CI) p value
No (%) No. (%)
AA 85 68 294 77 1
GA 37 30 84 22 1.52(0.97–2.40) 0.07
GG 3 2 3 1 3.46(0.69–17.45) 0.11
GG+GA 40 32 87 23 1.59(1.02–2.48) 0.04
AA+GA 122 98 378 99 1
GG 3 10 3 4 3.10(0.62–15.55) 0.15
A allele 207 83 672 88 1
G allele 43 17 90 12 1.55(1.05–2.30) 0.029

TBX20: rs336284 A>G

Genotype SV (n=34) Control (n=378) OR (95%CI) p value
No (%) No. (%)
AA 9 26 131 35 1
GA 14 41 181 48 1.13(0.47–2.68) 0.79
GG 11 32 66 17 2.42(0.96–6.14) 0.06
GG+GA 25 74 247 65 1.47(0.67–3.25) 0.33
AA+GA 23 68 312 83 1
GG 11 10 66 4 2.26(1.05–4.86) 0.033
A allele 32 47 443 59 1
G allele 36 53 313 41 1.59(0.97–2.62) 0.07

Patients’ Information

Number(%)
No. of patients (n) 383
Age (years) 2.22±1.99
Male gender(n, %) 216(56%)
Clinical diagnosis (n, %)
  simple CHD 125(33%)
    VSD 94(25%)
    ASD 19(5%)
    PDA 12(3%)
  ROVTO 223(58%)
    TOF 107(28%)
    PA or PS with VSD 67(17%)
    PA or PS with IVS 49(13%)
  SV 35(9%)

Main effects of SNPs on CHD risk

SNP Homozygotes (for common alleles) Heterozygotes Homozygotes (for rarer alleles)
Case Control Case Control OR (95%CI) p value Case Control OR (95%CI) p value
GATA5: rs6061243 G>C 103 182 200 82 4.31 (3.03–6.13) 1.03× 10−16 70 119 1.04 (0.71–1.52) 0.84
TBX20: rs336283 A>G 76 112 193 185 1.54 (1.08–2.19) 0.017 109 84 1.91 (1.27–2.87) 0.002
SMYD1: rs1542088 T>G 292 310 83 73 1.21 (0.85–1.72) 0.3 6 0 – –
MEF2C: rs80043958 A>G 280 294 96 83 1.21 (0.87–1.70) 0.26 5 3 1.75 (0.41–7.39) 0.44
GATA5: rs6587239 T>C 88 90 196 203 0.99 (0.69–1.41) 0.94 96 88 1.12 (0.74–1.69) 0.6
GATA5: rs41305803 G>A 128 147 188 178 1.21 (0.89–1.66) 0.23 62 58 1.23 (0.78–1.89) 0.35
MEF2C: rs304154 A>G 134 151 188 162 1.31 (0.96–1.79) 0.09 58 69 0.95 (0.62–1.44) 0.8
SMYD1: rs2919881 A>G 257 250 106 116 0.89 (0.65–1.22) 0.47 18 16 1.09 (0.55–2.19) 0.8
TBX20: rs336284 A>G 126 131 169 181 0.97 (0.70–1.34) 0.86 77 66 1.21 (0.81–1.83) 0.36
SMYD1: rs88387557 T>G 350 357 31 24 1.32 (0.76–2.29) 0.33 1 1 1.02 (0.06–16.37) 1
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