Association of maternal MTR gene polymorphism with offspring congenital heart disease: a case-control study
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摘要:
目的 研究母亲甲硫氨酸合成酶(MTR)基因多态性与子代先天性心脏病(CHD)间的关联性。 方法 于2017年11月 — 2019年12月在湖南省儿童医院心胸外科采用病例对照研究方法,在464例CHD患儿母亲和504例健康儿童母亲中,利用MassArray飞行时间质谱技术对MTR基因的单核苷酸多态性(SNPs)进行检测,采用SPSS24.0和Haploview软件分析MTR基因SNPs及其单倍型与CHD的关联。 结果 rs1266164(TT vs.CC:aOR = 3.39, 95 % CI = 1.48~7.76;隐性模型:aOR = 3.27,95 % CI = 1.44~7.45),rs3768139(CC vs.GG:aOR = 0.26,95 % CI = 0.11~0.58;显性模型:aOR = 0.29,95 % CI = 0.13~0.65;隐性模型:aOR = 0.62,95 % CI = 0.45~0.85),rs1050993(隐性模型:aOR = 0.59,95 % CI = 0.42~0.82),rs6668344(显性模型:aOR = 1.55,95 % CI = 1.12~2.16),rs3820571(GG vs. CC:aOR = 0.28, 95 % CI = 0.12~0.64;隐性模型:aOR = 0.56,95 % CI = 0.40~0.79)等5个位点与子代CHD的发生存在关联。TT和CT单倍型(rs6668344-rs3754255),AGTA单倍型(rs1805087-rs2275565-rs1266164-rs4659743)以及AT和GT单倍型(rs1050993-rs6676866)与CHD的发生相关。 结论 MTR基因多态性与子代CHD的患病存在关联,且其单倍型影响CHD的发生。 Abstract:Objective To explore the association between maternal methionine synthase (MTR) gene polymorphism and the risk of congenital heart disease (CHD) in offsprings. Methods A case-control study was conducted among 464 biological mothers of CHD children and 504 biological mothers of healthy children in the Department of Cardiothoracic Surgery, Hunan Children's Hospital from November 2017 to December 2019. Single nucleotide polymorphisms (SNPs) of MTR gene was detected with MassArray time-of-flight mass spectrometry. The association between MTR SNPs and offspring CHD was analyzed with SPSS 24.0 software, and Haploview software was used in haplotype analysis. Results The results of multivariate logistic regression analysis demonstrated that the SNPs of following MTR gene loci were significantly associated with increased risk of CHD incidence: rs1266164 (TT vs. CC: adjusted odds ratio [aOR] = 3.39, 95% confidence interval [95% CI]: 1.48 – 7.76; recessive model: aOR = 3.27, 95% CI: 1.44 – 7.45) and rs6668344 (dominant model: aOR = 1.55, 95% CI: 1.12 – 2.16); the results also revealed that SNPs of three MTR gene loci correlated with decreased risk of offspring CHD incidence included rs3768139 (CC vs. GG: aOR = 0.26, 95% CI: 0.11 – 0.58; dominant model: aOR = 0.29, 95% CI: 0.13 – 0.65; recessive model: aOR = 0.62, 95% CI: 0.45 – 0.85), rs1050993 (recessive model: aOR = 0.59, 95% CI: 0.42 – 0.82), and rs3820571 (GG vs. CC: aOR = 0.28, 95% CI: 0.12 – 0.64; recessive model: aOR = 0.56, 95% CI: 0.40 – 0.79). The haplotype TT and CT of rs6668344-rs3754255, AGTA of rs1805087-rs2275565-rs1266164- rs4659743, as well as AT and GT of rs1050993-rs6676866 were associated with the incidence risk of offspring CHD. Conclusion Both the polymorphism and haplotype of maternal MTR gene might be associated with the incidence risk of offspring CHD. -
Key words:
- congenital heart disease /
- methionine synthase /
- haplotype
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表 1 MTR基因位点信息及对照组Hardy-Weinberg平衡检验
SNPs 染色体位置 等位基因 MAF a 分组 基因型频率 HWE检验
P 值AA b AB BB 人数 % 人数 % 人数 % rs1266164 Chr1:236887651 C/T 0.1901 对照 344 68.3 150 29.8 10 2.0 0.168 病例 300 64.7 130 28.0 34 7.3 rs3768139 Chr1:236864368 C/G 0.2025 对照 10 2.0 150 29.8 344 68.3 0.168 病例 36 7.8 150 32.3 278 59.9 rs6676866 Chr1:236901326 G/T 0.4463 对照 104 20.6 244 48.4 156 31.0 0.632 病例 72 15.5 268 57.8 124 26.7 rs955516 Chr1:236817204 T/A 0.4143 对照 174 34.5 238 47.2 92 18.3 0.502 病例 152 32.8 244 52.6 68 14.7 rs1050993 Chr1:236899005 G/A 0.1643 对照 10 2.0 118 23.4 376 74.6 0.835 病例 24 5.2 132 28.4 308 66.4 rs10925252 Chr1:236859062 T/C 0.4318 对照 196 38.9 216 42.9 92 18.3 0.019 病例 124 26.7 244 52.6 96 20.7 rs2229276 Chr1:236891269 A/G 0.4525 对照 182 36.1 216 42.9 106 31.7 0.006 病例 116 25.0 248 53.4 100 21.6 rs4659743 Chr1:236896087 T/A 0.1767 对照 10 2.0 132 26.2 362 71.8 0.611 病例 30 6.5 130 28.0 304 65.5 rs12060570 Chr1:236825769 G/C 0.4101 对照 174 34.5 242 48.0 88 17.5 0.807 病例 160 34.5 232 50.0 72 15.5 rs1806505 Chr1:236833275 C/T 0.4123 对照 172 34.1 244 48.4 88 17.5 0.927 病例 156 33.6 238 51.3 70 15.1 rs3768142 Chr1:236865264 T/G 0.3905 对照 76 15.1 236 46.8 192 38.1 0.803 病例 72 15.5 224 48.3 168 36.2 rs4659724 Chr1:236810824 G/A 0.4256 对照 180 35.7 236 46.8 88 17.5 0.483 病例 144 31.0 228 49.1 92 19.9 rs6668344 Chr1:236838026 C/T 0.4215 对照 196 38.9 230 45.6 78 15.5 0.440 病例 124 26.7 250 53.9 90 19.4 rs1805087 Chr1:236885200 A/G 0.1064 对照 406 80.6 88 17.5 10 2.0 0.050 病例 370 79.7 90 19.4 4 0.9 rs4077829 Chr1:236824490 G/T 0.4163 对照 170 33.7 246 48.8 88 17.5 0.951 病例 154 33.2 236 50.9 74 15.9 rs2275565 Chr1:236885376 G/T 0.1643 对照 352 69.8 132 26.2 20 4.0 0.094 病例 332 71.6 118 25.4 14 3.0 rs3754255 Chr1:236846557 C/T 0.5021 对照 132 26.2 242 48.0 130 25.8 0.373 病例 100 21.6 258 55.6 106 22.8 rs3820571 Chr1:236897133 T/G 0.1736 对照 10 2.0 118 23.4 376 74.6 0.835 病例 36 7.8 126 27.2 302 65.1 注:a MAF为最小等位基因频率;b AA = 野生型,AB = 突变纯合子,BB = 突变杂合子。 表 2 病例组和对照组基本情况比较
基线资料 病例组(n = 464) 对照组(n = 504) Z/χ2 值 P 值 人数 % 人数 % 怀孕时年龄(岁) 0.191 0.662 < 35 404 87.1 434 86.1 ≥ 35 60 12.9 70 13.9 文化程度 12.306 0.000 小学或以下 66 14.2 6 1.2 初中 190 40.9 100 19.8 高中或中专 130 28.0 168 33.3 大专或本科及以上 78 16.8 230 45.6 不良妊娠史(有) 258 55.6 224 44.4 12.033 0.001 妊娠糖尿病史(有) 44 9.5 18 3.6 14.082 0.000 妊娠高血压史(有) 30 6.5 10 2.0 12.247 0.000 家族成员患先天畸形 28 6.0 4 0.8 20.759 0.000 孕早期感冒 158 34.1 104 20.6 22.030 0.000 孕早期暴露于二手烟环境 190 40.9 98 19.4 53.451 0.000 长期居住地附近有可疑污染源 94 20.3 34 6.7 38.443 0.000 居住地附近有噪声暴露 124 26.7 92 18.3 9.999 0.002 孕早期服用药物 150 32.3 100 19.8 19.662 0.000 孕前或孕早期叶酸服用 386 83.2 470 93.3 23.917 0.000 表 3 母亲MTR基因多态性与子代CHD的关联性分析
SNPs 单因素logistic回归 多因素logistic回归 OR 值 95 % CI P 值 aOR 值 a 95 % CI P 值 FDR-P rs1266164 CC 1 1 CT 0.99 0.75~1.32 0.965 1.11 0.79~1.55 0.548 0.797 TT 3.90 1.89~8.03 0.000 3.39 1.48~7.76 0.004 0.043 显性模型 1.18 0.90~1.54 0.236 1.26 0.92~1.74 0.156 0.416 隐性模型 3.91 1.91~8.00 0.000 3.27 1.44~7.45 0.005 0.020 rs3768139 GG 1 1 GC 0.28 0.13~0.58 0.001 0.37 0.16~0.85 0.019 0.101 CC 0.22 0.11~0.46 0.000 0.26 0.11~0.58 0.001 0.032 显性模型 0.24 0.12~0.49 0.000 0.29 0.13~0.65 0.003 0.048 隐性模型 0.70 0.53~0.91 0.007 0.62 0.45~0.85 0.003 0.016 rs1050993 AA 1 1 AG 0.47 0.21~1.02 0.055 0.66 0.26~1.64 0.367 0.652 GG 0.34 0.16~0.73 0.005 0.40 0.17~0.98 0.044 0.201 显性模型 0.37 0.18~0.79 0.009 0.47 0.19~1.12 0.087 0.278 隐性模型 0.67 0.51~0.89 0.005 0.59 0.42~0.82 0.002 0.016 rs6668344 CC 1 1 CT 1.72 1.29~2.29 0.000 1.57 1.11~2.23 0.011 0.088 TT 1.82 1.25~2.66 0.002 1.51 0.96~2.37 0.074 0.237 显性模型 1.75 1.33~2.29 0.000 1.55 1.12~2.16 0.009 0.048 隐性模型 1.31 0.94~1.84 0.108 1.14 0.77~1.69 0.517 0.689 rs3820571 TT 1 1 TG 0.30 0.14~0.62 0.001 0.45 0.19~1.06 0.069 0.245 GG 0.22 0.11~0.46 0.000 0.28 0.12~0.64 0.003 0.048 显性模型 0.24 0.12~0.49 0.000 0.32 0.14~0.73 0.007 0.056 隐性模型 0.64 0.48~0.84 0.001 0.56 0.40~0.79 0.001 0.016 注:a 调整因素为文化程度、不良妊娠史、妊娠糖尿病史、妊娠高血压史、家族成员是否患有先天畸形、孕早期是否感冒、孕早期是否暴露于二手烟环境、长期居住地附近是否有可疑的环境污染源、长期居住地附近是否有公路或者交通干道、孕早期是否服用药物、怀孕前或孕期是否服用叶酸。 表 4 母亲MTR基因单倍型分析结果
单倍型块 单倍型 频率(%) 病例组 对照组 χ2 值 P 值 OR 值 95 % CI 计数 % 计数 % Block1 TGGC 57.3 529.9 57.1 579.9 57.5 0.036 0.849 1.05 0.88~1.26 ATCT 39.8 358.0 38.6 412.0 40.9 1.063 0.303 0.95 0.79~1.14 Block2 CC 48.9 441.1 47.5 505.2 50.1 1.292 0.256 0.93 0.78~1.11 TT 41.2 413.1 44.5 385.2 38.2 7.921 0.005 1.34 1.11~1.60 CT 9.0 56.9 6.1 116.8 11.6 17.615 0.000 0.52 0.37~0.72 Block3 AGCT 64.3 579.8 62.5 664.5 65.9 2.498 0.114 0.89 0.74~1.08 AGTA 17.0 179.9 19.4 149.9 14.9 6.980 0.008 1.40 1.10~1.78 GTCT 10.0 89.8 9.7 103.1 10.2 0.164 0.686 0.93 0.69~1.25 ATCT 5.9 48.1 5.2 66.1 6.6 1.637 0.201 0.82 0.56~1.20 AGTT 1.7 14.1 1.5 19.4 1.9 0.478 0.489 0.77 0.39~1.54 Block4 GG 55.1 511.1 55.1 555.4 55.1 0.000 0.992 1.01 0.84~1.21 GT 28.5 236.9 25.5 314.6 31.2 7.661 0.006 0.77 0.63~0.93 AT 16.1 175.1 18.9 137.4 13.6 9.796 0.002 1.47 1.15~1.88 注:Block 1:rs955516-rs4077829-12060570-rs1806505; block 2: rs6668344-rs3754255; block 3: rs1805087-rs2275565-rs1266164-rs4659743; block 4: rs1050993-rs6676866。 -
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