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中华妇幼临床医学杂志(电子版)

中华妇幼临床医学杂志(电子版) ›› 2018, Vol. 14 ›› Issue (01) : 18 -24. doi: 10.3877/cma.j.issn.1673-5250.2018.01.003

所属专题： 文献；

论著

ABCC 2基因1249G>A多态位点与先天性间隔缺损的相关性研究
邓雨昕1, 唐昌青2, 马凡2, 张怡3, 周开宇2, 华益民2, 王川2,†()   
  1. 1. 610041　成都，四川大学华西第二医院西部妇幼研究院心脏发育与早期干预研究室；611730　成都，成都七中嘉祥外国语学校郫县分校
    2. 610041　成都，四川大学华西第二医院西部妇幼研究院心脏发育与早期干预研究室；610041　成都，四川大学华西第二医院儿科、出生缺陷与相关妇儿疾病教育部重点实验室
    3. 610041　成都，四川大学华西第二医院西部妇幼研究院心脏发育与早期干预研究室
  • 收稿日期:2017-10-11 修回日期:2018-01-19 出版日期:2018-02-01
  • 通信作者: 王川

Associations between ABCC2 gene 1249G>A polymorphism and congenital isolated septal defects

Yuxin Deng1, Changqing Tang2, Fan Ma2, Yi Zhang3, Kaiyu Zhou2, Yimin Hua2, Chuan Wang2,†()   

  1. 1. Cardiac Development and Early Intervention Research Unit, West China Institute of Women and Children′s Health, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China; Pidu Campus of Jiaxiang Foreign Languages School Attached Chengdu No.7 Middle School, Chengdu 611730, Sichuan Province, China
    2. Cardiac Development and Early Intervention Research Unit, West China Institute of Women and Children′s Health, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China; Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
    3. Cardiac Development and Early Intervention Research Unit, West China Institute of Women and Children′s Health, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
  • Received:2017-10-11 Revised:2018-01-19 Published:2018-02-01
  • Corresponding author: Chuan Wang
  • About author:
    Corresponding author: Wang Chuan, Email:
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引用本文：

邓雨昕, 唐昌青, 马凡, 张怡, 周开宇, 华益民, 王川. ABCC 2基因1249G>A多态位点与先天性间隔缺损的相关性研究[J]. 中华妇幼临床医学杂志(电子版), 2018, 14(01): 18-24.

Yuxin Deng, Changqing Tang, Fan Ma, Yi Zhang, Kaiyu Zhou, Yimin Hua, Chuan Wang. Associations between ABCC2 gene 1249G>A polymorphism and congenital isolated septal defects[J]. Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition), 2018, 14(01): 18-24.

目的

探讨ABCC 2基因1249G>A多态位点与先天性间隔缺损的相关性。

方法

选择2013年3月至2015年3月，于四川大学华西第二医院儿童心血管科就诊，并被确诊为先天性间隔缺损的300例患儿为研究对象，纳入病例组。其中，单纯膜周部室间隔缺损(Pm-VSD)及继发孔型房间隔缺损(s-ASD)各为150例，分别纳入Pm-VSD亚组与s-ASD亚组。选择同期因单纯呼吸道感染于病例组同一家医院住院治疗的300例患儿，纳入对照组。采用PCR测序，对病例组与对照组患儿ABCC 2基因1249G>A多态位点基因型进行检测。采用成组t检验，对病例组与对照组、Pm-VSD亚组与对照组、s-ASD亚组与对照组患儿的年龄进行比较。采用χ2检验，对病例组与对照组、Pm-VSD亚组与对照组、s-ASD亚组与对照组患儿性别构成比、ABCC 2基因1249G>A多态位点GG、GA、AA基因型频率进行比较。采用单因素非条件logistic回归分析，对病例组与对照组、Pm-VSD亚组与对照组、s-ASD亚组与对照组患儿ABCC 2基因1249G>A多态位点不同遗传模型的基因型频率进行比较。本研究遵循的程序符合四川大学华西第二医院人体试验委员会所制定的伦理学标准，得到该委员会批准，分组征得受试患儿监护人的知情同意，并与之签署临床研究知情同意书。

结果

①病例组及对照组、Pm-VSD亚组及与对照组、s-ASD亚组与对照组患儿的性别构成比及年龄比较，差异均无统计学意义(P>0.05)。②病例组、Pm-VSD亚组、s-ASD亚组及对照组ABCC 2基因1249G>A多态位点基因型频率分布，均符合Hardy-Weinberg平衡定律(χ2＝0.880，P＝0.820；χ2＝0.246，P＝0.913；χ2＝1.042，P＝0.748；χ2＝0.110，P＝0.925)。③病例组患儿ABCC 2基因1249G>A多态位点GG、GA、AA基因型频率分别为67.0%(201/300)、30.7%(92/300)、2.3%(7/300)，对照组分别为80.7%(242/300)、18.0%(54/300)、1.3%(4/300)，Pm-VSD亚组分别为62.3%(94/150)、35.1%(52/150)、2.6%(4/150)，s-ASD亚组分别为71.3%(107/150)、26.7%(40/150)、2.0%(3/150)，病例组与对照组、Pm-VSD亚组与对照组、s-ASD亚组与对照组患儿ABCC 2基因1249G>A多态位点GG、GA、AA基因型频率比较，差异均有统计学意义(χ2＝14.503，P＝0.001；χ2＝17.132，P<0.001；χ2＝5.005，P＝0.042)。④对ABCC 2基因1249G>A多态位点不同遗传模型的基因型频率，进行单因素非条件logistic回归分析的结果显示，病例组与对照组ABCC 2基因1249G>A多态位点隐性模型(GG、GA/AA)基因型频率与等位基因(G、A)频率比较，差异均有统计学意义(OR＝2.0，95%CI：1.4～3.0，P<0.001；OR＝1.9，95%CI：1.3～2.6，P<0.001)。在隐性模型(GG、GA/AA)中，GA/AA基因型患儿先天性间隔缺损发病风险，是GG基因型患儿的2.0倍；携带A等位基因患儿先天性间隔缺损发病风险，是携带G等位基因患儿的1.9倍。但是，2组ABCC 2基因1249G>A多态位点显性模型(GG/GA、AA)基因型频率比较，差异无统计学意义(P>0.05)。⑤在对先天性心脏病(CHD)类型进行分层分析后，对ABCC 2基因1249G>A多态位点不同遗传模型的基因型频率，进行单因素非条件logistic回归分析的结果显示，Pm-VSD亚组与对照组ABCC 2基因1249G>A多态位点隐性模型(GG、GA/AA)基因型频率与等位基因(G、A)频率比较，差异均有统计学意义(OR＝2.5，95%CI：1.6～3.9，P<0.001；OR＝2.2，95%CI：1.5～3.2，P<0.001)。在隐性模型(GG、GA/AA)中，GA/AA基因型患儿Pm-VSD发病风险，是GG基因型患儿的2.5倍。携带A等位基因患儿Pm-VSD发病风险，是携带G等位基因患儿的2.2倍。s-ASD亚组与对照组ABCC 2基因1249G>A多态位点不同遗传模型中，隐性模型(GG、GA/AA)基因型频率与等位基因(G、A)频率比较，差异均有统计学意义(OR＝1.6，95%CI：1.0～2.6，P＝0.040；OR＝1.6，95%CI：1.0～2.4，P＝0.038)。在隐性模型(GG、GA/AA)中，GA/AA基因型患儿s-ASD发病风险，是GG基因型患儿的1.6倍；携带A等位基因患儿s-ASD发病风险，是携带G等位基因患儿的1.6倍。

结论

ABCC 2基因1249G>A多态位点与先天性间隔缺损存在相关性。

关键词: ABCC 2基因, 1249G>A多态位点, 室间隔缺损, 房间隔缺损, 心脏病，先天性, 胎儿
Objective

To explore the associations between ABCC 2 gene 1249G>A polymorphism and congenital isolated septal defects.

Methods

From March 2013 and March 2015, a total of 300 children with congenital isolated septal defects from Department of Pediatric Cardiovascular, West China Second University Hospital, Sichuan University were selected as research subjects and enrolled as case group, while 300 children with respiratory tract infections and age, gender matched during the same period in the same hospital were recruited as control group. Case group was further divided into the perimembranous ventricular septal defect (Pm-VSD) subgroup (n=150) and the secondary atrial septal defect (s-ASD) subgroup (n=150). Genotypings of the ABCC 2 gene 1249G>A polymorphism in case group and control group were performed by PCR sequencing. Independent-samples t test was used to compared the ages between case group and control group, Pm-VSD subgroup and control group, s-ASD subgroup and control group, respectively. Chi-square test was used to compare the gender ratios, and GG, GA, AA genotypes of ABCC 2 gene 1249G>A polymorphism between case group and control group, Pm-VSD subgroup and control group, s-ASD subgroup and control group, respectively. Single-factor unconditional logistic regression analysis was used to compare genotypes frequencies of different genetic models in ABCC 2 gene 1249G>A polymorphism between case group and control group, Pm-VSD subgroup and control group, s-ASD subgroup and control group, respectively. This study was approved by the Ethics Committee of Human Beings in West China Second University Hospital, Sichuan University and the guardians of every subject signed informed consent of clinical research.

Results

①There were no significant differences in the gender ratio and age between case group and control group, Pm-VSD subgroup and control group, s-ASD subgroup and control group, respectively (P>0.05). ②The genotypes distributions of ABCC 2 gene 1249G>A polymorphism of case group, Pm-VSD subgroup, s-ASD subgroup, and control group all were in line with Hardy-Weinberg equilibrium law (χ2=0.880, P=0.820; χ2=0.246, P=0.913; χ2=1.042, P=0.748; χ2=0.110, P=0.925). ③The GG, GA, AA genotypes frequencies of ABCC 2 gene 1249G>A polymorphism in case group were 67.0% (201/300), 30.7% (92/300), and 2.3% (7/300), respectively, 80.7% (242/300), 18.0% (54/300), and 1.3% (4/300), respectively in control group, 62.3% (94/150), 35.1% (52/150), and 2.6% (4/150), respectively in Pm-VSD subgroup, 71.3% (107/150), 26.7% (40/150), and 2.0% (3/150), respectively in s-ASD subgroup. The genotypes distributions of ABCC 2 gene 1249G>A polymorphism were significantly different between control group and case group, Pm-VSD subgroup, and s-ASD subgroup (χ2=14.503, P=0.001; χ2=17.132, P<0.001; χ2=5.005, P=0.042). ④Results of single-factor unconditional logistic analysis for the different genetic models of ABCC 2 gene 1249G>A polymorphism showed that, there were statistically significant differences between case group and control group in genotypes frequencies of recessive model (GG, GA/AA) (OR=2.0, 95%CI: 1.4-3.0, P<0.001) and allele frequencies of G and A (OR=1.9, 95%CI: 1.3-2.6, P<0.001), which meant that in the recessive model (GG, GA/AA), the onset risk of congenital septal defect in children with GA/AA genotypes was 2.0 times of that in children with GG genotype; and the onset risk of congenital septal defect in children with A allele was 1.9 times of that in children with G allele. However, there was no significant difference when applying the dominant model (P>0.05). ⑤The stratified analysis of congenital heart disease (CHD) subtypes demonstrated that, there were statistically significant differences between Pm-VSD subgroup and control group in genotypes frequencies of recessive model (GG, GA/AA) (OR=2.5, 95%CI: 1.6-3.9, P<0.001) and allele frequencies of G and A (OR=2.2, 95%CI: 1.5-3.2, P<0.001), which meant that in the recessive model (GG, GA/AA), the onset risk of Pm-VSD in children with GA/AA genotypes was 2.5 times of that in children with GG genotype; and the onset risk of Pm-VSD in children with A allele is 2.2 times of that in children with G allele. And there were statistically significant differences between s-ASD subgroup and control group in genotypes frequencies of recessive model (GG, GA/AA) (OR=1.6, 95%CI: 1.0-2.6, P=0.040) and allele frequencies of G and A (OR=1.6, 95%CI: 1.0-2.4, P=0.038), which meant that in the recessive model (GG, GA/AA), the onset risk of s-ASD in children with GA/AA genotypes was 1.6 times of that in children with GG genotype; and the onset risk of s-ASD in children with A allele is 1.6 times of that in children with G allele.

Conclusion

There is a significant association between ABCC 2 gene 1249G>A polymorphism and congenital isolated septal defects.

Key words: ABCC 2 gene, 1249G>A polymorphism, Heart septal defects, ventricular, Heart septal defects, atrial, Heart disease, congenital, Fetus
表1 病例组与对照组、Pm-VSD亚组与对照组、s-ASD亚组与对照组一般临床资料比较
组别 例数 性别[例数(%)] 年龄(月，±s)
男 女
病例组 300 122(40.7) 178(59.3) 40.4±9.2
Pm-VSD亚组 150 64(42.7) 86(57.3) 38.6±7.6
s-ASD亚组 150 58(38.7) 92(61.3) 42.6±9.8
对照组 300 122(40.7) 178(59.3) 39.2±8.4
检验值a ? χ2＝0.000 t＝1.668
P值 ? 1.000 0.096
表2 病例组和对照组ABCC 2基因1249G>A多态位点基因型频率分布比较[例数(%)]
组别 例数 ABCC 2基因1249G>A多态位点基因型
GG GA AA
病例组 300 201(67.0) 92(30.7) 7(2.3)
对照组 300 242(80.7) 54(18.0) 4(1.3)
χ2值 ? ? 14.503 ?
P值 ? ? 0.001 ?
表3 病例组(n＝300)和对照组(n＝300) ABCC 2基因1249G>A多态位点不同遗传模型的基因型频率分布比较[例数(%)]
不同遗传模型 病例组 对照组 OR值 OR值95%CI P值
显性模型 ? ? ? ? ?
? GG/GA 293(97.7) 296(98.7) 1.8 0.5～6.1 0.545
? AA 7(2.3) 4(1.3) ? ? ?
隐性模型 ? ? ? ? ?
? GG 201(67.0) 242(80.7) 2.0 1.4～3.0 <0.001
? GA/AA 99(33.0) 58(19.3) ? ? ?
等位基因 ? ? ? ? ?
? G 494(82.3) 538(89.7) 1.9 1.3～2.6 <0.001
? A 106(17.7) 62(10.3) ? ? ?
表4 Pm-VSD亚组及s-ASD亚组分别和对照组ABCC 2基因1249G>A多态位点基因型频率分布比较[例数(%)]
组别 例数 ABCC2基因1249G>A多态位点基因型
GG GA AA
Pm-VSD亚组 150 94(62.3) 52(35.1) 4(2.6)
s-ASD亚组 150 107(71.3) 40(26.7) 3(2.0)
对照组 300 242(80.7) 54(18.0) 4(1.3)
表5 Pm-VSD亚组(n＝150)及s-ASD亚组(n＝150)分别和对照组(n＝300) ABCC 2基因1249G>A多态位点不同遗传模型的基因型频率分布比较[例数(%)]
不同遗传模型 Pm-VSD亚组 s-ASD亚组 对照组 Pm-VSD亚组与对照组 s-ASD亚组与对照组
OR值 OR值95%CI P值 OR值 OR值95%CI P值
显性模型 ? ? ? ? ? ? ? ? ?
? GG/GA 146(97.3) 147(98.0) 296(98.7) 2.0 0.5～8.2 0.450 1.5 0.3～6.8 0.691
? AA 4(2.6) 3(2.0) 4(1.3) ? ? ? ? ? ?
隐性模型 ? ? ? ? ? ? ? ? ?
? GG 94(62.3) 107(71.3) 242(80.7) 2.5 1.6～3.9 <0.001 1.6 1.0～2.6 0.040
? GA/AA 56(37.7) 42(28.7) 58(19.3) ? ? ? ? ? ?
等位基因 ? ? ? ? ? ? ? ? ?
? G 240(80.0) 254(84.7) 538(89.7) 2.2 1.5～3.2 <0.001 1.6 1.0～2.4 0.038
? A 60(20.0) 46(15.3) 62(10.3) ? ? ? ? ? ?
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