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北京大学学报（医学版） ›› 2026, Vol. 58 ›› Issue (3): 528-535. doi: 10.19723/j.issn.1671-167X.2026.03.012

• 论著 • 上一篇    下一篇

CTNNA基因家族遗传培育效应与缺血性脑卒中的关联分析

吴婧娴1, 郑柳燕1, 于欢1, 王淮蓉1, 解舒婷1, 陈雅霖1, 李腾1, 王梦莹2,3, 秦雪英1,2, 吴涛1,2, 陈大方1,2, 武轶群1,2,*(), 胡永华1,2   

  1. 1. 北京大学公共卫生学院流行病与卫生统计学系，北京 100191
    2. 重大疾病流行病学教育部重点实验室(北京大学)，北京 100191
    3. 北京大学公共卫生学院营养与食品卫生学系，北京 100191
  • 收稿日期:2026-03-10 出版日期:2026-06-18 发布日期:2026-04-09
  • 通讯作者: 武轶群

Association analysis between genetic nurturing effects of CTNNA gene family and ischemic stroke

Jingxian WU1, Liuyan ZHENG1, Huan YU1, Huairong WANG1, Shuting XIE1, Yalin CHEN1, Teng LI1, Mengying WANG2,3, Xueying QIN1,2, Tao WU1,2, Dafang CHEN1,2, Yiqun WU1,2,*(), Yonghua HU1,2   

  1. 1. Department of Epidemiology and Biostatistics, Peking University School of Public Health, Beijing 100191, China
    2. Key Laboratory of Epidemiology of Major Disease (Peking University), Ministry of Education, Beijing 100191, China
    3. Department of Nutrition and Food Hygiene, Peking University School of Public Health, Beijing 100191, China
  • Received:2026-03-10 Online:2026-06-18 Published:2026-04-09
  • Contact: Yiqun WU

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摘要：

目的: 评估亲代基因型对子代缺血性脑卒中(ischemic stroke, IS)风险的遗传培育效应，并解析该效应的父源与母源差异。方法: 依托“北方农村地区居民常见慢性非传染性疾病家系队列研究”，选取核心家系、同胞对等，检测CTNNA基因家族(CTNNA1、CTNNA2、CTNNA3)的单核苷酸多态性(single nucleotide polymorphisms, SNPs)。以子代为单位推断亲代未传递给子代的等位基因，构建线性混合效应模型，评估亲代未传递等位基因对子代IS的遗传培育效应，并对比其与个体遗传效应的差异，区分父源、母源效应，同时构建统计量η评估两者的相对大小。结果: 共纳入530个家系的1 005名子代，其中IS患者共308例(30.6%)，平均年龄56.3岁。共识别了16个具有IS遗传培育效应的独立SNPs(9个位于CTNNA2，6个位于CTNNA3，1个位于CTNNA1)，效应值为-0.282~0.480，rs117741773(CTNNA2)的效应最强(0.480，95%CI: 0.278~0.682)；其中，仅4个SNPs兼具个体遗传效应，且方向与遗传培育效应相反。亲本特异性分析显示，12个SNPs呈单一亲本遗传培育效应，4个仅表现为父源效应(效应值：-0.298~0.945，η：1.21~63.83)，8个仅表现为母源效应(效应值：-0.489~0.602，η：0.03~0.44)。结论: CTNNA基因家族中存在多个具有遗传培育效应的IS易感位点，且不同亲本来源效应存在异质性，提示亲本特异性遗传培育效应在IS病因中具有重要作用。

关键词: 遗传培育效应, 亲本特异性, 缺血性卒中, CTNNA基因家族, 基因-环境相互作用

Abstract:

Objective: To evaluate the genetic nurture effect of parental genotypes on the risk of ischemic stroke (IS) in offspring and to elucidate the parental origin-specific differences in this effect. Methods: This study utilized data from the "Family Cohort of Common Chronic Non-communicable Diseases in Rural Areas of Northern China". A total of 530 core families and sibling pairs were selected, comprising 1 005 offspring. Single nucleotide polymorphisms (SNPs) within the CTNNA gene family (CTNNA1, CTNNA2 and CTNNA3) were detected. Using offspring as the unit of analysis, parental non-transmitted alleles were inferred based on Mendelian inheritance principles. Rigorous quality control was implemented for genotype imputation, ensuring high reliability of the inferred data. Linear mixed-effects models were constructed to estimate the genetic nurture effect of non-transmitted alleles on offspring IS. These models compared differences between genetic nurture effects and individual genetic effects, distinguished between paternal and maternal effects, and calculated the statistic η to assess the relative magnitude of parental effects. Results: A total of 1 005 offspring from 530 families were included, comprising 308 IS patients (30.6%) with a mean age of 56.3 years. Sixteen independent SNPs associated with IS genetic nurture effects were identified (9 in CTNNA2, 6 in CTNNA3, and 1 in CTNNA1). The effect sizes ranged from -0.282 to 0.480, with rs117741773 (CTNNA2) showing the strongest effect (0.480, 95%CI: 0.278-0.682). Only four of these SNPs exhibited concurrent individual genetic effects, which acted in the opposite direction to the genetic nurture effects. Parent-of-origin specific analysis revealed that 12 SNPs exhibited genetic nurture effects from a single origin: 4 showed exclusively paternal effects (effect size: -0.298 to 0.945; η: 1.21 to 63.83), and 8 showed exclusively maternal effects (effect size: -0.489 to 0.602; η: 0.03 to 0.44). Conclusion: This study provides evidence that multiple IS susceptibility loci within the CTNNA gene family exhibit significant genetic nurture effects. The findings highlight the complex interplay between inherited genetics and the family environment. The heterogeneity of these effects based on parental origin underscores the significant role of parent-specific genetic nurture in the etiology of IS, offering new insights for understanding the missing heritability in stroke genetics.

Key words: Genetic nurture effect, Parent-of-origin specific, Ischemic stroke, CTNNA gene family, Gene-environment interactions

中图分类号: 

  • R181.33

表1

子代研究对象的基本特征"

Items Offsprings without IS
(n=697)		 Offsprings with IS
(n=308)		 Total Offsprings
(n=1 005)		 P value
Age/years, $\bar x \pm s$ 54.5±10.8 60.5±7.8 56.3±10.4 < 0.001
Gender, n (%) 0.002
  Male 386 (55.4) 203 (65.9) 589 (58.6)
  Female 311 (44.6) 105 (34.1) 416 (41.4)
Marital status, n (%) 0.961
  Married 612 (89.3) 267 (89.0) 879 (89.2)
  Other status 73 (10.7) 33 (11.0) 106 (10.8)
Educational status, n (%) < 0.001
  Primary school and below 234 (34.1) 148 (48.8) 382 (38.6)
  Junior high school 313 (45.6) 121 (39.9) 434 (43.9)
  Senior high school and above 139 (20.3) 34 (11.2) 173 (17.5)
Hypertension, n (%) 340 (57.1) 217 (73.3) 557 (62.4) < 0.001
Diabetes mellitus, n (%) 157 (26.7) 89 (29.7) 246 (27.7) 0.393
Hyperlipidemia, n (%) 181 (34.9) 132 (50.4) 313 (40.1) < 0.001
BMI/(kg/m2), $\bar x \pm s$ 26.3±3.8 26.3±3.6 26.3±3.5 0.780

表2

具有遗传培育效应的16个IS易感位点"

SNPs A1 A2 MAF βnT (95%CI) P value
CTNNA1
  rs76210266 T C 0.011 0.362 (0.108, 0.615) 5.21×10-3
CTNNA2
  rs117741773 A G 0.011 0.480 (0.278, 0.682) 3.29×10-6
  rs78592910 A C 0.011 0.361 (0.136, 0.586) 1.64×10-3
  rs55767232 G A 0.019 0.243 (0.067, 0.419) 6.84×10-3
  rs868032 C T 0.496 0.065 (0.020, 0.111) 4.68×10-3
  rs546179372 T TA 0.355 0.065 (0.016, 0.115) 9.90×10-3
  rs6547309 C A 0.408 0.068 (0.019, 0.116) 5.58×10-3
  rs149752934 T C 0.019 -0.282 (-0.452, -0.113) 1.11×10-3
  rs181654218 T C 0.016 -0.272 (-0.465, -0.079) 5.71×10-3
  rs10166591 C T 0.373 -0.063 (-0.111, -0.016) 8.67×10-3
CTNNA3
  rs16924512 G A 0.013 0.239 (0.067, 0.412) 6.50×10-3
  rs79767344 C T 0.027 0.206 (0.062, 0.351) 5.21×10-3
  rs78184651 C T 0.015 -0.267 (-0.460, -0.074) 6.79×10-3
  rs78365177 T C 0.021 -0.250 (-0.417, -0.083) 3.37×10-3
  rs78279947 C G 0.020 -0.238 (-0.416, -0.061) 8.56×10-3
  rs139947562 A G 0.026 -0.233 (-0.380, -0.085) 2.01×10-3

图1

16个IS易感位点的遗传培育效应、个体遗传效应和总遗传效应"

图2

16个IS易感位点的父源与母源遗传培育效应"

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ISSN 1671-167X
CN 11-4691/R
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