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北京大学学报（医学版） ›› 2023, Vol. 55 ›› Issue (3): 400-407. doi: 10.19723/j.issn.1671-167X.2023.03.003

• 论著 • 上一篇    下一篇

基因-环境交互作用对动脉僵硬度影响的家系研究

王雪珩1,王斯悦1,彭和香1,范梦1,郭煌达1,侯天姣1,王梦莹1,武轶群1,秦雪英1,唐迅1,李劲1,陈大方1,胡永华1,吴涛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 100191
  • 收稿日期:2023-03-01 出版日期:2023-06-18 发布日期:2023-06-12
  • 通讯作者: 吴涛 E-mail:twu@bjmu.edu.cn
  • 基金资助:
    国家自然科学基金(82204135);北京市自然科学基金(7232237);中国博士后科学基金(BX2021021);中国博士后科学基金(2022M710249)

Genotype-environment interaction on arterial stiffness: A pedigree-based study

Xue-heng WANG1,Si-yue WANG1,He-xiang PENG1,Meng FAN1,Huang-da GUO1,Tian-jiao HOU1,Meng-ying WANG1,Yi-qun WU1,Xue-ying QIN1,Xun TANG1,Jin LI1,Da-fang CHEN1,Yong-hua HU1,Tao WU1,2,*()   

  1. 1. Department of Epidemiology and Biostatistics, Peking University School of Public Health, Beijing 100191, China
    2. Key Laboratory of Epidemiology of Major Diseases, Ministry of Education, Beijing 100191, China
  • Received:2023-03-01 Online:2023-06-18 Published:2023-06-12
  • Contact: Tao WU E-mail:twu@bjmu.edu.cn
  • Supported by:
    the National Natural Science Foundation of China(82204135);the Beijing Natural Science Foundation(7232237);the China Postdoctoral Science Foundation(BX2021021);the China Postdoctoral Science Foundation(2022M710249)

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摘要：

目的: 利用北京房山家系队列研究的基线调查数据，探索基因-环境交互作用对动脉僵硬度的影响。方法: 选取来自北京市房山区9个乡镇的先证者及其亲属作为研究对象，以吸烟、饮酒、体重指数(body mass index，BMI)、膳食评分和体力活动作为行为生活方式因素，以肱-踝脉搏波传导速度(brachial-ankle pulse wave velocity，baPWV)和踝肱指数(ankle-brachial index，ABI)作为动脉僵硬度评价指标，采用方差组分模型估计动脉僵硬度的遗传度，利用极大似然法进行基因型-环境交互作用分析。基于基因型-环境交互作用分析识别的阳性环境因素，进一步选取糖脂代谢通路上的45个基因位点作为候选基因位点，利用广义估计方程模型，探索基因位点与生活方式间的交互作用对动脉僵硬度的影响。结果: 共纳入了来自3 225个家系的6 302名研究对象，研究对象的平均年龄为56.9岁，男性占比45.1%。估计得到baPWV和ABI的遗传度分别为0.360(95%CI：0.302~0.418)和0.243(95%CI：0.175~0.311)。基因型-环境交互作用结果显示，总体加性遗传效应与年龄、性别、膳食评分和BMI间存在交互作用，分别影响baPWV和ABI水平。以baPWV作为结局评价指标时，ADAMTS9-AS2基因上和CDH13基因上的2个单核苷酸多态性(single nucleotide polymorphism, SNP)位点均与膳食评分存在交互作用。高遗传风险的个体遵循健康的生活方式能够降低其动脉僵硬程度。以ABI作为研究终点时，CDKAL1、ATP8B2和SLC30A8基因上的3个SNP位点与BMI存在交互作用，影响动脉僵硬度水平。对于高遗传风险的个体，保持健康的BMI水平能够有效降低动脉僵硬度水平。结论: 本研究利用家系关系观察了基因型-健康膳食模式和基因型-BMI交互作用影响动脉僵硬度水平，发现5个SNP位点与二者存在交互作用；维持健康的生活方式和健康的BMI水平能够降低遗传因素对动脉僵硬度的影响，为识别动脉僵硬度的环境危险因素、制定人群精准预防控制策略提供了一定的研究基础和思路。

关键词: 血管硬化程度, 基因-环境相互作用, 生活方式, 系谱

Abstract:

Objective: To utilized the baseline data of the Beijing Fangshan Family Cohort Study, and to estimate whether the association between a healthy lifestyle and arterial stiffness might be modified by genetic effects. Methods: Probands and their relatives from 9 rural areas in Fangshan district, Beijing were included in this study. We developed a healthy lifestyle score based on five lifestyle behaviors: smoking, alcohol consumption, body mass index (BMI), dietary pattern, and physical activity. The measurements of arterial stiffness were brachial-ankle pulse wave velocity (baPWV) and ankle-brachial index (ABI). A variance component model was used to determine the heritability of arterial stiffness. Genotype-environment interaction effects were performed by the maximum likelihood methods. Subsequently, 45 candidate single nucleotide polymorphisms (SNPs) located in the glycolipid metabolism pathway were selected, and generalized estimated equations were used to assess the gene-environment interaction effects between particular genetic loci and healthy lifestyles. Results: A total of 6 302 study subjects across 3 225 pedigrees were enrolled in this study, with a mean age of 56.9 years and 45.1% male. Heritability of baPWV and ABI was 0.360 (95%CI: 0.302-0.418) and 0.243 (95%CI: 0.175-0.311), respectively. Significant genotype-healthy diet interaction on baPWV and genotype-BMI interaction on ABI were observed. Following the findings of genotype-environment interaction analysis, we further identified two SNPs located in ADAMTS9-AS2 and CDH13 might modify the association between healthy dietary pattern and arterial stiffness, indicating that adherence to a healthy dietary pattern might attenuate the genetic risk on arterial stiffness. Three SNPs in CDKAL1, ATP8B2 and SLC30A8 were shown to interact with BMI, implying that maintaining BMI within a healthy range might decrease the genetic risk of arterial stiffness. Conclusion: The current study discovered that genotype-healthy dietary pattern and genotype-BMI interactions might affect the risk of arterial stiffness. Furthermore, we identified five genetic loci that might modify the relationship between healthy dietary pattern and BMI with arterial stiffness. Our findings suggested that a healthy lifestyle may reduce the genetic risk of arterial stiffness. This study has laid the groundwork for future research exploring mechanisms of arterial stiffness.

Key words: Arterial stiffness, Gene-environment interaction, Lifestyle, Pedigree

中图分类号: 

  • R394

表1

研究对象的基线特征"

Items Low-risk lifestyle factors P
0-1 2-3 4-5
Total, n (%) 887 (14.1) 3 886 (61.7) 1 529 (24.3)
Male, n (%) 762 (85.9) 1 799 (46.3) 281 (18.4) < 0.01
Age/years, ${\bar x}$±s 55.28±11.30 56.88±10.71 57.84±9.48 < 0.01
baPWV/(cm/s), ${\bar x}$±s 1 675.20±350.82 1 690.77±381.67 1 687.54±386.26 0.54
SBP/mmHg, ${\bar x}$±s 138.17±19.33 136.65±20.37 135.39±19.53 < 0.01
DBP/mmHg, ${\bar x}$±s 84.78±15.79 81.20±14.68 79.34±10.90 < 0.01
ABI, ${\bar x}$±s 1.09±0.10 1.08±0.11 1.08±0.11 0.07
Educational levels, n (%) < 0.01
  Primary school or less 323 (36.4) 1 549 (39.9) 614 (40.1)
  Middle school 426 (48.0) 1 693 (43.6) 635 (41.5)
  High school or above 138 (15.6) 644 (16.6) 280 (18.3)
Hypertension, n (%) 635 (71.6) 2 558 (65.8) 1002 (65.5) < 0.01
Diabetes, n (%) 314 (35.4) 1 643 (42.3) 854 (55.9) < 0.01
Antihypertensive treatment, n (%) 350 (39.5) 1 704 (43.8) 751 (49.1) < 0.01
Diabetes mellitus treatment, n (%) 187 (21.1) 1 156 (29.7) 687 (44.9) < 0.01
Lipid-lowering treatment, n (%) 92 (10.4) 505 (13.0) 255 (16.7) < 0.01

图1

基因型-环境交互作用研究对动脉僵硬度的影响 Ⅰ-GenoXE, type Ⅰ genotype-environment interaction; Ⅱ-GenoXE, type Ⅱ genotype-environment interaction; BMI, body mass index; baPWV, brachial-ankle pulse wave velocity; ABI, ankle-brachial index."

表2

基因位点与健康膳食模式交互作用对baPWV的影响"

Variants Reference/Effect allele EAF Adherence to a healthy dietary pattern* P for interaction
No Yes
ADAMTS9-AS2 rs4607103 T/C 0.58 1.30 (1.06-1.60) 0.89 (0.78-1.03) 0.002
CDH13 rs7193788 G/A 0.53 1.23 (1.00-1.52) 0.90 (0.79-1.04) 0.01

表3

基因位点与BMI交互作用对ABI的影响"

Variants Reference/Effect allele EAF BMI group* P for interaction
Q1 Q2 Q3
CDKAL1 rs7756992 A/G 0.53 0.71 (0.55-0.92) 1.27 (1.03-1.57) 1.01 (0.78-1.32) < 0.001
ATP8B2 rs67156297 A/G 0.89 0.74 (0.50-1.09) 0.99 (0.69-1.41) 1.60 (0.91-2.80) 0.002
SLC30A8 rs3802177 T/C 0.64 0.73 (0.56-0.95) 0.97 (0.77-1.21) 0.99 (0.76-1.30) 0.01
1 Chirinos JA , Segers P , Hughes T , et al. Large-artery stiffness in health and disease: JACC state-of-the-art review[J]. J Am Coll Cardiol, 2019, 74 (9): 1237- 1263.
doi: 10.1016/j.jacc.2019.07.012
2 Boutouyrie P , Chowienczyk P , Humphrey JD , et al. Arterial stiffness and cardiovascular risk in hypertension[J]. Circ Res, 2021, 128 (7): 864- 886.
doi: 10.1161/CIRCRESAHA.121.318061
3 Willum-Hansen T , Staessen JA , Torp-Pedersen C , et al. Prognostic value of aortic pulse wave velocity as index of arterial stiffness in the general population[J]. Circulation, 2006, 113 (5): 664- 670.
doi: 10.1161/CIRCULATIONAHA.105.579342
4 Mitchell GF , Hwang SJ , Vasan RS , et al. Arterial stiffness and cardiovascular events[J]. Circulation, 2010, 121 (4): 505- 511.
doi: 10.1161/CIRCULATIONAHA.109.886655
5 Kim M , Yoo HJ , Lee HJ , et al. Longitudinal interaction between APOA-1131T>C and overweight in the acceleration of age-related increase in arterial stiffness through the regulation of circulating triglycerides[J]. Hypertens Res, 2019, 42 (2): 241- 248.
doi: 10.1038/s41440-018-0137-y
6 Choi S , Jung S , Kim MK , et al. Gene and dietary calcium interaction effects on brachial-ankle pulse wave velocity[J]. Clin Nutr, 2016, 35 (5): 1127- 1134.
doi: 10.1016/j.clnu.2015.08.009
7 Fung TT , Chiuve SE , McCullough ML , et al. Adherence to a DASH-style diet and risk of coronary heart disease and stroke in women[J]. Arch Intern Med, 2008, 168 (7): 713- 720.
doi: 10.1001/archinte.168.7.713
8 Li Y , Schoufour J , Wang DD , et al. Healthy lifestyle and life expectancy free of cancer, cardiovascular disease, and type 2 diabetes: Prospective cohort study[J]. BMJ, 2020, 368, l6669.
9 张存泰, 陶军, 田小利, 等. 血管衰老临床评估与干预中国专家共识(2018)[J]. 中华老年病研究电子杂志, 2019, 6 (1): 1- 8.
doi: 10.3877/cma.j.issn.2095-8757.2019.01.001
10 Arnett DK , Blumenthal RS , Albert MA , et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: A report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines[J]. J Am Coll Cardiol, 2019, 74 (10): e177- e232.
doi: 10.1016/j.jacc.2019.03.010
11 Mitchell GF , Verwoert GC , Tarasov KV , et al. Common genetic variation in the 3'-BCL11B gene desert is associated with carotid-femoral pulse wave velocity and excess cardiovascular disease risk: The AortaGen Consortium[J]. Circ Cardiovasc Genet, 2012, 5 (1): 81- 90.
doi: 10.1161/CIRCGENETICS.111.959817
12 Fung K , Ramirez J , Warren HR , et al. Genome-wide association study identifies loci for arterial stiffness index in 127, 121 UK Biobank participants[J]. Sci Rep, 2019, 9 (1): 9143.
doi: 10.1038/s41598-019-45703-0
13 Rode M , Teren A , Wirkner K , et al. Genome-wide association analysis of pulse wave velocity traits provide new insights into the causal relationship between arterial stiffness and blood pressure[J]. PLoS One, 2020, 15 (8): e0237237.
doi: 10.1371/journal.pone.0237237
14 Poveda A , Chen Y , Brändström A , et al. The heritable basis of gene-environment interactions in cardiometabolic traits[J]. Diabetologia, 2017, 60 (3): 442- 452.
doi: 10.1007/s00125-016-4184-0
15 Martin LJ , Kissebah AH , Sonnenberg GE , et al. Genotype-by-smoking interaction for leptin levels in the metabolic risk complications of obesity genes project[J]. Int J Obes Relat Metab Disord, 2003, 27 (3): 334- 340.
doi: 10.1038/sj.ijo.0802232
16 Sun K , Xiang X , Li N , et al. Gene-diet interaction between SIRT6 and soybean intake for different levels of pulse wave velocity[J]. Int J Mol Sci, 2015, 16 (7): 14338- 14352.
17 Boesgaard TW , Gjesing AP , Grarup N , et al. Variant near ADAMTS9 known to associate with type 2 diabetes is related to insulin resistance in offspring of type 2 diabetes patients: EUGENE2 study[J]. PLoS One, 2009, 4 (9): e7236.
doi: 10.1371/journal.pone.0007236
18 Berria R , Wang L , Richardson DK , et al. Increased collagen content in insulin-resistant skeletal muscle[J]. Am J Physiol Endocrinol Metab, 2006, 290 (3): E560- 565.
doi: 10.1152/ajpendo.00202.2005
19 Hwang CL , Muchira J , Hibner BA , et al. Alcohol consumption: A new risk factor for arterial stiffness?[J]. Cardiovasc Toxicol, 2022, 22 (3): 236- 245.
doi: 10.1007/s12012-022-09728-8
20 Chung CM , Lin TH , Chen JW , et al. A genome-wide association study reveals a quantitative trait locus of adiponectin on CDH13 that predicts cardiometabolic outcomes[J]. Diabetes, 2011, 60 (9): 2417- 2423.
doi: 10.2337/db10-1321
21 Antoniades C , Antonopoulos AS , Tousoulis D , et al. Adiponectin: From obesity to cardiovascular disease[J]. Obes Rev, 2009, 10 (3): 269- 279.
doi: 10.1111/j.1467-789X.2009.00571.x
22 Jo J , Sull JW , Park EJ , et al. Effects of smoking and obesity on the association between CDH13 (rs3865188) and adiponectin among Korean men: The KARE study[J]. Obesity, 2012, 20 (8): 1683- 1687.
doi: 10.1038/oby.2011.128
23 Li YY , Wang LS , Lu XZ , et al. CDKAL1 gene rs7756992 A/G polymorphism and type 2 diabetes mellitus: A meta-analysis of 62, 567 subjects[J]. Sci Rep, 2013, 3 (1): 3131.
doi: 10.1038/srep03131
24 Imamura M , Takahashi A , Yamauchi T , et al. Genome-wide association studies in the Japanese population identify seven novel loci for type 2 diabetes[J]. Nature Communications, 2016, 7 (1): 10531.
doi: 10.1038/ncomms10531
25 Lin Y , Li P , Cai L , et al. Association study of genetic variants in eight genes/loci with type 2 diabetes in a Han Chinese population[J]. BMC Med Genet, 2010, 11 (1): 97.
doi: 10.1186/1471-2350-11-97
26 Koskeridis F , Evangelou E , Said S , et al. Pleiotropic genetic architecture and novel loci for C-reactive protein levels[J]. Nat Commun, 2022, 13 (1): 6939.
doi: 10.1038/s41467-022-34688-6
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ISSN 1671-167X
CN 11-4691/R
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