Genome-wide association analyses identified novel susceptibility loci for pulmonary embolism among Han Chinese population

被引：27

作者：

Zhang, Zhu ^{[1
]}

Li, Haobo ^{[2
]}

Weng, Haoyi ^{[3
]}

Zhou, Geyu ^{[4
]}

Chen, Hong ^{[5
]}

Yang, Guoru ^{[6
]}

Zhang, Ping ^{[7
]}

Zhang, Xiangyan ^{[8
]}

Ji, Yingqun ^{[9
]}

Ying, Kejing ^{[10
]}

Liu, Bo ^{[11
]}

Xu, Qixia ^{[12
]}

Tang, Yongjun ^{[13
]}

Zhu, Guangfa ^{[14
]}

Liu, Zhihong ^{[15
]}

Xia, Shuyue ^{[16
]}

Yang, Xiaohong ^{[17
]}

Dong, Lixia ^{[18
]}

Zhu, Ling ^{[19
]}

Zeng, Mian ^{[20
]}

Yuan, Yadong ^{[21
]}

Yang, Yuanhua ^{[22
]}

Zhang, Nuofu ^{[23
,24
]}

Xu, Xiaomao

Pang, Wenyi ^{[25
]}

Zhang, Meng

Zhang, Yu ^{[26
]}

Zhen, Kaiyuan ^{[27
]}

Wang, Dingyi ^{[28
]}

Lei, Jieping ^{[28
]}

Wu, Sinan ^{[28
]}

Shu, Shi ^{[1
]}

Zhang, Yunxia ^{[1
]}

Zhang, Shuai ^{[1
]}

Gao, Qian ^{[1
]}

Huang, Qiang ^{[1
]}

Deng, Chao ^{[4
]}

Fu, Xi ^{[3
]}

Chen, Gang ^{[3
]}

Duan, Wenxin ^{[29
]}

Wan, Jun

Xie, Wanmu ^{[1
]}

Zhang, Peng ^{[30
]}

Wang, Shengfeng ^{[31
]}

Yang, Peiran ^{[29
]}

Zuo, Xianbo ^{[32
,34
]}

Zhai, Zhenguo ^{[1
]}

Wang, Chen ^{[33
,34
,35
,36
,37
,38
,39
,40
]}

机构：

[1] Chinese Acad Med Sci, China Japan Friendship Hosp, Inst Resp Med,Natl Clin Res Ctr Resp Dis, Natl Ctr Resp Med,Dept Pulm & Crit Care Med, Beijing 100029, Peoples R China

[2] Chinese Acad Med Sci & Peking Union Med Coll, China Japan Friendship Hosp, Dept Pulm & Crit Care Med,Chinese Acad Med Sci, Inst Resp Med,Ctr Resp Med,Natl Ctr Resp Med, Beijing 100029, Peoples R China

[3] Cent South Univ, Sch Comp Sci & Engn, Shenzhen WeGene Clin Lab,Shenzhen Zaozhidao Techn, Hunan Prov Key Lab Bioinformat,WeGene, Shenzhen 518042, Peoples R China

[4] Shanghai Jiao Tong Univ, Coll Life Sci & Biotechnol, SJTU Yale Joint Ctr Biostat, Dept Bioinformat & Biostat, Shanghai 200240, Peoples R China

[5] Chongqing Med Univ, Dept Pulm & Crit Care Med, Affiliated Hosp 1, Chongqing 400016, Peoples R China

[6] Weifang 2 Peoples Hosp, Dept Pulm & Crit Care Med, Weifang 261021, Peoples R China

[7] Dongguan Peoples Hosp, Dept Pulm & Crit Care Med, Dongguan 523059, Peoples R China

[8] Guizhou Prov Peoples Hosp, Dept Pulm & Crit Care Med, Guiyang 550002, Peoples R China

[9] Tongji Univ, Dept Pulm & Crit Care Med, Shanghai East Hosp, Shanghai 200120, Peoples R China

[10] Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Resp Med, Sch Med, Hangzhou 310020, Peoples R China

[11] Linzi Dist Peoples Hosp, Dept Pulm & Crit Care Med, Dept Clin Microbiol, Zibo City Key Lab Resp Infect & Clin Microbiol, Zibo 255400, Peoples R China

[12] Univ Sci & Technol China, Dept Pulm & Crit Care Med, Affiliated Hosp 1, Hefei 230001, Peoples R China

[13] Cent South Univ, Dept Pulm & Crit Care Med, Xiangya Hosp, Changsha 410008, Peoples R China

[14] Capital Med Univ, Beijing Anzhen Hosp, Dept Pulm & Crit Care, Beijing 100029, Peoples R China

[15] Chinese Acad Med Sci, Fuwai Hosp, Natl Ctr Cardiovasc Dis, Beijing 100037, Peoples R China

[16] Shenyang Med Coll, Dept Pulm & Crit Care Med, Cent Hosp, Shenyang 110001, Peoples R China

[17] Peoples Hosp Xinjiang Uygur Autonomous Reg, Dept Pulm & Crit Care Med, Xinjiang 830001, Peoples R China

[18] Tianjin Med Univ, Dept Pulm & Crit Care Med, Gen Hosp, Tianjin 300050, Peoples R China

[19] Shandong Prov Hosp, Dept Pulm & Crit Care Med, Jinan 250021, Peoples R China

[20] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Med, Intens Care Unit, Guangzhou 510080, Peoples R China

[21] Second Hosp Hebei Med Univ, Dept Pulm & Crit Care Med, Shijiazhuang 050004, Peoples R China

[22] Capital Med Univ, Beijing Chao Yang Hosp, Dept Pulm & Crit Care Med, Beijing 100026, Peoples R China

[23] Guangzhou Med Univ, State Key Lab Resp Dis, Affiliated Hosp 1, Guangzhou 510230, Peoples R China

[24] Guangzhou Med Univ, Affiliated Hosp 1, Natl Clin Res Ctr Resp Dis, Guangzhou 510230, Peoples R China

[25] Beijing Hosp, Dept Pulm & Crit Care Med, Beijing 100080, Peoples R China

[26] Beijing Jishuitan Hosp, Dept Pulm & Crit Care Med, Beijing 100035, Peoples R China

[27] Capital Med Univ, China Japan Friendship Hosp, Dept Pulm & Crit Care Med,Chinese Acad Med Sci, Inst Resp Med,Ctr Resp Med,Natl Ctr Resp Med, Beijing 100029, Peoples R China

[28] Chinese Acad Med Sci, China Japan Friendship Hosp, Inst Clin Med Sci,Natl Clin Res Ctr Resp Dis, Inst Resp Med,Dept Pulm & Crit Care Med,Ctr Resp, Beijing 100029, Peoples R China

[29] Chinese Acad Med Sci, China Japan Friendship Hosp, Inst Clin Med Sci, Inst Resp Med,Natl Ctr Resp Med,Natl Clin Res Ctr, Beijing 100029, Peoples R China

[30] Chinese Acad Med Sci & Peking Union Med Coll, Inst Basic Med Sci, Beijing 100005, Peoples R China

[31] Capital Med Univ, Beijing Childrens Hosp, Beijing Pediat Res Inst, Natl Ctr Childrens Hlth, Beijing 100045, Peoples R China

[32] Peking Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Beijing 100191, Peoples R China

[33] China Japan Friendship Hosp, Dept Dermatol, Beijing, Peoples R China

[34] China Japan Friendship Hosp, Dept Pharm, 2 East Yinghua Rd, Beijing 100029, Peoples R China

[35] China Japan Friendship Hosp, Ctr Resp Med, Dept Pulm & Crit Care Med, Beijing, Peoples R China

[36] Natl Ctr Resp Med, Beijing, Peoples R China

[37] Chinese Acad Med Sci, Inst Resp Med, Beijing, Peoples R China

[38] Natl Clin Res Ctr Resp Dis, Beijing, Peoples R China

[39] Chinese Acad Med Sci, Peking Union Med Coll, Beijing, Peoples R China

[40] Capital Med Univ, Dept Resp Med, Beijing, Peoples R China

来源：

BMC MEDICINE | 2023年 / 21卷 / 01期

基金：

中国国家自然科学基金;

关键词：

Pulmonary embolism; GWAS; Han Chinese; VENOUS THROMBOEMBOLISM; MENDELIAN RANDOMIZATION; RISK-FACTORS; VISUALIZATION; METAANALYSIS; INDIVIDUALS; CONTRIBUTE; INFERENCE; SCORE;

D O I：

10.1186/s12916-023-02844-4

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BackgroundA large proportion of pulmonary embolism (PE) heritability remains unexplained, particularly among the East Asian (EAS) population. Our study aims to expand the genetic architecture of PE and reveal more genetic determinants in Han Chinese.MethodsWe conducted the first genome-wide association study (GWAS) of PE in Han Chinese, then performed the GWAS meta-analysis based on the discovery and replication stages. To validate the effect of the risk allele, qPCR and Western blotting experiments were used to investigate possible changes in gene expression. Mendelian randomization (MR) analysis was employed to implicate pathogenic mechanisms, and a polygenic risk score (PRS) for PE risk prediction was generated.ResultsAfter meta-analysis of the discovery dataset (622 cases, 8853 controls) and replication dataset (646 cases, 8810 controls), GWAS identified 3 independent loci associated with PE, including the reported loci FGG rs2066865 (p-value = 3.81 x 10(-14)), ABO rs582094 (p-value = 1.16 x 10(-10)) and newly reported locus FABP2 rs1799883 (p-value = 7.59 x 10(-17)). Previously reported 10 variants were successfully replicated in our cohort. Functional experiments confirmed that FABP2-A163G(rs1799883) promoted the transcription and protein expression of FABP2. Meanwhile, MR analysis revealed that high LDL-C and TC levels were associated with an increased risk of PE. Individuals with the top 10% of PRS had over a fivefold increased risk for PE compared to the general population.ConclusionsWe identified FABP2, related to the transport of long-chain fatty acids, contributing to the risk of PE and provided more evidence for the essential role of metabolic pathways in PE development.

引用

页数：13

共 56 条

[1] Thrombomodulin gene c.1418C>T polymorphism and risk of recurrent venous thromboembolism [J].

Ahmad, Abrar ;

Sundquist, Kristina ;

Zoller, Bengt ;

Svensson, Peter J. ;

Sundquist, Jan ;

Memon, Ashfaque A. .

JOURNAL OF THROMBOSIS AND THROMBOLYSIS, 2016, 42 (01) :135-141

[2] Venous thromboembolism - a manifestation of the metabolic syndrome [J].

Ay, Cihan ;

Tengler, Theres ;

Vormittag, Rainer ;

Simanek, Ralph ;

Dorda, Wolfgang ;

Vukovich, Thomas ;

Pabinger, Ingrid .

HAEMATOLOGICA, 2007, 92 (03) :374-380

[3] Differential effect of statin use on coagulation markers: an active comparative analysis in the NEO study [J].

Bordbar, Mohammadreza ;

de Mutsert, Renee ;

Cevval, Melike ;

Rosendaal, Frits R. ;

Jukema, J. Wouter ;

Lijfering, Willem M. .

THROMBOSIS JOURNAL, 2021, 19 (01)

[4] Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression [J].

Bowden, Jack ;

Smith, George Davey ;

Burgess, Stephen .

INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, 2015, 44 (02) :512-525

[5] LD Score regression distinguishes confounding from polygenicity in genome-wide association studies [J].

Bulik-Sullivan, Brendan K. ;

Loh, Po-Ru ;

Finucane, Hilary K. ;

Ripke, Stephan ;

Yang, Jian ;

Patterson, Nick ;

Daly, Mark J. ;

Price, Alkes L. ;

Neale, Benjamin M. .

NATURE GENETICS, 2015, 47 (03) :291-+

[6] Sensitivity Analyses for Robust Causal Inference from Mendelian Randomization Analyses with Multiple Genetic Variants [J].

Burgess, Stephen ;

Bowden, Jack ;

Fall, Tove ;

Ingelsson, Erik ;

Thompson, Simon G. .

EPIDEMIOLOGY, 2017, 28 (01) :30-42

[7] Second-generation PLINK: rising to the challenge of larger and richer datasets [J].

Chang, Christopher C. ;

Chow, Carson C. ;

Tellier, Laurent C. A. M. ;

Vattikuti, Shashaank ;

Purcell, Shaun M. ;

Lee, James J. .

GIGASCIENCE, 2015, 4

[8] Acute pulmonary thromboembolism caused by factor V Leiden mutation in South Korea A case report [J].

Choe, Hun Jee ;

Suh, Koung Jin ;

Lee, Ji Yun ;

Kim, Minyoung ;

Kim, Man Jin ;

Park, Sung Sup ;

Kim, Ji-Won ;

Kim, Se Hyun ;

Kim, Jin Won ;

Lee, Jeong-Ok ;

Kim, Yu Jung ;

Lee, Keun-Wook ;

Kim, Jee Hyun ;

Bang, Soo-Mee ;

Lee, Jong Seok .

MEDICINE, 2019, 98 (28)

[9] PRSice-2: Polygenic Risk Score software for biobank-scale data [J].

Choi, Shing Wan ;

O'Reilly, Paul F. .

GIGASCIENCE, 2019, 8 (07)

[10] Completion of the Updated Caprini Risk Assessment Model (2013 Version) [J].

Cronin, MaryAnne ;

Dengler, Nancy ;

Krauss, Eugene S. ;

Segal, Ayal ;

Wei, Nicole ;

Daly, Madison ;

Mota, Frank ;

Caprini, Joseph A. .

CLINICAL AND APPLIED THROMBOSIS-HEMOSTASIS, 2019, 25

← 1 2 3 4 5 6 →