Proteome-wide mendelian randomization identifies causal plasma proteins in venous thromboembolism development

被引：20

作者：

Li, Haobo ^{[1
,2
]}

Zhang, Zhu ^{[1
]}

Qiu, Yuting ^{[3
]}

Weng, Haoyi ^{[4
,5
]}

Yuan, Shuai ^{[6
]}

Zhang, Yunxia ^{[1
]}

Zhang, Yu ^{[1
,3
]}

Xi, Linfeng ^{[1
,3
]}

Xu, Feiya ^{[1
,3
]}

Ji, Xiaofan ^{[1
,2
]}

Hao, Risheng ^{[1
,3
]}

Yang, Peiran ^{[7
,8
]}

Chen, Gang ^{[4
,5
]}

Zuo, Xianbo ^{[9
]}

Zhai, Zhenguo ^{[1
]}

Wang, Chen ^{[1
]}

机构：

[1] Chinese Acad Med Sci, China Japan Friendship Hosp, Inst Resp Med, Natl Ctr Resp Med,State Key Lab Resp Hlth & Multim, Beijing, Peoples R China

[2] Chinese Acad Med Sci & Peking Union Med Coll, China Japan Friendship Hosp, Beijing, Peoples R China

[3] Capital Med Univ, Beijing, Peoples R China

[4] WeGene, Shenzhen, Peoples R China

[5] Cent South Univ, Sch Comp Sci & Engn, Hunan Prov Key Lab Bioinformat, Changsha, Peoples R China

[6] Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, Stockholm, Sweden

[7] Chinese Acad Med Sci, Inst Basic Med Sci, Dept Physiol, State Key Lab Resp Hlth & Multimorbid, Beijing, Peoples R China

[8] Chinese Acad Med Sci & Peking Union Med Coll, Inst Resp Med, Natl Ctr Resp Med, Sch Basic Med,Natl Clin Res Ctr Resp Dis, Beijing, Peoples R China

[9] China Japan Friendship Hosp, Dept Pharm, Beijing, Peoples R China

来源：

JOURNAL OF HUMAN GENETICS | 2023年 / 68卷 / 12期

基金：

中国国家自然科学基金;

关键词：

THROMBOSIS; ASSOCIATION; NEXIN-1; GWAS;

D O I：

10.1038/s10038-023-01186-6

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Genome-wide association studies (GWAS) have identified numerous risk loci for venous thromboembolism (VTE), but it is challenging to decipher the underlying mechanisms. We employed an integrative analytical pipeline to transform genetic associations to identify novel plasma proteins for VTE. Proteome-wide association studies (PWAS) were determined by functional summary-based imputation leveraging data from a genome-wide association analysis (14,429 VTE patients, 267,037 controls), blood proteomes (1348 cases), followed by Mendelian randomization, Bayesian colocalization, protein-protein interaction, and pathway enrichment analysis. Twenty genetically regulated circulating protein abundances (F2, F11, ABO, PLCG2, LRP4, PLEK, KLKB1, PROC, KNG1, THBS2, SERPINA1, RARRES2, CEL, GP6, SERPINE2, SERPINA10, OBP2B, EFEMP1, F5, and MSR1) were associated with VTE. Of these 13 proteins demonstrated Mendelian randomized correlations. Six proteins (F2, F11, PLEK, SERPINA1, RARRES2, and SERPINE2) had strong support in colocalization analysis. Utilizing multidimensional data, this study suggests PLEK, SERPINA1, and SERPINE2 as compelling proteins that may provide key hints for future research and possible diagnostic and therapeutic targets for VTE.

引用

页码：805 / 812

页数：8

共 48 条

[11] Deep vein thrombosis and pulmonary embolism [J].

Di Nisio, Marcello ;

van Es, Nick ;

Bueller, Harry R. .

LANCET, 2016, 388 (10063) :3060-3073

[12] Platelet Proteome Analysis Reveals Integrin-dependent Aggregation Defects in Patients with Myelodysplastic Syndromes [J].

Froebel, Julia ;

Cadeddu, Ron-Patrick ;

Hartwig, Sonja ;

Bruns, Ingmar ;

Wilk, Christian M. ;

Kuendgen, Andrea ;

Fischer, Johannes C. ;

Schroeder, Thomas ;

Steidl, Ulrich G. ;

Germing, Ulrich ;

Lehr, Stefan ;

Haas, Rainer ;

Czibere, Akos .

MOLECULAR & CELLULAR PROTEOMICS, 2013, 12 (05) :1272-1280

[13] Bayesian Test for Colocalisation between Pairs of Genetic Association Studies Using Summary Statistics [J].

Giambartolomei, Claudia ;

Vukcevic, Damjan ;

Schadt, Eric E. ;

Franke, Lude ;

Hingorani, Aroon D. ;

Wallace, Chris ;

Plagnol, Vincent .

PLOS GENETICS, 2014, 10 (05)

[14] Integrative approaches for large-scale transcriptome-wide association studies [J].

Gusev, Alexander ;

Ko, Arthur ;

Shi, Huwenbo ;

Bhatia, Gaurav ;

Chung, Wonil ;

Penninx, Brenda W. J. H. ;

Jansen, Rick ;

de Geus, Eco J. C. ;

Boomsma, Dorret I. ;

Wright, Fred A. ;

Sullivan, Patrick F. ;

Nikkola, Elina ;

Alvarez, Marcus ;

Civelek, Mete ;

Lusis, Aldons J. ;

Lehtimaki, Terho ;

Raitoharju, Emma ;

Kahonen, Mika ;

Seppala, Ilkka ;

Raitakari, Olli T. ;

Kuusisto, Johanna ;

Laakso, Markku ;

Price, Alkes L. ;

Pajukanta, Paivi ;

Pasaniuc, Bogdan .

NATURE GENETICS, 2016, 48 (03) :245-252

[15] Genome-wide association studies for common diseases and complex traits [J].

Hirschhorn, JN ;

Daly, MJ .

NATURE REVIEWS GENETICS, 2005, 6 (02) :95-108

[16] Reciprocal regulation of urokinase receptor (CD87)-mediated cell adhesion by plasminogen activator inhibitor-1 and protease nexin-1 [J].

Kanse, SM ;

Chavakis, T ;

Al-Fakhri, N ;

Hersemeyer, K ;

Monard, D ;

Preissner, KT .

JOURNAL OF CELL SCIENCE, 2004, 117 (03) :477-485

[17] Genome-wide association analysis of venous thromboembolism identifies new risk loci and genetic overlap with arterial vascular disease [J].

Klarin, Derek ;

Busenkell, Emma ;

Judy, Renae ;

Lynch, Julie ;

Levin, Michael ;

Haessler, Jeffery ;

Aragam, Krishna ;

Chaffin, Mark ;

Haas, Mary ;

Lindstrom, Sara ;

Assimes, Themistocles L. ;

Huang, Jie ;

Lee, Kyung Min ;

Shao, Qing ;

Huffman, Jennifer E. ;

Kabrhel, Christopher ;

Huang, Yunfeng ;

Sun, Yan, V ;

Vujkovic, Marijana ;

Saleheen, Danish ;

Miller, Donald R. ;

Reaven, Peter ;

DuVal, Scott ;

Boden, William E. ;

Pyarajan, Saiju ;

Reiner, Alex P. ;

Tregouet, David-Alexandre ;

Henke, Peter ;

Kooperberg, Charles ;

Gaziano, J. Michael ;

Concato, John ;

Rader, Daniel J. ;

Cho, Kelly ;

Chang, Kyong-Mi ;

Wilson, Peter W. F. ;

Smith, Nicholas L. ;

O'Donnell, Christopher J. ;

Tsao, Philip S. ;

Kathiresan, Sekar ;

Obi, Andrea ;

Damrauer, Scott M. ;

Natarajan, Pradeep .

NATURE GENETICS, 2019, 51 (11) :1574-+

[18] Whole blood gene expression analyses in patients with single versus recurrent venous thromboembolism [J].

Lewis, Deborah A. ;

Stashenko, Gregg J. ;

Akay, Olga M. ;

Price, Lulit I. ;

Owzar, Kouros ;

Ginsburg, Geoffrey S. ;

Chi, Jen-Tsan ;

Ortel, Thomas L. .

THROMBOSIS RESEARCH, 2011, 128 (06) :536-540

[19] Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism [J].

Lindstrom, Sara ;

Wang, Lu ;

Smith, Erin N. ;

Gordon, William ;

Vlieg, Astrid van Hylckama ;

de Andrade, Mariza ;

Brody, Jennifer A. ;

Pattee, Jack W. ;

Haessler, Jeffrey ;

Brumpton, Ben M. ;

Chasman, Daniel I. ;

Suchon, Pierre ;

Chen, Ming-Huei ;

Turman, Constance ;

Germain, Marine ;

Wiggins, Kerri L. ;

MacDonald, James ;

Braekkan, Sigrid K. ;

Armasu, Sebastian M. ;

Pankratz, Nathan ;

Jackson, Rebecca D. ;

Nielsen, Jonas B. ;

Giulianini, Franco ;

Puurunen, Marja K. ;

Ibrahim, Manal ;

Heckbert, Susan R. ;

Damrauer, Scott M. ;

Natarajan, Pradeep ;

Klarin, Derek ;

de Vries, Paul S. ;

Sabater-Lleal, Maria ;

Huffman, Jennifer E. ;

Bammler, Theo K. ;

Frazer, Kelly A. ;

McCauley, Bryan M. ;

Taylor, Kent ;

Pankow, James S. ;

Reiner, Alexander P. ;

Gabrielsen, Maiken E. ;

Deleuze, Jean-Francois ;

O'Donnell, Chris J. ;

Kim, Jihye ;

McKnight, Barbara ;

Kraft, Peter ;

Hansen, John-Bjarne ;

Rosendaal, Frits R. ;

Heit, John A. ;

Psaty, Bruce M. ;

Tang, Weihong ;

Kooperberg, Charles .

BLOOD, 2019, 134 (19) :1645-1657

[20] Abundant associations with gene expression complicate GWAS follow-up [J].

Liu, Boxiang ;

Gloudemans, Michael J. ;

Rao, Abhiram S. ;

Ingelsson, Erik ;

Montgomery, Stephen B. .

NATURE GENETICS, 2019, 51 (05) :768-+

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