Genetic Profile of Endotoxemia Reveals an Association With Thromboembolism and Stroke

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FinnGen , Leskelä , J , Toppila , I , Härmä , M-A , Palviainen , T , Salminen , A , Sandholm , N , Pietiäinen , M , Kopra , E , Pais de Barros , J-P , Lassenius , M I , Kumar , A , Harjutsalo , V , Roslund , K , Forsblom , C , Loukola , A , Havulinna , A S , Lagrost , L , Salomaa , V , Groop , P-H , Perola , M , Kaprio , J , Lehto , M & Pussinen , P J 2021 , ' Genetic Profile of Endotoxemia Reveals an Association With Thromboembolism and Stroke ' , Journal of the American Heart Association , vol. 10 , no. 21 , 022482 .

Title: Genetic Profile of Endotoxemia Reveals an Association With Thromboembolism and Stroke
Author: FinnGen; Leskelä, Jaakko; Toppila, Iiro; Härmä, Mari-Anne; Palviainen, Teemu; Salminen, Aino; Sandholm, Niina; Pietiäinen, Milla; Kopra, Elisa; Pais de Barros, Jean-Paul; Lassenius, Mariann I.; Kumar, Anmol; Harjutsalo, Valma; Roslund, Kajsa; Forsblom, Carol; Loukola, Anu; Havulinna, Aki S.; Lagrost, Laurent; Salomaa, Veikko; Groop, Per-Henrik; Perola, Markus; Kaprio, Jaakko; Lehto, Markku; Pussinen, Pirkko J.
Contributor organization: Department of Oral and Maxillofacial Diseases
HUS Head and Neck Center
HUS Abdominal Center
Nefrologian yksikkö
Institute for Molecular Medicine Finland
Genetic Epidemiology
HUS Internal Medicine and Rehabilitation
Department of Medicine
Research Programs Unit
CAMM - Research Program for Clinical and Molecular Metabolism
University Management
Department of Public Health
Complex Disease Genetics
Per Henrik Groop / Principal Investigator
Helsinki University Hospital Area
Date: 2021-11-02
Language: eng
Number of pages: 58
Belongs to series: Journal of the American Heart Association
ISSN: 2047-9980
Abstract: Background Translocation of lipopolysaccharide from gram-negative bacteria into the systemic circulation results in endotoxemia. In addition to acute infections, endotoxemia is detected in cardiometabolic disorders, such as cardiovascular diseases and obesity. Methods and Results We performed a genome-wide association study of serum lipopolysaccharide activity in 11 296 individuals from 6 different Finnish study cohorts. Endotoxemia was measured by limulus amebocyte lysate assay in the whole population and by 2 other techniques (Endolisa and high-performance liquid chromatography/tandem mass spectrometry) in subpopulations. The associations of the composed genetic risk score of endotoxemia and thrombosis-related clinical end points for 195 170 participants were analyzed in FinnGen. Lipopolysaccharide activity had a genome-wide significant association with 741 single-nucleotide polymorphisms in 5 independent loci, which were mainly located at genes affecting the contact activation of the coagulation cascade and lipoprotein metabolism and explained 1.5% to 9.2% of the variability in lipopolysaccharide activity levels. The closest genes included KNG1, KLKB1, F12, SLC34A1, YPEL4, CLP1, ZDHHC5, SERPING1, CBX5, and LIPC. The genetic risk score of endotoxemia was associated with deep vein thrombosis, pulmonary embolism, pulmonary heart disease, and venous thromboembolism. Conclusions The biological activity of lipopolysaccharide in the circulation (ie, endotoxemia) has a small but highly significant genetic component. Endotoxemia is associated with genetic variation in the contact activation pathway, vasoactivity, and lipoprotein metabolism, which play important roles in host defense, lipopolysaccharide neutralization, and thrombosis, and thereby thromboembolism and stroke.
Subject: coagulation
contact activation
genome-wide association study
3121 General medicine, internal medicine and other clinical medicine
Peer reviewed: Yes
Rights: cc_by_nc
Usage restriction: openAccess
Self-archived version: publishedVersion

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