Genetic Profile of Endotoxemia Reveals an Association With Thromboembolism and Stroke.
Jaakko LeskeläIiro ToppilaMari-Anne HärmaTeemu PalviainenAino SalminenErkka ValoMilla PietiäinenElisa KopraJean-Paul Pais de Barrosnull nullMariann I LasseniusAnmol KumarJoanne B ColeKajsa RoslundCarol M ForsblomAnu LoukolaAki Samuli HavulinnaLaurent LagrostVeikko V SalomaaPer-Henrik GroopMarkus PerolaJaakko A KaprioMarkku LehtoPirkko J PussinenPublished in: Journal of the American Heart Association (2021)
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.
Keyphrases
- lps induced
- genome wide
- pulmonary embolism
- inflammatory response
- dna methylation
- liquid chromatography tandem mass spectrometry
- venous thromboembolism
- toll like receptor
- copy number
- genome wide association study
- cardiovascular disease
- pulmonary hypertension
- atrial fibrillation
- metabolic syndrome
- inferior vena cava
- gene expression
- insulin resistance
- liver failure
- ms ms
- transcription factor
- direct oral anticoagulants
- coronary artery disease
- intensive care unit
- bioinformatics analysis
- acute respiratory distress syndrome
- aortic dissection
- blood brain barrier
- skeletal muscle
- subarachnoid hemorrhage
- genome wide analysis