Genome-wide association studies (GWAS) have identified hundreds of cardiometabolic disease (CMD) risk loci. However, they contribute little to genetic variance, and most downstream gene-regulatory mechanisms are unknown. We genotyped and RNA-sequenced vascular and metabolic tissues from 600 coronary artery disease patients in the Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task study (STARNET). Gene expression traits associated with CMD risk single-nucleotide polymorphism (SNPs) identified by GWAS were more extensively found in STARNET than in tissue- and disease-unspecific gene-tissue expression studies, indicating sharing of downstream cis-/trans-gene regulation across tissues and CMDs. In contrast, the regulatory effects of other GWAS risk SNPs were tissue-specific; abdominal fat emerged as an important gene-regulatory site for blood lipids, such as for the low-density lipoprotein cholesterol and coronary artery disease risk gene PCSK9 STARNET provides insights into gene-regulatory mechanisms for CMD risk loci, facilitating their translation into opportunities for diagnosis, therapy, and prevention.

/pdf/cardiometabolic-risk-loci-share-downstream-cis-and-trans-lqw7rnsxs1.pdf

Cardiometabolic risk loci share downstream cis- and trans-gene regulation across tissues and diseases.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jth.12229

Fibrin(ogen) and thrombotic disease

Fibrinogen is cleaved by thrombin to fibrin, which provides the blood clot with its essential structural backbone. As an acute phase protein, the plasma levels of fibrinogen are increased in response to inflammatory conditions. In addition to fibrinogen levels, fibrin clot structure is altered by a number of factors. These include thrombin levels, treatment with common cardiovascular medications, such as aspirin, anticoagulants, statins and fibrates, as well as metabolic disease states such as diabetes mellitus and hyperhomocysteinaemia. In vitro studies of fibrin clot structure can provide information regarding fibre density, clot porosity, the mechanical strength of fibres and fibrinolysis. A change in fibrin clot structure, to a denser clot with smaller pores which is more resistant to lysis, is strongly associated with cardiovascular disease. This pathological change is present in patients with arterial as well as venous diseases, and is also found in a moderate form in relatives of patients with cardiovascular disease. Pharmacological therapies, aimed at both the treatment and prophylaxis of cardiovascular disease, appear to result in positive changes to the fibrin clot structure. As such, therapies aimed at 'normalising' fibrin clot structure may be of benefit in the prevention and treatment of cardiovascular disease.

https://th.schattauer.de/en/contents/archive/issue/2145/manuscript/21217/download.html

Clot properties and cardiovascular disease

http://kooperberg.fhcrc.org/papers/2015huffman.pdf

Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF

Purpose of reviewFibrinogen is the protein substrate of the multifaceted procoagulant and proinflammatory enzyme, thrombin. Fibrin, the product of thrombin's proteolytic cleavage of fibrinogen, provides biophysical and biochemical support to blood clots, and subsequent degradation of fibrin by plasm

Determinants of fibrin formation, structure, and function.

Objective— γ′ fibrinogen is a newly emerging biomarker that is associated with cardiovascular disease (CVD). However, the genetic determinants of γ′ fibrinogen levels are unknown. We therefore conducted a genome-wide association study on 3042 participants from the Framingham Heart Study Offspring Cohort. Methods and Results— A genome-wide association study with 2.5 million single-nucleotide polymorphisms (SNPs) was carried out for γ′ fibrinogen levels from the cycle 7 examination. Fifty-four SNPs in or near the fibrinogen gene locus demonstrated genome-wide significance ( P −8 ) for association with γ′ fibrinogen levels. The top-signal SNP was rs7681423 ( P =9.97×10 −110 ) in the fibrinogen gene locus near FGG , which encodes the γ chain. Conditional on the top SNP, the only other SNP that remained genome-wide significant was rs1049636. Associations between SNPs, γ′ fibrinogen levels, and prevalent CVD events were examined using multiple logistic regression. γ′ fibrinogen levels were associated with prevalent CVD ( P =0.02), although the top 2 SNPs associated with γ′ fibrinogen levels were not associated with CVD. These findings contrast those for total fibrinogen levels, which are associated with different genetic loci, particularly FGB , which encodes the Bβ chain. Conclusion— γ′ fibrinogen is associated with prevalent CVD and with SNPs exclusively in and near the fibrinogen gene locus.

Jing Wang

Papers

Assessment of Genetic Determinants of the Association of γ′ Fibrinogen in Relation to Cardiovascular Disease