Multiethnic Meta-Analysis of Genome-Wide Association Studies in >100 000 Subjects Identifies 23 Fibrinogen-Associated Loci but No Strong Evidence of a Causal Association Between Circulating Fibrinogen and Cardiovascular Disease

Abstract

Background Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease (CVD), range from 34 to 50%. Genetic variants so far identified by genome-wide association (GWA) studies only explain a small proportion (< 2%) of its variation. Methods and Results We conducted a meta-analysis of 28 GWA studies, including more than 90,000 subjects of European ancestry, the first GWA meta-analysis of fibrinogen levels in 7 African Americans studies totaling 8,289 samples, and a GWA study in Hispanic-Americans totaling 1,366 samples. Evaluation for association of SNPs with clinical outcomes included a total of 40,695 cases and 85,582 controls for coronary artery disease (CAD), 4,752 cases and 24,030 controls for stroke, and 3,208 cases and 46,167 controls for venous thromboembolism (VTE). Overall, we identified 24 genome-wide significant (P<5×10−8) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the three structural fibrinogen genes and pathways related to inflammation, adipocytokines and thyrotrophin-releasing hormone signaling. Whereas lead SNPs in a few loci were significantly associated with CAD, the combined effect of all 24 fibrinogen-associated lead SNPs was not significant for CAD, stroke or VTE. Conclusion We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and CAD, stroke or VTE.

Enhanced efferocytosis by dendritic cells underlies memory T-cell expansion and susceptibility to autoimmune disease in CD300f-deficient mice

“…56,57 An intronic SNP (rs10512597) of CD300f has been associated with the etiology of psoriasis disease and possibly with cardiovascular diseases. 58,59 A nonsynonymous SNP (rs2034310) in the region encoding the cytoplasmic part of CD300f has been associated with multiple sclerosis. 60 All those data imply that CD300 family members are likely to be important in the pathogenesis of autoimmune diseases, and highlight the potential of targeting CD300f, as well as CD300a, for the autoimmune disease therapies.…”

Elevated Interleukin-38 Level Associates with Clinical Response to Atorvastatin in Patients with Hyperlipidemia

“…IL-38 binds to IL-36R similar to IL-36Ra, which can inhibit the pro-inflammation function of IL-36 [22]. Moreover, polymorphisms in IL-38 were associated with CRP concentrations in humans [23] and were found to be significantly associated with coronary artery disease (CAD) [24]. In addition, IL-38 mRNA was found in human atheromatous plaques of coronary artery disease patients [25].…”

Shared genetic susceptibility of vascular-related biomarkers with ischemic and recurrent stroke

“…Investigating biomarkers in populations potentially enriched for genetic determinants can complement studies in the general population, facilitate the identification of genetic risk factors, and address whether the genetic factors influencing the biomarker also influence risk of the disease. 4 Because of the known associations between biomarker status and disease risk, GWAS in human biomarker variability can contribute understanding of biomarker pathophysiology 5 and development of treatment strategies. 6 We hypothesize an association between genetic variability and circulating levels of inflammatory biomarkers and risk for stroke.…”