Association between single nucleotide polymorphisms in thrombospondins genes and coronary artery disease: A meta-analysis

Zhang, Xiaojie; Wei, Chunyan; Li, Wenbo; Zhang, Lingli; Zhou, Ying; Wang, Zhi-Hao; Tang, Mengxiong; Zhang, Wei; Zhang, Yun; Zhong, Ming

doi:10.1016/j.thromres.2015.04.019

Cited by 14 publications

(8 citation statements)

References 26 publications

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“…THBS4 encodes thrombospondin 4, a matricellular protein found in blood vessel walls and highly expressed in heart and adipose 20 . THBS4 may regulate vascular inflammation 21 and has been implicated in heart disease risk 22 .…”

Section: Resultsmentioning

confidence: 99%

Exome sequencing of Finnish isolates enhances rare-variant association power

FinnGen

2019

Nature

180

189

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Exome sequencing studies have generally been underpowered to identify deleterious alleles with a large effect on complex traits, as such alleles are mostly rare. Because the population of northern and eastern Finland has expanded dramatically and in isolation following a series of bottlenecks, it harbors numerous deleterious alleles at relatively high frequency. Capitalizing on this circumstance, we exome sequenced nearly 20,000 individuals from these regions. Exome-wide association studies for 64 quantitative traits clinically relevant to cardiovascular and metabolic disease identified 26 newly associated deleterious alleles. Nineteen of these alleles are either unique to or >20 times more frequent in Finns than in other Europeans and show geographical clustering comparable to Mendelian disease mutations characteristic of the Finnish population. We estimate that sequencing studies in populations without this unique history would require hundreds of thousands to millions of participants to achieve comparable association power.

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Section: Resultsmentioning

confidence: 99%

Exome sequencing of Finnish isolates enhances rare-variant association power

FinnGen

2019

Nature

180

189

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“…In addition, they suggest that it may be interesting to investigate thrombospondin 2 as a modifier of the heart and vascular phenotypes in ALGS. Indeed, recent studies have found an association of THBS2 with a variety of heart conditions, including coronary artery disease, 40 , 41 thoracic aortic dissection, 42 and heart failure with preserved ejection fraction. 43 …”

Section: Discussionmentioning

confidence: 99%

THBS2 Is a Candidate Modifier of Liver Disease Severity in Alagille Syndrome

Tsai

Gilbert

Grochowski

et al. 2016

Cellular and Molecular Gastroenterology and Hepatology

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Background & AimsAlagille syndrome is an autosomal-dominant, multisystem disorder caused primarily by mutations in JAG1, resulting in bile duct paucity, cholestasis, cardiac disease, and other features. Liver disease severity in Alagille syndrome is highly variable, however, factors influencing the hepatic phenotype are unknown. We hypothesized that genetic modifiers may contribute to the variable expressivity of this disorder.MethodsWe performed a genome-wide association study in a cohort of Caucasian subjects with known pathogenic JAG1 mutations, comparing patients with mild vs severe liver disease, followed by functional characterization of a candidate locus.ResultsWe identified a locus that reached suggestive genome-level significance upstream of the thrombospondin 2 (THBS2) gene. THBS2 codes for a secreted matricellular protein that regulates cell proliferation, apoptosis, and angiogenesis, and has been shown to affect Notch signaling. By using a reporter mouse line, we detected thrombospondin 2 expression in bile ducts and periportal regions of the mouse liver. Examination of Thbs2-null mouse livers showed increased microvessels in the portal regions of adult mice. We also showed that thrombospondin 2 interacts with NOTCH1 and NOTCH2 and can inhibit JAG1–NOTCH2 interactions.ConclusionsBased on the genome-wide association study results, thrombospondin 2 localization within bile ducts, and demonstration of interactions of thrombospondin 2 with JAG1 and NOTCH2, we propose that changes in thrombospondin 2 expression may further perturb JAG1–NOTCH2 signaling in patients harboring a JAG1 mutation and lead to a more severe liver phenotype. These results implicate THBS2 as a plausible candidate genetic modifier of liver disease severity in Alagille syndrome.

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“…The TSP4 A387P polymorphism is associated with increased CAD risk in American population (homozygote model: OR = 1.29 [95% CI: 1.04–1.61]; recessive model: OR = 1.27 [95% CI: 1.02–1.58]). No association was shown for the THS2 3′ (untranslated region) UTR polymorphism and higher CAD risk [ 41 ].…”

Section: Thrombospondins Structurementioning

confidence: 99%

“…The TMP2 T/G 3′UTR polymorphism was associated with lower risk of familial MI [ 34 ]. A global meta-analysis confirmed association with CAD only for the TMP1 N700S and TMP4 A387P polymorphisms but not for the TMP2 T/G 3′UTR [ 41 ]. The TSP4 A387P polymorphism was associated with increased coronary risk in post-MI subjects who had elevated levels of high density lipoprotein (HDL) cholesterol and C-reactive protein (CRP), an inflammatory marker [ 39 ].…”

Section: Tsps In Myocardial Infarctionmentioning

confidence: 99%

Thrombospondins: A Role in Cardiovascular Disease

Chistiakov

Melnichenko

Myasoedova

et al. 2017

IJMS

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Thrombospondins (TSPs) represent extracellular matrix (ECM) proteins belonging to the TSP family that comprises five members. All TSPs have a complex multidomain structure that permits the interaction with various partners including other ECM proteins, cytokines, receptors, growth factors, etc. Among TSPs, TSP1, TSP2, and TSP4 are the most studied and functionally tested. TSP1 possesses anti-angiogenic activity and is able to activate transforming growth factor (TGF)-β, a potent profibrotic and anti-inflammatory factor. Both TSP2 and TSP4 are implicated in the control of ECM composition in hypertrophic hearts. TSP1, TSP2, and TSP4 also influence cardiac remodeling by affecting collagen production, activity of matrix metalloproteinases and TGF-β signaling, myofibroblast differentiation, cardiomyocyte apoptosis, and stretch-mediated enhancement of myocardial contraction. The development and evaluation of TSP-deficient animal models provided an option to assess the contribution of TSPs to cardiovascular pathology such as (myocardial infarction) MI, cardiac hypertrophy, heart failure, atherosclerosis, and aortic valve stenosis. Targeting of TSPs has a significant therapeutic value for treatment of cardiovascular disease. The activation of cardiac TSP signaling in stress and pressure overload may be therefore beneficial.

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Association between single nucleotide polymorphisms in thrombospondins genes and coronary artery disease: A meta-analysis

Cited by 14 publications

References 26 publications

Exome sequencing of Finnish isolates enhances rare-variant association power

Exome sequencing of Finnish isolates enhances rare-variant association power

THBS2 Is a Candidate Modifier of Liver Disease Severity in Alagille Syndrome

Thrombospondins: A Role in Cardiovascular Disease

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