The miRNA targetome of coronary artery disease is perturbed by functional polymorphisms identified and prioritized by in-depth bioinformatics analyses exploiting genome-wide association studies

Coronary artery disease (CAD) is a multifactorial disease with environmental and genetic determinants. The genetic determinants of CAD have previously been explored by the candidate gene approach. Recently, the data from the International HapMap Project and the development of dense genotyping chips have enabled us to perform genome-wide association studies (GWAS) on a large number of subjects without bias towards any particular candidate genes. In 2007, three chip-based GWAS simultaneously revealed the significant association between common variants on chromosome 9p21 and CAD. This association was replicated among other ethnic groups and also in a meta-analysis. Further investigations have detected several other candidate loci associated with CAD. The chip-based GWAS approach has identified novel and unbiased genetic determinants of CAD and these insights provide the important direction to better understand the pathogenesis of CAD and to develop new and improved preventive measures and treatments for CAD.

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Identification of Phosphorylation Associated SNPs for Blood Pressure, Coronary Artery Disease and Stroke from Genome-wide Association Studies

Current Molecular Medicine ◽

10.2174/1566524019666190828151540 ◽

2019 ◽

Vol 19 (10) ◽

pp. 731-738

Author(s):

Xingchen Wang ◽

Xingbo Mo ◽

Huan Zhang ◽

Yonghong Zhang ◽

Yueping Shen

Keyword(s):

Blood Pressure ◽

Coronary Artery Disease ◽

Coronary Artery ◽

Cardiovascular Diseases ◽

Association Studies ◽

Serum Levels ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Artery Disease

Purpose: Phosphorylation-related SNP (phosSNP) is a non-synonymous SNP that might influence protein phosphorylation status. The aim of this study was to assess the effect of phosSNPs on blood pressure (BP), coronary artery disease (CAD) and ischemic stroke (IS). Methods: We examined the association of phosSNPs with BP, CAD and IS in shared data from genome-wide association studies (GWAS) and tested if the disease loci were enriched with phosSNPs. Furthermore, we performed quantitative trait locus analysis to find out if the identified phosSNPs have impacts on gene expression, protein and metabolite levels. Results: We found numerous phosSNPs for systolic BP (count=148), diastolic BP (count=206), CAD (count=20) and IS (count=4). The most significant phosSNPs for SBP, DBP, CAD and IS were rs1801131 in MTHFR, rs3184504 in SH2B3, rs35212307 in WDR12 and rs3184504 in SH2B3, respectively. Our analyses revealed that the associated SNPs identified by the original GWAS were significantly enriched with phosSNPs and many well-known genes predisposing to cardiovascular diseases contain significant phosSNPs. We found that BP, CAD and IS shared for phosSNPs in loci that contain functional genes involve in cardiovascular diseases, e.g., rs11556924 (ZC3HC1), rs1971819 (ICA1L), rs3184504 (SH2B3), rs3739998 (JCAD), rs903160 (SMG6). Four phosSNPs in ADAMTS7 were significantly associated with CAD, including the known functional SNP rs3825807. Moreover, the identified phosSNPs seemed to have the potential to affect transcription regulation and serum levels of numerous cardiovascular diseases-related proteins and metabolites. Conclusion: The findings suggested that phosSNPs may play important roles in BP regulation and the pathological mechanisms of CAD and IS.

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High-Resolution Regulatory Maps Connect Vascular Risk Variants to Disease-Related Pathways

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.118.002353 ◽

2019 ◽

Vol 12 (3) ◽

Cited By ~ 3

Author(s):

Örjan Åkerborg ◽

Rapolas Spalinskas ◽

Sailendra Pradhananga ◽

Anandashankar Anil ◽

Pontus Höjer ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

High Resolution ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Expression Levels ◽

Risk Variants ◽

Genome Wide ◽

Artery Disease

Background: Genetic variant landscape of coronary artery disease is dominated by noncoding variants among which many occur within putative enhancers regulating the expression levels of relevant genes. It is crucial to assign the genetic variants to their correct genes both to gain insights into perturbed functions and better assess the risk of disease. Methods: In this study, we generated high-resolution genomic interaction maps (≈750 bases) in aortic endothelial, smooth muscle cells and THP-1 (human leukemia monocytic cell line) macrophages stimulated with lipopolysaccharide using Hi-C coupled with sequence capture targeting 25 429 features, including variants associated with coronary artery disease. We also sequenced their transcriptomes and mapped putative enhancers using chromatin immunoprecipitation with an antibody against H3K27Ac. Results: The regions interacting with promoters showed strong enrichment for enhancer elements and validated several previously known interactions and enhancers. We detected interactions for 727 risk variants obtained by genome-wide association studies and identified novel, as well as established genes and functions associated with cardiovascular diseases. We were able to assign potential target genes for additional 398 genome-wide association studies variants using haplotype information, thereby identifying additional relevant genes and functions. Importantly, we discovered that a subset of risk variants interact with multiple promoters and their expression levels were strongly correlated. Conclusions: In summary, we present a catalog of candidate genes regulated by coronary artery disease–related variants and think that it will be an invaluable resource to further the investigation of cardiovascular pathologies and disease.

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2018 George Lyman Duff Memorial Lecture

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.119.311392 ◽

2019 ◽

Vol 39 (10) ◽

pp. 1925-1937 ◽

Cited By ~ 2

Author(s):

Ruth McPherson

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Disease Risk ◽

Association Studies ◽

Genome Wide Association ◽

Data Sets ◽

Genome Wide Association Studies ◽

Coronary Artery Disease Risk ◽

Genome Wide ◽

Artery Disease

Recent studies have led to a broader understanding of the genetic architecture of coronary artery disease and demonstrate that it largely derives from the cumulative effect of multiple common risk alleles individually of small effect size rather than rare variants with large effects on coronary artery disease risk. The tools applied include genome-wide association studies encompassing over 200 000 individuals complemented by bioinformatic approaches including imputation from whole-genome data sets, expression quantitative trait loci analyses, and interrogation of ENCODE (Encyclopedia of DNA Elements), Roadmap Epigenetic Project, and other data sets. Over 160 genome-wide significant loci associated with coronary artery disease risk have been identified using the genome-wide association studies approach, 90% of which are situated in intergenic regions. Here, I will describe, in part, our research over the last decade performed in collaboration with a series of bright trainees and an extensive number of groups and individuals around the world as it applies to our understanding of the genetic basis of this complex disease. These studies include computational approaches to better understand missing heritability and identify causal pathways, experimental approaches, and progress in understanding at the molecular level the function of the multiple risk loci identified and potential applications of these genomic data in clinical medicine and drug discovery.

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Transethnic Meta-Analysis of Genome-Wide Association Studies Identifies Three New Loci and Characterizes Population-Specific Differences for Coronary Artery Disease

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.119.002670 ◽

2020 ◽

Vol 13 (3) ◽

Cited By ~ 1

Author(s):

Hiroshi Matsunaga ◽

Kaoru Ito ◽

Masato Akiyama ◽

Atsushi Takahashi ◽

Satoshi Koyama ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Association Studies ◽

Meta Analysis ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Artery Disease

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Genetics of coronary artery disease: Genome-wide association studies and beyond

Atherosclerosis ◽

10.1016/j.atherosclerosis.2012.05.015 ◽

2012 ◽

Vol 225 (1) ◽

pp. 1-10 ◽

Cited By ~ 40

Author(s):

Bram P. Prins ◽

Vasiliki Lagou ◽

Folkert W. Asselbergs ◽

Harold Snieder ◽

Jingyuan Fu

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Artery Disease

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Inflammation-Related Risk Loci in Genome-Wide Association Studies of Coronary Artery Disease

Cells ◽

10.3390/cells10020440 ◽

2021 ◽

Vol 10 (2) ◽

pp. 440

Author(s):

Carina Mauersberger ◽

Heribert Schunkert ◽

Hendrik B. Sager

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Molecular Mechanisms ◽

Association Studies ◽

Genome Wide Association ◽

Considerable Proportion ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Related Risk ◽

Artery Disease

Although the importance of inflammation in atherosclerosis is now well established, the exact molecular processes linking inflammation to the development and course of the disease are not sufficiently understood. In this context, modern genetics—as applied by genome-wide association studies (GWAS)—can serve as a comprehensive and unbiased tool for the screening of potentially involved pathways. Indeed, a considerable proportion of loci discovered by GWAS is assumed to affect inflammatory processes. Despite many well-replicated association findings, however, translating genomic hits to specific molecular mechanisms remains challenging. This review provides an overview of the currently most relevant inflammation-related GWAS findings in coronary artery disease and explores their potential clinical perspectives.

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