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New paper published in Science about rare variant in SCARB1 raises HDL cholesterol and increases risk of coronary heart disease

60311W_AntheroCoronary heart disease is a tale of two forms of plasma cholesterol. In contrast to the well-established effects of “bad” cholesterol (LDL-C), the role of “good” cholesterol (HDL-C) is mysterious. Elevated HDL-C correlates with a lower risk of heart disease, yet drugs that raise HDL-C levels do not reduce risk. Zanoni et al. found that some people with exceptionally high levels of HDL-C carry a rare sequence variant in the gene encoding the major HDL-C receptor, scavenger receptor BI. This variant destroys the receptor’s ability to take up HDL-C. Interestingly, people with this variant have a higher risk of heart disease despite having high levels of HDL-C. This remarkable study was published yesterday in Science with contribution of the IIEG.

The interesting background of this project is nicely described here.

Bildschirmfoto 2016 02 25 um 22.05.30

New paper published in NEJM about “Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease”

Through DNA genotyping using the Exome-Array, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with CAD and 120,770 controls who did not have CAD. Furthermore, through DNA sequencing, we studied the effects of loss-of-function mutations in selected
genes.

Bildschirmfoto 2016-02-25 um 22.05.30Here, we confirmed previously observed significant associations between CAD and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between CAD and low frequency
missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P = 4.2×10−10) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P = 4.0×10−8), which encodes angiopoietin-like 4.

In a next step, through sequencing of ANGPTL4, we identified 9 loss-of-function mutation carriers among 6924 patients with myocardial infarction, as compared with 19 loss-of-function mutation carriers among 6834 controls (odds ratio, 0.47; P = 0.04).

Interestingly, carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P = 0.003).

Functionally, Angiopoietin-like 4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of CAD (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P = 2.0×10−4) and a gain-of-function variant that was associated with protection from CAD (p.S447*; minor-allele frequency, 9.9%; odds ratio,
0.94; P = 2.5×10−7).

This highly collaborative study – involving 129 scientists from 15 countries – was published online on March 2nd, 2016 in the New England Journal of Medicine.

beitrag

Most comprehensive genetic study for CAD in 185,000 cases and controls revealed novel insights in disease pathology

Members of the IIEG together with colleagues from the CARDIoGRAMplusC4D consortium published the most comprehensive genetic study for CAD. Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association studies (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of 185,000 CAD cases and controls, interrogating 6.7 million common as well as 2.7 million low frequency variants. In addition to confirmation of most known CAD loci, we identified 10 novel loci, eight additive and two recessive, that contain candidate genes that newly implicate biological processes in vessel walls. Moreover, we observed intra-locus allelic heterogeneity but little evidence of low frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size. Furthermore, we report that only 20% of loci are related to known cardiovascular risk factors. This work has been published in Nature Genetics online ahead of print on September 7th, 2015. A Comprehensive 1000 Genomes-based GWAS meta-analysis of Coronary Artery Disease

A circular Manhattan plot summarizing the 1000 Genomes Project CAD association results.

New study published in ATVB: Prediction of Causal Candidate Genes in Coronary Artery Disease Loci

Genome-wide association studies (GWAS) have to date identified 159 significant and suggestive loci for coronary artery disease (CAD). Almost all of these loci have been identified with major contributions of members of the IIEG.
Here, a study co-led by Ingrid Brænne from the IIEG together with colleagues from the CADgenomics network, funded by the Leducq fondation, now report comprehensive bioinformatics analyses of sequence variation in these loci to predict candidate causal genes. They conclude that the great majority of causal variations affecting CAD risk occur in noncoding regions, with 41% affecting gene expression robustly versus 6% leading to amino acid changes. Interestingly, many of these genes differed from the traditionally annotated genes, which was usually based on proximity to the lead single-nucleotide polymorphism. Indeed, the study obtained evidence that genetic variants at CAD loci affect 98 genes, which had not been linked to CAD previously. However, for a full understanding, each CAD locus will have to be individually investigated using tools, such as experimental organisms and iPS cells. In this study, they have used  standard tools to refine the list of candidate genes. Additional approaches that could be useful at present include chromosome conformation analyses, application of novel algorithms for causal SNP analysis, network analyses, and identification of rare variants. Looking forward, new resources and tools, such as noncoding RNA annotation, RNA-binding maps, splicing variants and code annotation, and detailed enhancer and transcription maps in a variety of cell types relevant to atherosclerosis, will greatly assist such efforts. The members of the IIEG are well prepared to be part of these endeavours.

Full reference:

Prediction of Causal Candidate Genes in Coronary Artery Disease Loci.

Ingrid Brænne*, Mete Civelek*, Baiba Vilne*, Antonio Di Narzo, Andrew D. Johnson, Yuqi Zhao, Benedikt Reiz, Veronica Codoni, Thomas R. Webb, Hassan Foroughi Asl, Stephen E. Hamby, Lingyao Zeng, David-Alexandre Trégouët, Ke Hao, Eric J. Topol, Eric E. Schadt, Xia Yang, Nilesh J. Samani, Johan L.M. Björkegren, Jeanette Erdmann, Heribert Schunkert†, Aldons J. Lusis†, on behalf of the Leducq Consortium CAD Genomics‡

Arterioscler Thromb Vasc Biol 2015; first published on August 20 2015 as doi:10.1161/ATVBAHA.115.306108

*denotes equal contribution

Members of the CADgenomics network funded by the Leducq fondation

San Diego, February 2015

Genome research. Quo vadis, Germany?

Currently, all over the world large-scale projects aiming at sequencing thousands of probands get kicked-off, like the „precision medicine initiative“ in the US, the 100,000 Genomes initiative in UK, or the 50,000 Genome sequencing project in Saudi-Arabia, just to name a few.
The potential of large-scale genome sequencing project is very well justified in a speech held by President Barack Obama at the White House earlier this year to kick-off the „precision medicine initiative“.

Unfortunately, in Germany no large-scale genome sequencing project is on the horizon and it seems like German genome researchers might loose their leading role in the field.

An essay (in German) asking about the future role of German researchers in the field of Genomics has been published in the Laborjournal by Heribert Schunkert and Jeanette Erdmann.

Genetic research identifies novel pathway leading to myocardial infarction

Starting with a severely affected family, a research team led by Jeanette Erdmann, Christian Hengstenberg and Heribert Schunkert (Institut für Integrative und Experimentelle Genomik, University of Lübeck and Deutsches Herzzentrum München) identified a novel mechanism leading to myocardial infarction. Specifically, the scientists detected two mutations that jointly blocked nitric oxide signalling in platelets leading to accelerated thrombus formation. Another variant of the same enzyme, affecting a large proportion of the population, was also found to affect coronary risk, albeit to a much lesser extend. The work was published on December 13th, 2013 in the prestigious journal Nature.

Link: http://www.nature.com/nature/journal/v504/n7480/full/nature12722.html

Shorter height is genetically associated with an increased risk of coronary artery disease

For long it is known that shorter adult height is associated with an increased risk of coronary artery disease. This association is mainly explained by
by the association between shorter height and an adverse lipid profile.
A collaborative effort with national and international colleagues led by Nilesh Samani (University of Leicester) studied the association between height-associated
genetic variants and CAD.
The main advantage of our genetic approach is that it reduces the likelihood of known and unknown demographic, lifestyle, socioeconomic, or behavioral
confounders that have an independent effect on height and the risk of CAD and could give rise to a false association between the two factors.
It is possible that the association between the studied genetic variants and height and the association with CAD are through completely different mechanisms. However, the more likely scenario on the basis of our findings is that height variants affect biologic pathways, which on the one hand determine achieved height and on the other hand
influence the risk of CAD. It is also possible that genetically determined height itself alters lifestyle or behavior, which then affects the risk of CAD.
The study is published online in the New England Journal of Medicine.

Novel mechanism identified by which ADAMTS-7 affects neointima formation.

In a collaborative study, mainly between Munich (Thorsten Kessler and Heribert Schunkert) and colleagues from the Department of Physiology and Pathophysiology in Beijing (Lu Zhang and Wei Kong), as well as Cor de Wit and Kjestine Schmidt from the University of Lübeck, members of the IIEG (Zouhair Aherrahrou as shared senior author and Jeanette Erdmann) have identified a novel mechanism by which ADAMTS-7 affects neointima formation.

ADAMTS-7, a hitherto rather unknown gene, had been found to be genome-wide significantly associated with coronary artery disease (CAD) by CARDIoGRAM, a consortium lead by Heribert Schunkert, Nilesh Samani and Jeanette Erdmann. However, the mechanisms that link ADAMTS-7 and CAD risk remained elusive.

Here, by employing transgenic mice we now revealed that ADAMTS-7 plays a pivotal role in vascular remodelling. After vascular injuryAdamts7-/- mice were resistant to neointima formation. Thus, inhibition of ADAMTS-7 might represent a promising therapeutic strategy for the prevention of restenosis after PCI. Moreover, Adamts7-/- mice displayed accelerated re-endothelialisation. As drug-eluting stents designed to reduce restenosis rates may actually retard re-endothelialisation – and thereby provoke stent thrombosis – the finding that ADAMTS-7 affects both processes may be of interest. In fact, inhibition of ADAMTS-7 may solve two problems at once, i.e. decrease restenosis and augment re-endothelialisation. Furthermore, the identification of thrombospondin-1 as an ADAMTS-7 target on one hand and as a modulator of vascular remodelling on the other hand might lead to the elucidation of further druggable downstream targets.

Link to the paper:
http://circ.ahajournals.org/content/early/2015/02/20/CIRCULATIONAHA.114.014072.abstract

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