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Genome-wide studies in cardiovascular disease - has the promise been fulfilled?


In this ESC session held on August 31st, 2009, chaired by myself and Dr Aroon Hingorani from London, UK, four excellent talks concerned genome-wide association studies (GWAS) in cardiovascular diseases (CVD).

Dr. Panos Deloukas from the Sanger Institute, Cambridge, UK, presented a summary of GWAS in CVD studies carried out at the Sanger Institute. The WTCCC study had 2000 cases of CHD and 3000 controls. It found CHD-associated regions in chromosomes 1p, 1q, 2, 6, 9, 10 and 15. Four loci were replicated in the German MI study. They have started the WTCCC resequencing pilot in 32 CEPH individuals, sequencing 16 loci totalling 2.8 Mb of genome. They found 6076 new polymorphic SNPs in 31 subjects and 275 novel insertion-deletions. They observed that the coverage of marker SNPs is not perfect. Based on typing 10,240 SNPs in 13 associated regions in 2000 controls and 2000 cases from each disease phenotype from T2D, CAD, AITD, they estimated that it takes between 13 and 319 SNPS depending on the trait and region to achieve 95% confidence. The next Sanger studies will be e.g. in deep exon resequencing, integrating CNV data, UPEN array 55k, blood cells, PROMIS 5000 cases and 5000 controls from Pakistan.

Dr. Francois Cambien from INSERM, Paris, presented the “Cardiogenics” study, which is an EU-funded meta-analysis of 22,755 cases and controls. Interesting findings include the association of the chromosome 9p21region, previously associated only with CHD, even more strongly with abdominal and intracranial aneurysms. This suggests that the pathophysiology may not have to do with atherosclerosis. They also confirmed a large number of gene-trait associations than smaller GWAS studies.

Dr. Mark Caulfield from London, UK, summarized WGA studies concerning blood pressure and hypertension, such as the Global BP Gen consortium. This consists of 13 European population-based cohorts, totalling 34,433 individuals, with replication in 70,000 people. They confirmed eight new genes for BP. In the CHARGE consortium with 29,136 subjects, about quarter of genes were the same in both studies. They will do meta-analysis in 69,000 and replication in 41,000 and 32,000 subjects. They will study 8000 severe hypertensives and 8000 normotensives. Fine mapping will be done with 200,000 SNPs. Even though the effect of each SNP is 0.5-1mmHg on SBP or DBP, this is significant from the population perspective, taking into account that 2 mmHg lowering of SBP is expected to lower stroke risk by 6% and CHD risk by 5% on the population level.

Dr. Nilesh Samani from Leicester, UK, discussed the promises and problems of the WGA studies in CAD. He pointed out that the replicated SNPs are not the causal variants but common HapMap variants. The actual causal variants are likely to have a large effect than the marker SNPs. In his view the future challenges will be (1) Understanding mechanisms, (2) explaining missing heritability and (3) translating findings to clinical benefits such as novel therapies and computing individual risk. 


The GWASs in CVD in Europe in the 2000s have become larger and larger. Huge case-control GWAS and meta-analyses have been launched. For organizational reasons it has been difficult to define exact phenotypes, ensure perfect case-control representativeness and comparability and avoid the survival bias, which is inherent in all retrospective case-control studies, even though the exposure – gene variant – is constant. The “Mendelian randomization” - random allocation of alleles in the meiosis – was thought to take care of confounding. However, there is a wealth of selective factors influencing the mate selection and the survival of the fetus and the infant. These are both genetic and environmental. Gene-environment interactions, CNVs and epigenetics have been studied very little. Extreme phenotypes will be studied in the future.

The results of the large GWAS studies have been promising, although some say that genetic epidemiology could do better. I would propose that the studies carried out so far are part of an exercise or learning experience. The largest advances in understanding the mechanisms and in clinical applications will be made in the next five to 20 years. I think that on the basis of the current findings already we can expect genetic profiling to be part of risk assessment of individuals in the foreseeable future. 




Genome-wide studies in cardiovascular disease - has the promise been fulfilled?

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.