Candidate genes in coronary syndromes: seeing the bigger picture

Behavioural habits such as diet, tobacco abuse or physical inactivity play an important role in the pathogenesis of coronary artery disease (CAD). However, CAD has also been demonstrated to exhibit a noteworthy heritability.¹ In the past decade, impressive progress has been made in understanding the basis of several of these using both candidate gene approaches as well as genome-wide association studies (GWASs).

Candidate genes, coding for peptides or proteins of known biological function in physiology and pathophysiology, provide a reasonable initial step in understanding the genetics of a disease. Populations of affected and unaffected individuals are investigated by genotyping single-nucleotide polymorphisms (SNPs) inside a gene and its regulatory sequences. Economically attractive, this approach is hampered by several limitations. These studies are limited to genes with a known or presumed function in defining a given phenotype, but often provide no new insight into biological pathways leading to disease or disease progression. In addition, these associations often do not succeed as a result of small sample sizes in relation to the rather small effects of the SNPs or the given heterogeneity of causality due to the previously mentioned environmental risk factors.

GWASs provide an alternative approach, allowing the pervasive analysis of literally millions of markers across the genome. It has led to the identification of – sometimes not anticipated – loci associated with several complex phenotypes/diseases including CAD and it is only of limited bias. Those GWASs have identified genetic variants linked to type 2 diabetes or loci associated with lipoprotein metabolism/disorders, supporting the validity of this approach.² Functional studies of these regions may provide new insights into metabolism and reveal potential therapeutic targets for the risk reduction of CAD. However, despite the indisputable successes of the GWAS approach, the ability to identify the genetic basis of complex disease is rather moderate. In addition to a lack of rare variant coverage, some platforms provide gaps in coverage.³

In the current issue of the journal, Severino and colleagues report on their investigation of the prevalence of SNPs in the KCNJ11 gene encoding the Kir6.2 subunit of the adenosine triphosphate (ATP)-dependent potassium (KATP) channel in patients with CAD and coronary microvascular disease versus patients with normal coronary arteries.⁴

In a total of 603 study participants divided into three groups, the authors investigated SNPs of a Kir6.2 subunit of the KATP channel. The major finding was the identification of a polymorphism in that candidate gene as an independent protector of CAD.

Despite the overt and inevitable limitations of that study, such as the single centre design, the missing ethnic variance and the between-group variation, the work nicely confirms previous data and provides new insights into potential candidate genes involved in cardiovascular disease. The function of the described SNP has not been characterised in depth, however.

This work again highlights that valid interest remains in the use of a candidate gene approach for the evaluation of cardiovascular risk. However, more attention is suggested to be given to ascertain the phenotype and functional consequence in both GWASs and candidate gene studies. A candidate gene approach is valuable and eventually complementary to the discovering ability of GWASs. Several genome-wide accompanied by candidate gene studies have provided new insights, for example, into the genetic basis of variability in plasma lipoprotein concentrations and its impact on cardiovascular disease and of gene loci that probably harbour multiple rare variants of assumed cumulative importance.⁵

The quest for gene variants associated with the risk of cardiovascular disease is and remains worth the perseverance invested, as it has the potential to strengthen risk assessment in cardiovascular medicine and provide potential therapeutic or interventional targets.⁶ However, more research and the perception of the functional consequences of the gene variants identified are urgently needed. In addition, given the fact that acute and chronic coronary syndromes vary widely in their respective pathophysiology, discriminators might also be identified at the genetic level.

Finally, the authors have to be congratulated on their findings and should be encouraged to pursue further investigation of candidate genes related to their current work.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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