The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

Abstract

Cardiovascular diseases are leading causes for death worldwide. Genetic disposition jointly with traditional risk factors precipitates their manifestation. Whereas the implications of a positive family history for individual risk have been known for a long time, only in the past few years have genome‐wide association studies (GWAS) shed light on the underlying genetic variations. Here, we review these studies designed to increase our understanding of the pathophysiology of cardiovascular diseases, particularly coronary artery disease and myocardial infarction. We focus on the newly established pathways to exemplify the translation from the identification of risk‐related genetic variants to new preventive and therapeutic strategies for cardiovascular disease.

Exploring the fitness hypothesis in ALS: a population-based case-control study of parental cause of death and lifespan

“…A relation between cardiovascular fitness and being more physically active could not be shown in our study, as neither parental cardiovascular death nor survival was related to the extent to which patients are physically active. As the heritability of cardiovascular diseases is relatively high,16 our results strengthen the concept that a favourable cardiovascular fitness profile is associated with developing ALS. These findings are in line with previous studies showing a lower rate of hospital admissions for coronary heart disease,7 less frequent use of medication for hypertension or congestive heart failure,17 and a lower frequency of a history of a myocardial infarction or cardiac arrhythmia6 among patients with ALS compared with the general population or to controls and a lower rate of stroke and myocardial infarction in relatives of patients with ALS compared with relatives of controls 18.…”

In Search for Genes Related to Atherosclerosis and Dyslipidemia Using Animal Models

“…GWAS helped to reveal the association between several genes implicated in triglyceride metabolism and cardiovascular disease, including APOA5 and APOC3 [43]. Rare APOA5 mutations were shown to be associated with enhanced plasma triglyceride levels and, at the same time, the elevated risk of coronary artery disease [44].…”

High-resolution regulatory maps connect cardiovascular risk variants to disease related pathways

“…According to GWAS, a locus on chromosome 9p21 has the strongest association signal 12,13 . Although it is established that the risk allele is associated with formation and progression of plaques but not with their rupture 14,15 , the mechanistic understanding of the conferred risk by these loci remains elusive [16][17][18] . Pathways such as cholesterol and triglyceride metabolism, blood pressure, inflammation, vascular proliferation and remodeling, nitric oxide signaling, vascular tone, extracellular matrix integrity and axon guidance and signaling are also enriched for target genes of GWAS variants [17][18][19][20] .…”

“…Although it is established that the risk allele is associated with formation and progression of plaques but not with their rupture 14,15 , the mechanistic understanding of the conferred risk by these loci remains elusive [16][17][18] . Pathways such as cholesterol and triglyceride metabolism, blood pressure, inflammation, vascular proliferation and remodeling, nitric oxide signaling, vascular tone, extracellular matrix integrity and axon guidance and signaling are also enriched for target genes of GWAS variants [17][18][19][20] . GWAS studies do not in themselves provide functional insight for the large subset of hits that are non-coding 21,22 : only one-third of the time a variant affects the expression level of its nearest gene, highlighting the limitations of the nearestgene assignment approach 23,24 .…”