Cardiovascular disease (CVD) is the leading cause of mortality worldwide, with 18 million deaths each year according to WHO, accounting for about a third of global deaths. Half of these deaths can be attributed to coronary artery disease (CAD) alone. The primary cause of CAD is atherosclerosis—the build-up of plaques inside blood vessels that supply the heart muscle. CVD, CAD, and atherosclerosis share several risk factors, including high cholesterol, high blood pressure, smoking, diabetes, and obesity.
Many underlying genetic risk factors for atherosclerosis and CAD have also been uncovered; one of the first genes is low-density lipoprotein receptor (LDLR), located on chromosome 19 band 19p13.2. LDLR helps cells to internalise LDL cholesterol, and people carrying LDLR mutations have high levels of plasma LDL cholesterol—an inherited condition termed familial hypercholesterolaemia (FH). Patients with FH are thus predisposed to developing atherosclerosis and CAD, and can have fatal heart attacks at a young age. For the discovery of LDLR and its role in cholesterol regulation and FH, Michael Brown and Joseph Goldstein (University of Texas, Dallas, TX, USA) received the Nobel Prize in Physiology or Medicine in 1985.
At the turn of the century, with the introduction of new high-throughput sequencing technologies, large genome-wide association studies (GWAS) became a reality. Many other genetic risk alleles for atherosclerosis and CAD have been identified and confirmed by such genetic association studies, including the 9p21.3 region that was first reported a decade ago. 9p21.3 lies in an intergenic segment on chromosome 9 and does not contain any known protein-coding genes. It is found only in humans, making it challenging to study its functions and potential phenotypic effects.
In an article in Cell, published on Dec 6, 2018, Kristin Baldwin and colleagues at the Scripps Research Institute (La Jolla, CA, USA) created vascular smooth muscle cells (VSMCs; the main cell type making up blood vessels) using induced pluripotent stem cells from people carrying either risk or non-risk 9p21.3 haplotype. VSMCs carrying the risk 9p21.3 haplotype showed a transcriptome overlapping with known CAD risk genes and pathways, while deleting the risk haplotype using genome editing rescued VSMC stability. Risk VSMCs also had higher levels of long non-coding RNAs called ANRIL (antisense non-coding RNA in the INK4 locus). When ANRIL was added to healthy VSMCs, these cells developed key signatures of CAD, indicating that these ANRIL RNAs could be master conductors of the switch between healthy and disease-promoting states in VSMCs. The study thus provides new insight into how the 9p21.3 intergenic region could regulate distant genes and pathways leading to CAD phenotypes in VSMCs.
Previous GWAS have reported that another risk gene locus, phosphatase and actin regulator 1 (PHACTR1) rs9349379, located on chromosome 6 band 6p24.1, is associated with several CVDs, including CAD and fibromuscular dysplasia (FMD). FMD is a type of arterial anomaly commonly found in spontaneous coronary artery dissection (SCAD). SCAD is an atypical form of heart attack affecting mainly women of young and middle age, with underlying mechanisms poorly understood. In a large case-control study of patients from France, UK, USA, and Australia, Nabila Bouatia-Naji and colleagues at INSERM (Paris, France) have shown that people carrying PHACTR1 rs9349379-A allele have an increased risk of developing SCAD (odd ratio 1·67, 95% CI 1·50–1·86, per copy of rs9349379-A). rs9349379-A allele is very common in the general population, yet the risk of developing SCAD is moderate, suggesting that other genetic, epigenetic, and environmental factors might be involved in the pathogenesis of this disease. The study was published in the Journal of the American College of Cardiology on January 7, 2019. In a cell, PHACTR1 binds to actin molecules and coordinates actin cytoskeleton rearrangement. Very little is known about the function of PHACTR1 in the cardiovascular system, although it is thought to have a role in cell motility and vascular morphogenesis. Given the strong genetic association of PHACTR1 alleles and CAD, FMD, and SCAD, more mechanistic studies are needed to identify potential therapeutic targets once the molecular pathways of those CVDs have been mapped out.
LDLR mutations were first implied to cause atherosclerosis more than three decades ago, and many other genetic mutations have since been uncovered and their functions confirmed, including ApoB, PCSK9, and LDLRAP1. Genetic tests are available to people with high blood cholesterol, and therapeutic drugs have been clinically approved, including statins and PCSK9 inhibitors. Statins inhibit HMG-CoA reductase (an enzyme that regulates cholesterol-producing metabolic pathways), thereby increasing LDLR expression in the liver and reducing plasma LDL cholesterol. PCSK9 inhibitors block PCSK9–LDLR binding, thus freeing up more LDLRs to remove LDL cholesterol from circulation. Substantial basic research has been done to understand the underlying mechanisms and pathways of lipid metabolism and homoeostasis. CVD is now accepted as a polygenic disease, yet genetics is only one factor, and epigenetics and environmental influences (particularly smoking and diet) play an undeniable part in CVD pathogenesis. Several polygenic risk scores for atherosclerosis and CAD have also been developed, showing that people with higher scores would benefit more from interventions.
EBioMedicine welcomes large, solid genetic association studies like that of Bouatia-Naji and colleagues, which lay the foundation for future functional validation studies into such genetic regions. We also applaud innovative approaches like that taken by Baldwin and colleagues to circumvent challenges and unveil the functions of those genetic regions in human diseases. Such translational work paves the way for other researchers to further our knowledge in CVD genetics and pathways, to identify new therapeutic targets and to develop new drugs, with the eventual aim to improve our health.