Genetics of coronary artery disease: discovery, biology and clinical translation

Key Points

  • Coronary artery disease is a heritable disorder that remains the leading cause of global mortality despite advances in treatment and prevention strategies. Human genetics studies have started to unravel the genetic underpinnings of this disorder.

  • Gene discovery efforts have rapidly transitioned from family-based studies (for example, those that led to the discovery of familial hypercholesterolaemia) to large cohorts that facilitate both common and rare variant association studies.

  • Common variant association studies have confirmed 60 genetic loci with a robust association with coronary disease, the majority of which are of modest effect size and in non-coding regions. Rare variant association studies have linked inactivating mutations in at least nine genes with risk of coronary artery disease.

  • Human genetics and large-scale biobanks can facilitate drug development for coronary artery disease by highlighting causal biology and helping to understand the phenotypic consequences of lifelong deficiency of a given protein.

  • Genomic medicine may provide patients and their health care providers with genetic data that will aid in coronary artery disease prevention and treatment.

  • Genome editing to introduce mutations that are protective against coronary artery disease into the population could prove curative with a one-time injection, although substantial additional work is needed to confirm efficacy and safety, and to address the underlying ethics.


Coronary artery disease is the leading global cause of mortality. Long recognized to be heritable, recent advances have started to unravel the genetic architecture of the disease. Common variant association studies have linked approximately 60 genetic loci to coronary risk. Large-scale gene sequencing efforts and functional studies have facilitated a better understanding of causal risk factors, elucidated underlying biology and informed the development of new therapeutics. Moving forwards, genetic testing could enable precision medicine approaches by identifying subgroups of patients at increased risk of coronary artery disease or those with a specific driving pathophysiology in whom a therapeutic or preventive approach would be most useful.

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Figure 1: Physiological pathways related to genetic loci associated with coronary artery disease.
Figure 2: The LPL pathway.
Figure 3: Human genetics to facilitate drug development: lipoprotein(a).
Figure 4: Mendelian randomization to identify causal biomarkers for risk of CAD.
Figure 5: Precision medicine for CAD guided by human genetics.


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A.V.K. is supported by a John S. LaDue Memorial Fellowship in Cardiology and a KL2/Catalyst Medical Research Investigator Training award (an appointed KL2 award) from Harvard Catalyst. S.K. is supported by an Ofer and Shelley Nemirovsky MGH Research Scholar Award and by grants HL127564 and UM1HG008895 from the US National Institutes of Health.

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Correspondence to Sekar Kathiresan.

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A.V.K. has received consulting fees from Amarin Pharmaceuticals and Merck & Co. S.K. has received grant support from Bayer Healthcare and Amarin, equity in San Therapeutics, and Catabasis, and received personal fees for scientific advisory board participation for Bayer Healthcare, Catabasis, Regeneron Genetics Center, Merck, Celera, Genomics PLC, Novartis, Sanofi, AstraZeneca, Alnylam, Eli Lilly & Company, Leerink Partners, Noble Insights and Ionis Pharmaceuticals.

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Capable of being transmitted from parent to offspring via genetic variation.

Genetic architecture

The full spectrum of common and rare genetic variation that contributes to a trait of interest.

Linkage analysis

Systematic localization of a genetic region that is co-inherited with a trait of interest in members of a family.

Monogenic drivers

Variations in a single gene dictates the observed variation in a trait of interest; also referred to as Mendelian disorders.

Allele frequency

The relative frequency of an allele (specific genetic variant) in the population; typically reported as the proportion of all chromosomes in the population that carry an allele.

Inactivating mutations

Variants that disrupt the ability of a given gene to produce its protein product, that is, due to premature truncation, scrambling of the amino acid code or disrupting gene splicing.

Mendelian randomization

A human genetics tool that leverages the random assortment of genetic variants at time of conception to assess causality of observed associations.


Production of offspring by related individuals (for example, second cousins or closer).

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Khera, A., Kathiresan, S. Genetics of coronary artery disease: discovery, biology and clinical translation. Nat Rev Genet 18, 331–344 (2017).

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