Chromosome 1q21.2 and additional loci influence risk of spontaneous coronary artery dissection and myocardial infarction

Nat Commun. 2020 Sep 4;11(1):4432. doi: 10.1038/s41467-020-17558-x.

Abstract

Spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic cause of myocardial infarction (MI), typically in young women. We undertook a genome-wide association study of SCAD (Ncases = 270/Ncontrols = 5,263) and identified and replicated an association of rs12740679 at chromosome 1q21.2 (Pdiscovery+replication = 2.19 × 10-12, OR = 1.8) influencing ADAMTSL4 expression. Meta-analysis of discovery and replication samples identified associations with P < 5 × 10-8 at chromosome 6p24.1 in PHACTR1, chromosome 12q13.3 in LRP1, and in females-only, at chromosome 21q22.11 near LINC00310. A polygenic risk score for SCAD was associated with (1) higher risk of SCAD in individuals with fibromuscular dysplasia (P = 0.021, OR = 1.82 [95% CI: 1.09-3.02]) and (2) lower risk of atherosclerotic coronary artery disease and MI in the UK Biobank (P = 1.28 × 10-17, HR = 0.91 [95% CI :0.89-0.93], for MI) and Million Veteran Program (P = 9.33 × 10-36, OR = 0.95 [95% CI: 0.94-0.96], for CAD; P = 3.35 × 10-6, OR = 0.96 [95% CI: 0.95-0.98] for MI). Here we report that SCAD-related MI and atherosclerotic MI exist at opposite ends of a genetic risk spectrum, inciting MI with disparate underlying vascular biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ADAMTS Proteins / genetics
  • Carotid Artery Diseases / complications
  • Carotid Artery Diseases / genetics
  • Chromosomes / genetics
  • Cohort Studies
  • Coronary Artery Disease / genetics
  • Coronary Vessel Anomalies / genetics*
  • Female
  • Fibromuscular Dysplasia / complications
  • Fibromuscular Dysplasia / genetics
  • Genes, Neoplasm*
  • Genome-Wide Association Study
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-1 / genetics
  • Male
  • Meta-Analysis as Topic
  • Microfilament Proteins / genetics
  • Myocardial Infarction / genetics*
  • Risk Factors
  • Vascular Diseases / congenital*
  • Vascular Diseases / genetics

Substances

  • ADAMTSL4 protein, human
  • LRP1 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Microfilament Proteins
  • PHACTR1 protein, human
  • ADAMTS Proteins

Supplementary concepts

  • Coronary Artery Dissection, Spontaneous