D-Dimer in African Americans: Whole Genome Sequence Analysis and Relationship to Cardiovascular Disease Risk in the Jackson Heart Study

Arterioscler Thromb Vasc Biol. 2017 Nov;37(11):2220-2227. doi: 10.1161/ATVBAHA.117.310073. Epub 2017 Sep 14.

Abstract

Objective: Plasma levels of the fibrinogen degradation product D-dimer are higher among African Americans (AAs) compared with those of European ancestry and higher among women compared with men. Among AAs, little is known of the genetic architecture of D-dimer or the relationship of D-dimer to incident cardiovascular disease.

Approach and results: We measured baseline D-dimer in 4163 AAs aged 21 to 93 years from the prospective JHS (Jackson Heart Study) cohort and assessed association with incident cardiovascular disease events. In participants with whole genome sequencing data (n=2980), we evaluated common and rare genetic variants for association with D-dimer. Each standard deviation higher baseline D-dimer was associated with a 20% to 30% increased hazard for incident coronary heart disease, stroke, and all-cause mortality. Genetic variation near F3 was associated with higher D-dimer (rs2022030, β=0.284, P=3.24×10-11). The rs2022030 effect size was nearly 3× larger among women (β=0.373, P=9.06×10-13) than among men (β=0.135, P=0.06; P interaction =0.009). The sex by rs2022030 interaction was replicated in an independent sample of 10 808 multiethnic men and women (P interaction =0.001). Finally, the African ancestral sickle cell variant (HBB rs334) was significantly associated with higher D-dimer in JHS (β=0.507, P=1.41×10-14), and this association was successfully replicated in 1933 AAs (P=2.3×10-5).

Conclusions: These results highlight D-dimer as an important predictor of cardiovascular disease risk in AAs and suggest that sex-specific and African ancestral genetic effects of the F3 and HBB loci contribute to the higher levels of D-dimer among women and AAs.

Keywords: cardiovascular disease; coagulation; genetic epidemiology.

Publication types

  • Comparative Study
  • Multicenter Study
  • Observational Study
  • Research Support, N.I.H., Intramural
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • African Americans / genetics*
  • Aged
  • Aged, 80 and over
  • Biomarkers / blood
  • Cardiovascular Diseases / blood
  • Cardiovascular Diseases / ethnology
  • Cardiovascular Diseases / genetics*
  • Cardiovascular Diseases / mortality
  • Female
  • Fibrin Fibrinogen Degradation Products / analysis*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Hemoglobins, Abnormal / genetics*
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Molecular Epidemiology
  • Phenotype
  • Prognosis
  • Prospective Studies
  • Risk Assessment
  • Risk Factors
  • Sex Factors
  • Sickle Cell Trait / blood
  • Sickle Cell Trait / ethnology
  • Sickle Cell Trait / genetics*
  • Sickle Cell Trait / mortality
  • Thromboplastin / genetics*
  • Time Factors
  • United States / epidemiology
  • Young Adult

Substances

  • Biomarkers
  • Fibrin Fibrinogen Degradation Products
  • Hemoglobins, Abnormal
  • fibrin fragment D
  • Thromboplastin