Genome-wide association study of vitamin D concentrations and bone mineral density in the African American-Diabetes Heart Study

PLoS One. 2021 May 20;16(5):e0251423. doi: 10.1371/journal.pone.0251423. eCollection 2021.


Relative to European Americans, African Americans have lower 25-hydroxyvitamin D (25OHD) and vitamin D binding protein (VDBP) concentrations, higher 1,25-dihydroxyvitamin D (1,25(OH)2D3) concentrations and bone mineral density (BMD), and paradoxically reduced burdens of calcified atherosclerotic plaque (subclinical atherosclerosis). To identify genetic factors contributing to vitamin D and BMD measures, association analysis of >14M variants was conducted in a maximum of 697 African American-Diabetes Heart Study participants with type 2 diabetes (T2D). The most significant association signals were detected for VDBP on chromosome 4; variants rs7041 (β = 0.44, SE = 0.019, P = 9.4x10-86) and rs4588 (β = 0.17, SE = 0.021, P = 3.5x10-08) in the group-specific component (vitamin D binding protein) gene (GC). These variants were found to be independently associated. In addition, rs7041 was also associated with bioavailable vitamin D (BAVD; β = 0.16, SE = 0.02, P = 3.3x10-19). Six rare variants were significantly associated with 25OHD, including a non-synonymous variant in HSPG2 (rs116788687; β = -1.07, SE = 0.17, P = 2.2x10-10) and an intronic variant in TNIK (rs143555701; β = -1.01, SE = 0.18, P = 9.0x10-10), both biologically related to bone development. Variants associated with 25OHD failed to replicate in African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Evaluation of vitamin D metabolism and bone mineral density phenotypes in an African American population enriched for T2D could provide insight into ethnic specific differences in vitamin D metabolism and bone mineral density.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Black or African American / genetics
  • Bone Density*
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / physiopathology
  • Female
  • Genome-Wide Association Study
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Genetic
  • Vitamin D / analogs & derivatives*
  • Vitamin D / blood
  • Vitamin D / genetics
  • Vitamin D-Binding Protein / blood
  • Vitamin D-Binding Protein / genetics


  • Vitamin D-Binding Protein
  • Vitamin D
  • 1,25-dihydroxyvitamin D
  • 25-hydroxyvitamin D