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

Nicholette D Palmer,Meijian Guan,Donald W Bowden,J Jeffrey Carr,Anthony J Hanley,S Carrie Smith,Thomas C Register,Latchezar Dimitrov,Corinne D Engelman,Lingyi Lu,Barry I Freedman,Carl D Langefeld,Jasmin Divers,Jianzhao Xu,Leon Lenchik,Pamela J Hicks,Maggie C Y Ng,Lynne E Wagenknecht,Jill M Norris,Yii‐Der I Chen ,Jacob M Keaton

doi:10.1371/journal.pone.0251423

Abstract

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.

Highlights

type 2 diabetes (T2D) and osteoporosis are diseases of aging which contribute to increased fracture risk [1]
American-Diabetes Heart Study (AA-DHS) includes African Americans with T2D recruited from two Wake Forest School of Medicine (WFSM) studies: the family-based Diabetes Heart Study (DHS) and unrelated individuals in the AA-DHS
genome-wide association studies (GWAS) analyses were conducted for traits 25OHD, 1,25(OH)2D3, vitamin D binding protein (VDBP), bioavailable vitamin D (BAVD), intact parathyroid hormone (iPTH), thoracic volumetric bone mineral density (BMD) (vBMD), and lumbar vBMD

Summary

Introduction

T2D and osteoporosis are diseases of aging which contribute to increased fracture risk [1]. In concert with differences in vitamin D metabolism, African (versus European) ancestry is associated with higher bone mineral density (BMD) and lower prevalence of osteoporosis [7,8,9]. The effects of 25OHD, 1,25(OH)2D3 and iPTH on their target organs/cells may differ based on race/ethnicity. Beyond population ancestry-based differences in bone mineral density and vitamin D metabolism, calcified atherosclerotic plaque [11] and calcium-containing kidney stones [12] develop significantly less often in African Americans than European Americans. Inverse relationships exist between the development and progression of calcified atherosclerotic plaque (e.g., subclinical atherosclerosis) with bone mineralization; this relationship is independent from ethnicity [13]. Literature evidence supports higher risks for development of subclinical atherosclerosis and osteoporosis in populations of European ancestry [14]

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