Vitamin D Metabolism-Related Gene Haplotypes and Their Association with Metabolic Disturbances Among African-American Urban Adults

May A Beydoun,Marie Kuczmarski,Salman M Tajuddin,Jose A Canas,Hind A Beydoun,Sharmin Hossain,Michele K Evans,Alan B Zonderman

doi:10.1038/s41598-018-26230-w

Abstract

Epidemiological studies have confirmed associations of the vitamin D receptor (VDR) and vitamin D-related gene polymorphisms with adiposity and other metabolic disturbances. Those associations may be sex-specific. We evaluated the cross-sectional and longitudinal relationships between metabolic disturbances and haplotypes constructed from single nucleotide polymorphisms of VDR (BsmI:G/A: rs1544410; ApaI:A/C: rs7975232; and TaqI:G/A: rs731236) and MEGALIN (rs3755166:G/A; rs2075252:C/T and rs2228171:C/T) genes, in a sample of African-American adults. From 1,024 African Americans participating in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS, 2004–2013, Baltimore, MD), our analyses included 539 participants with complete genetic, baseline covariate and metabolic outcome data (at baseline and follow-up). Mean ± SD period of follow-up was 4.64 ± 0.93 y. Multivariable-adjusted Cox proportional hazards and logistic regression models were conducted. Among key findings, in men, incident hypertension was inversely related to MEGALIN1 (GCC), [HR = 0.45, 95% CI: 0.23–0.90, p = 0.024]. Overall, there was a direct, linear dose-response association between VDR2 (AAG: BAt) and MetS at baseline [OR = 1.60, 95% CI: 1.11–2.31, p = 0.012], while among men, VDR3 (GAA: bAT) was inversely related to baseline MetS [OR = 0.40, 95% CI: 0.19–0.81, p = 0.011]. In conclusion, VDR and MEGALIN gene variations can affect prevalent MetS and the incidence rate of hypertension, respectively, among African-American urban adults.

Highlights

Obesity may be directly involved in the etiology of vitamin D deficiency, with prior evidence of an inverse relationship between serum 25-hydroxyvitamin D [25(OH)D] concentration and various measures of adiposity[10]
In the baseline visit, screening, followed by recruitment and household interviews were completed during phase 1, while phase 2 consisted of in-depth examinations in a mobile Medical Research Vehicles (MRV)[30]
Variants within each vitamin D receptor (VDR) and MEGALIN (LRP2) gene were deemed in low linkage equilibrium (r2 < 0.30)

Summary

Introduction

Obesity may be directly involved in the etiology of vitamin D deficiency, with prior evidence of an inverse relationship between serum 25-hydroxyvitamin D [25(OH)D] concentration and various measures of adiposity[10]. The effect of VDR gene polymorphism can potentially be sex-specific as shown in at least one previous study with adiposity phenotypes[14]. Epidemiological studies have confirmed associations of VDR polymorphisms with adiposity and other metabolic disturbances[6,14,15,16,17,18,19,20,21,22,23]. MEGALIN acting as the receptor for sex-hormone binding globulin (SHBG), is involved in interactions between estrogen, vitamin D and intracellular calcium within adipocytes, leading to a potentially sex-specific effect of MEGALIN polymorphisms on various phenotypes of obesity, as indicated by findings from previous studies[14,29]. We hypothesize that selected VDR and MEGALIN gene polymorphisms have sex-specific associations with several key metabolic disturbances in a longitudinal study of African-American urban adults

Methods

Discussion

Conclusion