Vitamin D receptor gene methylation is associated with ethnicity, tuberculosis, and TaqI polymorphism

Abstract

The Vitamin D Receptor (VDR) gene encodes a transcription factor which, on activation by vitamin D, modulates diverse biological processes including calcium homeostasis and immune function. Genetic variation involving VDR shows striking differences in allele frequency between populations and has been associated with disease susceptibility including tuberculosis and autoimmunity, although results have often been conflicting. We hypothesized that methylation of VDR may be population specific and that the combination of differential methylation and genetic variation may characterise TB predisposition. We use bisulphite conversion and/or pyrosequencing to analyse the methylation status of 17 CpGs of VDR and to genotype 7 SNPs in the 3′ CpG Island (CGI 1060), including the commonly studied SNPs ApaI (rs7975232) and TaqI (rs731236). We show that for lymphoblastoid cell lines from two ethnically diverse populations (Yoruba from HapMap, n=30 and Caucasians, n=30) together with TB cases (n=32) and controls (n=29) from the Venda population of South Africa there are methylation variable positions (MVPs) in the 3′ end that significantly distinguish ethnicity (9/17 CpGs) and TB status (3/17 CpGs). Moreover methylation status shows complex association with TaqI genotype highlighting the need to consider both genetic and epigenetic variants in genetic studies of VDR association with disease.

Factors influencing the higher incidence of tuberculosis among migrants and ethnic minorities in the UK

“…Epigenetic variation in the VDR gene in different ethnic groups, arising from differential exposure to environmental factors, may influence gene regulation and therefore contribute to differential TB susceptibility. Indeed, methylation variable positions at the 3' end of VDR have been identified that are significantly correlated with ethnicity and TB status 113 .…”

Comparative epigenetics: relevance to the regulation of production and health traits in cattle

“…Vitamin D3 reduces the pro-inflammatory response and also induces a protective response via expression of cathelicidin antimicrobial peptide (Khoo et al 2011). The activity of the vitamin D receptor gene (VDR) can be epigenetically regulated (Karlic & Varga 2011), and VDR methylation status has been shown to correlate with TB status in a human population (Andraos et al 2011). Within a CpG island at the 3 0 end of VDR, one CpG site showed significantly higher methylation in controls than in TB cases, whereas two additional CpGs showed higher methylation in TB cases than in controls.…”

Update on Microbe-Induced Epigenetic Changes: Bacterial Effectors and Viral Oncoproteins as Epigenetic Dysregulators

“…Pennini et al were able to show that this chromatin remodeling effect was caused by M. tuberculosis 19K lipoprotein (LpqH) signaling via TLR2 [75,76]. Comparing the methylation statuses of CpG islands in the vitamin D receptor gene has uncovered variations at several CpG dinucleotides between different ethnic groups and between M. tuberculosis-infected and -uninfected individuals [77]. It may be interesting to speculate whether a person's CpG-methylation profile may be predictive for M. tuberculosis susceptibility, or whether different CpGmethylation profiles may have been induced by M. tuberculosis infection.…”

“…This is certainly an interesting field for further research (reviewed in [78]). However, as a note of caution, methylation analyses were performed from EBV-transformed lymphoblastoid cell lines obtained from the respective donors [77]. EBV by itself may contribute to an altered methylation profile in the host cell [79].…”