Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study

Wilkinson, Robert J.; Llewelyn, Martin J.; Toossi, Zahra; Patel, Punita; Pasvol, Geoffrey; Lalvani, Ajit; Wright, D. J.; Latif, Mohammed; Davidson, Robert N.

doi:10.1016/s0140-6736(99)02301-6

Cited by 669 publications

(524 citation statements)

References 27 publications

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“…A study in India showed the tt genotype to be associated with TB [14]. Wilkinson et al [36] suggested geneenvironment interaction, associating TB with TT/Tt genotype in combination with 25-hydroxycholecalciferol deficiency. Yet others found no association [37].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2011

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2011

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“…112 Similarly, associations between vitamin D deficiency and TB susceptibility were described over 20 years ago 113 and there is a good correlation between active disease and low vitamin D levels in TB. 114 Vitamin D acts in the body through binding to its receptor. Once this ligand-receptor complex is internalized, it forms a heterodimer with the retinoid X receptor and acts as a transcription factor, binding to vitamin D response elements (VDREs) in the promoter region of several nuclear genes.…”

Section: Environmental Factors In Mhc Class II Gene Regulationmentioning

confidence: 99%

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

et al. 2009

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Major histocompatibility complex (MHC) class II molecules are central to adaptive immune responses and maintenance of selftolerance. Since the early 1970s, the MHC class II region at chromosome 6p21 has been shown to be associated with a remarkable number of autoimmune, inflammatory and infectious diseases. Given that a full explanation for most MHC class II disease associations has not been reached through analysis of structural variation alone, in this review we examine the role of genetic variation in modulating gene expression. We describe the intricate architecture of the MHC class II regulatory system, indicating how its unique characteristics may relate to observed associations with disease. There is evidence that haplotypespecific variation involving proximal promoter sequences can alter the level of gene expression, potentially modifying the emergence and expression of key phenotypic traits. Although much emphasis has been placed on cis-regulatory elements, we also examine the role of more distant enhancer elements together with the evidence of dynamic inter-and intra-chromosomal interactions and epigenetic processes. The role of genetic variation in such mechanisms may hold profound implications for susceptibility to common disease.

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“…Vitamin D receptor activity has multiple potential roles in granulomatous disease, including activation of macrophages, inhibition of intracellular organisms, and regulation of interferon gamma activity. A strong negative gene-environment relationship has been demonstrated between one polymorphism and the presence of 25-Vitamin D deficiency on the risk of tuberculosis [38]. In this example, the odds ratios for the polymorphism, ff, was 3.6 (p=NS), and for 25-Vitamin D deficiency was 5.7.…”

Section: Modeling Interactionsmentioning

confidence: 71%

“…Polymorphisms in the vitamin D receptor are intriguing, and have been used in conjunction with an internal phenotype (Vitamin D deficiency) to suggest the presence of a gene-environment interaction between diet and VDR for risk of pulmonary tuberculosis among Gujaratis [38]. Vitamin D receptor activity has multiple potential roles in granulomatous disease, including activation of macrophages, inhibition of intracellular organisms, and regulation of interferon gamma activity.…”

Section: Modeling Interactionsmentioning

confidence: 99%

Gene-environment interactions in sarcoidosis: challenge and opportunity

Culver¹,

Newman²,

Kavuru³

2007

Clinics in Dermatology

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Susceptibility to most human diseases is polygenic, with complex interactions between functional polymorphisms of single genes governing disease incidence, phenotype, or both. In this context, the contribution of any discrete gene is generally modest for a single individual, but may confer substantial attributable risk on a population level. Environmental exposure can modify the effects of a polymorphism, either by providing a necessary substrate for development of human disease or because the effects of a given exposure modulate the effects of the gene. In several diseases, genetic polymorphisms have been shown to be context-dependent, i.e. the effects of a genetic variant are realized only in the setting of a relevant exposure. Since sarcoidosis susceptibility is dependent on both genetic and environmental modifiers, the study of gene-environment interactions may yield important pathogenetic information and will likely be crucial for uncovering the range of genetic susceptibility loci. However, the complexity of these relationships implies that investigations of geneenvironment interactions will require the study of large cohorts with carefully-defined exposures and similar clinical phenotypes. A general principle is that the study of gene-environment interactions requires a sample size at least several-fold greater than for either factor alone. To date, the presence of environmental modifiers has been demonstrated for one sarcoidosis susceptibility locus, HLA-DQB1, in African-American families. This article reviews general considerations obtaining for the study of gene-environment interactions in sarcoidosis. It also describes the limited current understanding of the role of environmental influences on sarcoidosis susceptibility genes.

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Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study

Cited by 669 publications

References 27 publications

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

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

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

Gene-environment interactions in sarcoidosis: challenge and opportunity

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