Vitamin D Receptor Polymorphisms and Cancer.

Increasing scientific evidence supports the link between vitamin D and cancer risk. The active metabolite 1,25(OH)2D exerts its activity by binding to the vitamin D receptor (VDR), an intracellular receptor that mediates transcriptional activation and repression of target genes. The binding of 1,25(OH)2D to VDR is able to regulate hundreds of different genes. VDR is active in virtually all tissues including the colon, breast, lung, ovary, bone, kidney, parathyroid gland, pancreatic b-cells, monocytes, T lymphocytes, melanocytes, keratinocytes, and also cancer cells.The relevance of VDR gene restriction fragment length polymorphisms for various types of cancer has been investigated by a great number of studies.We have carried out a systematic review of the literature to analyze the relevance of more VDR polymorphisms (Fok1, Bsm1, Taq1, Apa1, and Cdx2) for individual malignancies considering ethnicity as a key factor for heterogeneity.Up to December 2018, we identified 176 independent studies with data to assess the risk of breast, prostate, colorectal, skin (melanoma and non-melanoma skin cancer), lung, ovarian, kidney, bladder, gallbladder, esophageal, thyroid, head and neck, liver and pancreatic cancer, oral squamous cell carcinoma, non-Hodgkin lymphoma, multiple myeloma and sarcoma.Significant associations with VDR polymorphisms have been reported for prostate (Fok1, Bsm1, Taq1, Apa1, Cdx2), breast (Fok1, Bsm1, Taq1, Apa1, CdX2), colorectal (Fok1, Bsm1, Taq1, Apa1), and skin cancer (Fok1, Bsm1, Taq1). Very few studies reported risk estimates for the other cancer sites.Conflicting data have been reported for most malignancies, and at present, it is still not possible to make any definitive statements about the importance of the VDR genotype for cancer risk. It seems probable that other factors such as ethnicity, phenotype, 25(OH)D plasma levels, and UV radiation exposure play a role as confounding factors and introduce heterogeneity.To conclude, there is some indication that VDR polymorphisms may modulate the risk of some cancer sites and in future studies VDR genetic variation should be integrated also with assessment of vitamin D status and stratified by ethnicity.

High glucose stimulates proliferative capacity of liver cancer cells possibly via O-GlcNAcylation-dependent transcriptional regulation of GJC1.

Although it is generally accepted that diabetes is one of the most important risk factors for liver cancer, the underlying mechanism is still not well understood. The purpose of the current study is to further investigate how high concentrations of glucose (HG), a major symptom of diabetes, stimulate the development of liver malignancy. Using data mining, gap junction protein gamma 1 (GJC1) was identified as a critical proto-oncoprotein that is essential for the HG stimulation of proliferative capacity in liver cancer cells. Furthermore, enhanced transcriptional expression of GJC1 might occur after stimulation by HG. A transcription factor zinc finger protein 410 (APA1)-binding motif was found to be located at the -82 to -77 nt region within the GJC1 promoter. Without APA1, HG was unable to increase GJC1 expression. Interestingly, APA1, but not GJC1, can be O-GlcNAcylated in liver cancer cells. Moreover, O-GlcNAcylation is essential for HG-induced APA1 binding to the GJC1 promoter. Notably, global O-GlcNAcylation and expression of APA1 and GJC1 were highly elevated in liver cancer patients with diabetes compared to those in patients without diabetes. The HG-stimulated proliferative capacity was abolished upon decreasing O-GlcNAcylation, which could be reversed gradually by the simultaneous overexpression of APA1 and GJC1. Therefore, GJC1 could be a potential target for preventing liver cancer in patients with diabetes.

Vitamin D receptor gene polymorphisms (Apa1 and Taq1) in temporomandibular joint internal derangement/osteoarthritis in a group of Turkish patients.

Genetic variations might play a role in susceptibility to temporomandibular joint internal derangement (TMJ-ID) and osteoarthritis of the joint (TMJOA). Vitamin D receptor (VDR) polymorphisms have been shown to be associated with disc degeneration-linked pathologies, particularly osteoarthritis (OA). The aim of this study was to evaluate whether VDR polymorphisms present susceptibility to TMJ-ID/TMJOA. The study included 49 unrelated TMJ-ID patients with OA (31.7 ± 7.9) that were grouped and evaluated as having anterior disk displacement with reduction (ADDwR, n = 24) (31.58 ± 8.25) and without reduction (ADDwoR, n = 25) (31.8 ± 7.53) and 70 healthy controls (28.22 ± 5.9). DNA was extracted from blood samples using the standard proteinase K/phenol-chloroform method. Apa1 and Taq1 polymorphisms were investigated using a polymerase chain reaction-based restriction fragment length polymorphism assay. When TMJ-ID patients, ADDwR cases and ADDwoR cases versus healthy controls were compared, Apa1 Aa genotype compared to AA genotype had odds ratios of 1.65, 1.79 and 1.64 respectively (p > 0.05). In TMJ-ID women versus healthy women Aa genotype had 2.06 fold (p = 0.15) odds compared to AA genotype. Taq1 results showed that in TMJ-ID patients and ADDwoR cases the Tt genotype had odds ratios of 0.63 and 0.44 fold (p > 0.05) respectively. In TMJ-ID women the Tt and tt genotypes had odds ratios of 0.53 and 0.73 (p > 0.05). Combined VDR genotypes revealed that AATT had a 3.3 fold (p = 1.21) odds ratio while AATt had a 2.0 fold odds ratio (p = 0.29) (OR 0.59, 95% CI 0.23-1.49, p = 0.26) compared to AaTt. Although our results do not confirm susceptibility of VDR polymorphisms to TMJ-ID/TMJOA ,this relation needs to be further evaluated in a large cohort study.

Serum vitamin D levels and gene polymorphisms (Fok1 and Apa1) in children with type I diabetes and healthy controls.

OBJECTIVE: To compare the pattern of Vitamin D receptor (VDR) polymorphisms (Apa I and Fok I) in Type I Diabetes mellitus (T1DM) as cases vs healthy population as control and to investigate the association of VDR polymorphism with vitamin D levels in cases and controls. METHODS: The hypothesis of the study was "VDR gene polymorphisms (Fok 1 and Apa 1) and vitamin D levels are associated with the T1DM". The case-control study was carried out on 44 cases and 44 controls. Clinically diagnosed unrelated cases were recruited from the Diabetic Clinic of Jinnah Hospital, Lahore during Aug. 2012 to Jan 2013. Unrelated controls with normal glucose levels and no first-degree family history of T1DM were selected by convenient sampling. Vitamin D levels of both cases and controls were measured using Enzyme Linked Immunosorbant Assay (ELISA). Genotyping was performed by Restriction Fragment Length Polymorphism (RFLP)-PCR method and the data were analyzed statistically with IBM-SPSS 21. RESULTS: Our results demonstrated suboptimal vitamin D levels in whole of our sample population, whether control or cases (p = 0.529). There was no statistically significant difference in 25-Hydroxyvitamin D3 levels between cases (11.351 ± 5.92) and controls (12.335 ± 6.64). VDR polymorphism was not associated with susceptibility to T1DM in our sample population. Similarly, no association between VDR polymorphism and vitamin D levels was observed i.e. FokI p=0.507 and p=0.543 and ApaI p=0.986 and p=0.307 for cases and controls respectively. CONCLUSIONS: There is an overall deficiency of Vitamin D levels in cases and control subjects while SNPs association studies suggested that in our sample population there was no association of VDR gene polymorphisms Fok I and Apa I with TIDM.

Influence of Apa1 (rs7975232), Taq1 (rs731236) and Bsm1 (rs154410) polymorphisms of vitamin D receptor on preterm birth risk in the Polish population.

OBJECTIVES: Vitamin D receptor (VDR) is expressed in the placenta and tissues related to the immune system occurrence of various variants of VDR may modify the effects of vitamin D on pregnancy. The aim of this study was to evaluate the association between the parturients' Apa1, Taq1, and Bsm1 polymorphisms of the VDR and their combinations and the risk of preterm birth in the Polish population. MATERIAL AND METHODS: Determination of polymorphism for VDR was assayed using the RT-PCR method. 199 Caucasian women at childbirth were qualified:100 patients who had a spontaneous preterm birth and 99 patients who had a term birth. RESULTS: Three separate genotypes of the Apa1, Taq1, and Bsm1 polymorphisms were detected. No significant differences in the frequency of particular genotypes in the compared groups were found. Some of the genotype combinations were significantly more frequent in the preterm group - the bb/AA/TT genotype (28.0% vs. 10.1%; p = 0.0013) and the BB/aa/tt genotype (14.0% vs. 4.04% p = 0.0277). The Bb/AA/Tt and the BB/Aa/tt genotypes were found only in the control group (16.1% and 7.0% of patients, respectively). The bb/aa/TT was significantly more frequent in the control group (2.0% vs. 11.1%; p = 0,0207). Two genotype combinations reduced the risk of preterm birth - the Bb/AA/Tt genotype by 94% (OR = 0.43, 95% CI: 0.002-0.885, p = 0.041) and the BB/Aa/tt genotype by 98% (OR = 0.029, 95% CI: 0.001-0.838, p = 0.039). CONCLUSIONS: Our result suggests that there may be a relationship between certain VDR genotype combinations and the risk of preterm birth. Further research is needed in order to substantiate this finding.

Exploring the Influence of Fok1/Apa1 Polymorphic Variants on Adolescent Mental Health and Response to Vitamin D Supplementation in Embryonic Hippocampal Cell Lines.

Several single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) have been observed in association with susceptibility to various pathologies, including autism, major depression, age-related changes in cognitive functioning, and Parkinson's and Alzheimer's diseases. This study aimed to establish the association between Fok1/Apa1 polymorphic variants and anxious/depressive symptoms in nonclinical adolescents from central Italy, with the goal of identifying the risk of developing both symptoms. We found no significant difference in genotype distribution or dominant/recessive models of Fok1/Apa1 VDR polymorphic variants between subjects with anxious/depressive symptoms and controls. HN9.10e cell lines carrying the AA genotype for Fok1 and the CC genotype for Apa1 responded better to treatment with vitamin D3 than cell lines carrying the AG genotype for Fok1 and CA genotype for Apa1. Cell lines carrying the GG genotype for Fok1 and the AA genotype for Apa1 did not respond at all, suggesting avenues for future studies in both the general population and individuals with mental and/or neuropsychiatric disorders. These studies suggest that the level of response to vitamin D3 administered to prevent and/or treat mental or neurological disorders could depend on the polymorphic variants of the vitamin D receptor.

Apa1 (rs7975232) SNP in the vitamin D receptor is linked to hepatocellular carcinoma in hepatitis C virus cirrhosis.

Background: As hepatocellular carcinoma (HCC) arising from chronic hepatitis C virus (HCV) infection in liver cirrhosis is a major problem in public health, early and rapid prediction of HCC is urgent. We hypothesized that a single nucleotide polymorphism in the Apa1 SNP in the vitamin D receptor may help diagnosis.Methods: We recruited 3 groups: 80 HCC patients with HCV cirrhosis, 80 HCV cirrhotic patients free of HCC and 80 healthy controls. Apa1 rs7975232 SNP was detected by PCR- RFLP technique. Routine laboratory markers were determined by standard methods.Results: The Apa1 CC genotype was more frequent (75%) in HCC than in the cirrhosis (35%) and control (20%) groups (P<0.0001). CC patients were more likely to have a more severe Child-Pugh score (P=0.027) and MELD score (P<0.05). In multivariate analysis, the CC genotype out-performed AFP is determining HCC.Conclusion: Apa1 CC genotype is linked to HCC in HCV C cirrhotic patients, and so has the potential to be an independent biomarker predictor for HCC occurrence in HCV cirrhosis.

Association of vitamin D receptor gene polymorphisms with type 2 diabetes mellitus in Taif population: a case-control study / Associação de polimorfismos do gene do receptor de vitamina D com diabetes mellitus tipo 2 na população Taif: um estudo de caso-controle

Abstract Several reasons may underlie the dramatic increase in type2 diabetes mellitus. One of these reasons is the genetic basis and variations. Vitamin D receptor polymorphisms are associated with different diseases such as rheumatoid arthritis and diabetes. The aim of this study is to investigate the possible association of two identified mutations ApaI (rs7975232) and TaqI (rs731236). Eighty-nine healthy individuals and Fifty-six Type 2 Diabetic (T2D) patients were investigated using RFLP technique for genotyping and haplotyping as well. The distribution of Apal genotypes was not statistically significant among the control (P=0.65) as well as for diabetic patients (P=0.58). For Taql allele frequencies of T allele was 0.61 where of G allele was 0.39. The frequency distribution of Taql genotypes was not statistically significant among the control (P=0.26) as well as diabetic patients (P=0.17). Relative risk of the allele T of Apa1 gene is 1.28 and the odds ratio of the same allele is 1.53, while both estimates were < 1.0 of the allele G. Similarly, with the Taq1 gene the relative risk and the odds ratio values for the allele T are 1.09 and 1.27 respectively and both estimates of the allele C were 0.86 for the relative risk and 0.79 for the odds ratio. The pairwise linkage disequilibrium between the two SNPs Taq1/apa1 was statistically significant in control group (D = 0.218, D' = 0.925 and P value < 0.001) and similar data in diabetic groups (D = 0.2, D' = 0.875 and P value < 0.001). These data suggest that the T allele of both genes Apa1 and Taq1 is associated with the increased risk of type 2 diabetes. We think that we need a larger number of volunteers to reach a more accurate conclusion.

Resumo Várias razões podem estar subjacentes ao aumento dramático da diabetes mellitus tipo 2. Um desses motivos é a base genética e variações. Os polimorfismos do receptor da vitamina D estão associados a diferentes doenças, como artrite reumatoide e diabetes. O objetivo deste estudo é investigar a possível associação de duas mutações identificadas ApaI (rs7975232) e TaqI (rs731236). Oitenta e nove indivíduos saudáveis ​​e 56 pacientes com diabetes tipo 2 (T2D) foram investigados usando a técnica RFLP para genotipagem e haplotipagem também. A distribuição dos genótipos Apal não foi estatisticamente significativa entre o controle (P = 0,65), bem como para os pacientes diabéticos (P = 0,58). Para as frequências do alelo Taql, o alelo T foi de 0,61, onde o alelo G foi de 0,39. A distribuição de frequência dos genótipos Taql não foi estatisticamente significativa entre o controle (P = 0,26), bem como os pacientes diabéticos (P = 0,17). O risco relativo do alelo T do gene Apa1 é 1,28 e a razão de chances do mesmo alelo é 1,53, enquanto ambas as estimativas foram < 1,0 do alelo G. Da mesma forma, com o gene Taq1, os valores de risco relativo e razão de chances para o alelo T são 1,09 e 1,27, respectivamente, e ambas as estimativas do alelo C foram de 0,86 para o risco relativo e 0,79 para o odds ratio. O desequilíbrio de ligação par a par entre os dois SNPs Taq1 / apa1 foi estatisticamente significativo no grupo de controle (D = 0,218, D' = 0,925 e valor P < 0,001) e dados semelhantes em grupos diabéticos (D = 0,2, D' = 0,875 e valor P < 0,001). Esses dados sugerem que o alelo T de ambos os genes Apa1 e Taq1 está associado ao aumento do risco de diabetes tipo 2. Achamos que precisamos de um número maior de voluntários para chegar a uma conclusão mais precisa.

Association of vitamin D receptor gene polymorphisms with type 2 diabetes mellitus in Taif population: a case-control study

Abstract Several reasons may underlie the dramatic increase in type2 diabetes mellitus. One of these reasons is the genetic basis and variations. Vitamin D receptor polymorphisms are associated with different diseases such as rheumatoid arthritis and diabetes. The aim of this study is to investigate the possible association of two identified mutations ApaI (rs7975232) and TaqI (rs731236). Eighty-nine healthy individuals and Fifty-six Type 2 Diabetic (T2D) patients were investigated using RFLP technique for genotyping and haplotyping as well. The distribution of Apal genotypes was not statistically significant among the control (P=0.65) as well as for diabetic patients (P=0.58). For Taql allele frequencies of T allele was 0.61 where of G allele was 0.39. The frequency distribution of Taql genotypes was not statistically significant among the control (P=0.26) as well as diabetic patients (P=0.17). Relative risk of the allele T of Apa1 gene is 1.28 and the odds ratio of the same allele is 1.53, while both estimates were 1.0 of the allele G. Similarly, with the Taq1 gene the relative risk and the odds ratio values for the allele T are 1.09 and 1.27 respectively and both estimates of the allele C were 0.86 for the relative risk and 0.79 for the odds ratio. The pairwise linkage disequilibrium between the two SNPs Taq1/apa1 was statistically significant in control group (D = 0.218, D' = 0.925 and P value 0.001) and similar data in diabetic groups (D = 0.2, D' = 0.875 and P value 0.001). These data suggest that the T allele of both genes Apa1 and Taq1 is associated with the increased risk of type 2 diabetes. We think that we need a larger number of volunteers to reach a more accurate conclusion.

Resumo Várias razões podem estar subjacentes ao aumento dramático da diabetes mellitus tipo 2. Um desses motivos é a base genética e variações. Os polimorfismos do receptor da vitamina D estão associados a diferentes doenças, como artrite reumatoide e diabetes. O objetivo deste estudo é investigar a possível associação de duas mutações identificadas ApaI (rs7975232) e TaqI (rs731236). Oitenta e nove indivíduos saudáveis e 56 pacientes com diabetes tipo 2 (T2D) foram investigados usando a técnica RFLP para genotipagem e haplotipagem também. A distribuição dos genótipos Apal não foi estatisticamente significativa entre o controle (P = 0,65), bem como para os pacientes diabéticos (P = 0,58). Para as frequências do alelo Taql, o alelo T foi de 0,61, onde o alelo G foi de 0,39. A distribuição de frequência dos genótipos Taql não foi estatisticamente significativa entre o controle (P = 0,26), bem como os pacientes diabéticos (P = 0,17). O risco relativo do alelo T do gene Apa1 é 1,28 e a razão de chances do mesmo alelo é 1,53, enquanto ambas as estimativas foram 1,0 do alelo G. Da mesma forma, com o gene Taq1, os valores de risco relativo e razão de chances para o alelo T são 1,09 e 1,27, respectivamente, e ambas as estimativas do alelo C foram de 0,86 para o risco relativo e 0,79 para o odds ratio. O desequilíbrio de ligação par a par entre os dois SNPs Taq1 / apa1 foi estatisticamente significativo no grupo de controle (D = 0,218, D' = 0,925 e valor P 0,001) e dados semelhantes em grupos diabéticos (D = 0,2, D' = 0,875 e valor P 0,001). Esses dados sugerem que o alelo T de ambos os genes Apa1 e Taq1 está associado ao aumento do risco de diabetes tipo 2. Achamos que precisamos de um número maior de voluntários para chegar a uma conclusão mais precisa.