Immunohistochemical evaluation of vitamin D receptor(VDR) expression in cutaneous melanoma tissues and four VDR gene polymorphisms

Objective:Vitamin D receptor(VDR)mediates vitamin D activity.We examined whether VDR expression in excised melanoma tissues is associated with VDR gene(VDR)polymorphisms.Methods:We evaluated VDR protein expression(by monoclonal antibody immunostaining),melanoma characteristics,and carriage of VDR-Fok I-rs2228570(C>T),VDR-Bsm I-rs1544410(G>A),VDR-ApaI-rs7975232(T>G),and VDR-TaqI-rs731236(T>C)polymorphisms(by restriction fragment length polymorphism).Absence or presence of restriction site was denoted by a capital or lower letter,respectively:"F"and"f"for Fok I,"B"and"b"for Bsm I,"A"and"a"for ApaI,and "T"and"t"for TaqI endonuclease.Seventy-four Italian cutaneous primary melanomas(52.1±12.7 years old)were studied;51.4% were stage Ⅰ,21.6% stage Ⅱ ,13.5% stage Ⅲ,and 13.5% stage Ⅳ melanomas.VDR expression was categorized as follows:100% positive vs.<100%;over the median 20%(high VDR expression)vs.≤20%(low VDR expression);absence vs.presence of VDR-expressing cells.Results:Stage I melanomas,Breslow thickness of<1.00 mm,level II Clark invasion,Aa heterozygous genotype,and AaTT combined genotype were more frequent in melanomas with high vs.low VDR expression.Combined genotypes BbAA,bbAa,AATt,BbAATt,and bbAaTT were more frequent in 100%vs.<100%VDR-expressing cells.Combined genotype AATT was more frequent in melanomas lacking VDR expression(odds ratio=14.5;P=0.025).VDR expression was not associated with metastasis,ulceration,mitosis>1,regression,tumor-infiltrating lymphocytes,tumoral infiltration of vascular tissues,additional skin and non-skin cancers,and melanoma familiarity.Conclusions:We highlighted that VDR polymorphisms can affect VDR expression in excised melanoma cells.Low VDR expression in AATT carriers is a new finding that merits further study.VDR expression possibly poses implications for vitamin D supplementation against melanoma.VDR expression and VDR genotype may become precise medicinal tools for melanoma in the future.

Study of Vitamin D Receptor (VDR) Gene Polymorphisms among Egyptian Cohort Patients with Different Stages of Colorectal Cancer

Colorectal cancer represents the third cancer worldwide. Studies showed thatinsufficient levels of vitamin D may result in colorectal cancer. Genetic variations in genes controlling vitamin D activity would play a role in determining susceptibility to colorectal cancer. Aim of the work: to study the different genotypes of VDR polymorphisms and detect the association between serum levels of 25(OH)VitD and 1,25(OH)2VitD among sample of Egyptian patients with different stages of colorectal cancer. Methods: Ninety patients (60 with different stages of colorectal cancer and 30 patients with benign pathology of the colon) together with 30 healthy controls were examined using PCR-RFLP analysis for FokI, ApaI and TaqI polymorphisms. Results: Genotype distribution for ApaI polymorphism showed no statistically significant difference between patients (colorectal cancer and benign) and controls with p = 0.1. There was no statistically significant difference in FokI polymorphism where p = 0.26 and genotype distribution for TaqI was also insignificant with p = 0.016. The median serum level of 25(OH)VitD was low in cancer cases compared to the control group and benign cases with (p 0.001). There was no statisticallysignificant difference of median serum level of 1,25(OH)2VitD between benign and cancer cases. There was statistically significant difference of median serum level of 25(OH)VitD and 1,25(OH)2VitD between stage I and stage II with (p = 0.004) and (p 0.001), and between stage I and stage III with (p = 0.001)and (p 0.001), but no statistically significant difference between stage II and III with (p = 0.514). Conclusions: There is ethnic variability in vitamin D receptor gene polymorphisms. The lack of significant association of the studied gene polymorphism in our population suggests that its association with other functionally known gene polymorphism might have a role in the pathogenesis of colorectal cancer.

VDR基因多态性与宫颈病变及HPV感染转归的相关性

目的 分析维生素D受体(vitamin D receptor, VDR)基因多态性与宫颈病变的关系,并探讨其对高危型人乳头瘤病毒(high risk-human papillomavirus, HR-HPV)感染转归的影响。方法 选取2020年9月至2021年10月于山西医科大学第二医院行阴道镜检查的患者376例,将病理结果示慢性宫颈炎和宫颈上皮内瘤变Ⅰ级者设为对照组(188例),宫颈上皮内瘤变Ⅱ级及以上者(CINⅡ+)为病例组(188例)。收集患者外周静脉血行VDR基因多态性检测,包括FOKI、BsmL、Apal和Taql的单核苷酸多态性(single nucleotide polymorphisms, SNPs)位点,分析VDR基因多态性与宫颈病变的关系。对选择行宫颈锥形切除术进行治疗的142例CINⅡ-Ⅲ级患者的HPV转归情况进行6个月的随访,根据随访结果分为HPV转阴者和同一型别HPV持续感染者,即转阴组和持续感染组,分析VDR基因多态性是否影响HPV感染的转归。结果 随访结果显示,104例患者的HPV感染呈转阴状态,33例患者持续感染同一型别的HPV,而另外5例患者则感染了其他型别的HPV。VDR基因多态性检测结果表明,FOKI SNPs ff基因型及f等位基因与CINⅡ+发生显著相关(P<0.05),并且与HR-HPV持续感染相关(P<0.05);TaqI SNPs tt及Tt基因型均增加CINⅡ+发生的风险(P<0.05),t等位基因与CINⅡ+发生风险增加有关(P<0.05),但与HPV持续感染未见相关性(P>0.05)。结论 VDR基因多态性与宫颈病变及HR-HPV感染转归相关,其中FOKI SNPs ff基因型及f等位基因和TaqI SNPs tt、Tt基因型及t等位基因与宫颈病变的发生存在关联,并且FOKI SNPs ff基因型及f等位基因可能影响HR-HPV感染的转归结果。

Vitamin D receptor gene polymorphisms and hepatocellular carcinoma in alcoholic cirrhosis

AIM: To assess the relationship between vitamin D re-ceptor (VDR) gene polymorphisms and the presence of hepatocellular carcinoma (HCC). METHODS: Two-hundred forty patients who underwent liver transplantation were studied. The etiologies of liver disease were hepatitis C (100 patients), hepatitis B (37) and alcoholic liver disease (103). A group of 236 healthy subjects served as controls. HCC in the explanted liver was detected in 80 patients. The following single nucle-otide gene polymorphisms of the VDR were investigatedby polymerase chain reaction and restriction fragment length polymorphism: FokI C>T (F/f), BsmI A>G (B/b), ApaI T>G (A/a) and TaqI T>C (T/t) (BAT). RESULTS: The frequencies of genotypes in patients without and with HCC were for FokI F/F = 69, F/f = 73, f/f = 18 and F/F = 36, F/f = 36, f/f = 8; BsmI b/b = 45, B/b = 87, B/B = 28 and b/b = 33, B/b = 35, B/B = 12; for ApaI A/A = 53, A/a = 85, a/a = 22 and A/A = 27, A/a = 38, a/a = 15; for TaqI T/T = 44, T/t = 88, t/t = 28 and T/T = 32, T/t = 38, t/t = 10. Carriage of the b/b genotype of BsmI and the T/T genotype of TaqI was signif icantly associated with HCC (45/160 vs 33/80, P < 0.05 and 44/160 vs 32/80, P < 0.05, respectively). The absence of the A-T-C protective allele of BAT was signif i-cantly associated with the presence of HCC (46/80 vs 68/160, P < 0.05). A strong association was observed between carriage of the BAT A-T-C and G-T-T haplotypes and HCC only in alcoholic liver disease (7/46 vs 12/36 vs 11/21, P < 0.002, respectively).CONCLUSION: VDR genetic polymorphisms are sig-nificantly associated with the occurrence of HCC in patients with liver cirrhosis. This relationship is more specific for patients with an alcoholic etiology.

Bsm I(rs1544410) and Fok I(rs2228570) vitamin D receptor polymorphisms, smoking, and body mass index as risk factors of cutaneous malignant melanoma in northeast Italy

Objective:To investigate whether vitamin D receptor gene(VDR)Bsm I-rs1544410 and Fok I-rs2228570 polymorphisms,smoking duration,and body mass index(BMI)are risk factors for cutaneous melanoma,especially metastatic melanoma.Methods:We studied 120 cutaneous melanoma cases[68 stage I and II non-metastatic melanoma(NMet M)patients,plus 52Stage III and IV metastatic melanoma(Met M)patients],and 120 matching healthy controls from northeast Italy.VDR polymorphisms were measured by restriction fragment length polymorphism analysis.Absence or presence of Bsm I and Fok I restriction sites was denoted by"B"and"F"or by"b"and"f,"respectively.Results:VDR-Bsm I bb genotype was more frequent among Met M(32.7%)than among NMet M cases(13.2%),with odds ratio(OR)=3.18.Comparison of all melanoma patients vs healthy controls showed that the following biomarkers were at risk:≥20 years of smoking(OR=2.43);≥20 years of smoking combined with bb(OR=4.78),Bb+bb(OR=2.30),Ff(OR=3.04),and Ff+ff(OR=3.08);obesity(BMI>30Conclusions:Risk factors for cutaneous Met M include two VDR polymorphisms combined with smoking duration and obesity.Results suggest gene-environment implications in melanoma susceptibility and severity.Future studies in larger cohorts and in subjects with different genetic background are warranted to extend our findings.

Serum vitamin D and colonic vitamin D receptor in inflammatory bowel disease

AIM: To determine serum vitamin D levels and colonic vitamin D receptor(VDR) expression in inflammatory bowel disease(IBD) and non-IBD patients and correlate these with histopathology.METHODS: Puerto Rican IBD(n = 10) and non-IBD(n = 10) patients ≥ 21 years old scheduled for colonoscopy were recruited. Each patient completed a questionnaire and provided a serum sample and a colonic biopsy of normal-appearing mucosa. For IBD patients, an additional biopsy was collected from visually diseased mucosa. Serum vitamin D levels were measured by ultra-performance liquid chromatography and mass spectrometry. Hematoxylin and eosin stained tissue sections from colonic biopsies were classified histologically as normal or colitis(active/inactive), and scored for the degree of inflammation present(0-3, inactive/absent to severe). Tissue sections from colonic biopsies were also stained by immunohistochemistry for VDR, for which representative diagnostic areas were photographed and scored for staining intensity using a 4-point scale.RESULTS: The IBD cohort was significantly younger(40.40 ± 5.27, P < 0.05) than the non-IBD cohort(56.70 ± 1.64) with a higher prevalence of vitamin D deficiency(40% vs 20%, respectively) and insufficiency(70% vs 50%, respectively). Histologic inflammation was significantly higher in visually diseased mucosa from IBD patients(1.95 ± 0.25) than in normalappearing mucosa from control patients(0.25 ± 0.08, P < 0.01) and from IBD patients(0.65 ± 0.36, P < 0.05) and correlated inversely with VDR expression in visually diseased colonic tissue from IBD patients(r =-0.44, P < 0.05) and from IBD patients with Crohn's disease(r =-0.69, P < 0.05), but not in normal-appearing colonic tissue from control patients or IBD patients. Control and IBD patient serum vitamin D levels correlated positively with VDR expression in normal colon from control and IBD patients(r = 0.38, P < 0.05) and with patient age(r = 0.54, P < 0.01). CONCLUSION: Levels of serum vitamin D correlate positively with colonic VDR expression in visually normal mucosa whereas inflammation correlates negatively with colonic VDR expression in visually diseased mucosa in Puerto Rican patients.

Vitamin D receptor gene polymorphisms and colorectal cancer risk:A systematic meta-analysis

AIM:To investigate the relationship between polymorphisms present in the vitamin D receptor(VDR) gene and colorectal cancer risk,a systematic meta-analysis of population-based studies was performed.METHODS:A total of 38 relevant reports published between January 1990 and August 2010 were identified,of which only 23 qualified for this meta-analysis based on our selection criteria.Five polymorphic variants of the VDR gene,including Cdx-2(intron 1e) and FokI(exon 2) present in the 5' region of the gene,and BsmI(intron 8),ApaI(intron 8),and TaqI(exon 9) sites present in the 3' untranslated region(UTR),were evaluated for possible associations with colorectalcancer risk.Review manager 4.2 was used to perform statistical analyses.RESULTS:In the meta-analysis performed,only the BsmI polymorphism was found to be associated with colorectal cancer risk.In particular,the BsmI B genotype was found to be related to an overall decrease in the risk for colorectal cancer [BB vs bb:odds ratio(OR) = 0.87,95% CI:0.80-0.94,P = 3 × 10-4;BB vs Bb + bb:OR = 0.90,95% CI:0.84-0.97,P = 5 × 10-4].Moreover,in subgroup analyses,the BsmI B genotype was significantly associated with colon cancer,and not rectal cancer.An absence of between-study heterogeneity was also observed.CONCLUSION:A meta-analysis of 23 published studies identified the BsmI polymorphism of the VDR gene to be associated with an increased risk of colon cancer.

Overview of studies of the vitamin D/vitamin D receptor system in the development of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD)is the most common chronic liver disease in the world.NAFLD is known to be associated with obesity,type 2 diabetes,metabolic syndrome and increased cardiovascular events:for these reasons,it is becoming a global public health problem and represents an important challenge in terms of prevention and treatment.The mechanisms behind the pathogenesis of NAFLD are multiple and have not yet been completely unraveled;consequently,at moment there are not effective treatments.In the past few years a large body of evidence has been assembled that attributes an important role in hepatic aberrant fat accumulation,inflammation and fibrosis,to the vitamin D/vitamin D receptor(VD/VDR)axis,showing a strong association between hypovitaminosis D and the diagnosis of NAFLD.However,the data currently available,including clinical trials with VD supplementation,still provides a contrasting picture.The purpose of this editorial is to provide an overview of recent advances in the pathogenesis of NAFLD in relation to VD/VDR.Based on recent data from literature,we focused in particular on the hypothesis that VDR itself,independently from its traditional ligand VD,may have a crucial function in promoting hepatic fat accumulation.This might also offer new possibilities for future innovative therapeutic approaches in the management of NAFLD.

EFFECTS OF VITAMIN D RECEPTOR GENE POLYMORPHISMS ON SUSCEPTIBILITY TO TYPE 1 DIABETES MELLITUS

Objective To investigate the influence of vitamin D receptor （VDR） gene polymorphisms on susceptibility to type 1 diabetes mellitus （T1DM） in the Chinese Han population. Method One hundred and thirty-six Chinese Han people, including 54 T1DM patients and 82 unrelated healthy subjects as control were genotyped by polymerase chain reaction-restriction fragment length polymorphism for three restriction sites in the VDR gene, which were ApaI, TaqI, and BamL Results The frequency of B allele of BsmI site in VDR gene was significantly higher in T1DM patients than in healthy subjects （ P = 0. 033 ） while no difference was found between the two groups in the distribution of ApaI and TaqI polymorphisms. Conclusion The BsmI polymorphism of VDR gene may be associated with the susceptibihty to T1DM in the Chinese Han population of Beijing.

Loss of the vitamin D receptor in human breast and prostate cancers strongly induces cell apoptosis through downregulation of Wnt/β-catenin signaling

Vitamin D co-regulates cell proliferation, differentiation and apoptosis in numerous tissues, including cancers. The known anti-proliferative and pro-apoptotic actions of the active metabolite of vitamin D, 1,25-dihydroxy-vitamin D [1,25（OH）2D] are mediated through binding to the vitamin D receptor （VDR）. Here, we report on the unexpected finding that stable knockdown of VDR expression in the human breast and prostate cancer cell lines, MDA-MB-231 and PC3, strongly induces cell apoptosis and inhibits cell proliferation in vitro. Implantation of these VDR knockdown cells into the mammary fat pad （MDA-MB-231）, subcutaneously （PC3） or intra-tibially （both cell lines） in immune-incompetent nude mice resulted in reduced tumor growth associated with increased apoptosis and reduced cell proliferation compared with controls. These growth-retarding effects of VDR knockdown occur in the presence and absence of vitamin D and are independent of whether cells were grown in bone or soft tissues. Transcriptome analysis of VDR knockdown and non-target control cell lines demonstrated that loss of the VDR was associated with significant attenuation in the Wnt/0-catenin signaling pathway. In particular, cytoplasmic and nuclear β-catenin protein levels were reduced with a corresponding downregulation of downstream genes such as Axin2, Cyclin D1, interleukin-6 （IL-6）, and IL-8. Stabilization of 0-catenin using the GSK-3β inhibitor BIO partly reversed the growth-retarding effects of VDR knockdown. Our results indicate that the unliganded VDR possesses hitherto unknown functions to promote breast and prostate cancer growth, which appear to be operational not only within but also outside the bone environment. These novel functions contrast with the known anti-proliferative nuclear actions of the liganded VDR and may represent targets for new diagnostic and therapeutic approaches in breast and prostate cancer.

Is vitamin D receptor a druggable target for non-alcoholic steatohepatitis?

Nonalcoholic steatohepatitis(NASH)is a progressed stage of non-alcoholic fatty liver disease,and available therapeutic strategies for NASH are limited.Vitamin D receptor(VDR)is proposed as a druggable target for NASH due to the discovery of vitamin D deficiency in NASH patients.To date,vitamin D supplementation has not consistently conferred expected therapeutic benefits,raising the question of whether VDR can serve as a proper drug target for NASH.It is known that VDR can interact with other ligands such as bile acids in addition to vitamin D,and its expression can be induced by fatty acids,and insulin.It has also been shown that while activation of VDR in hepatic macrophages and hepatic stellate cells resulted in attenuation of hepatic inflammation and fibrosis,activation of VDR in hepatocytes could accelerate lipid accumulation.Thus,the multiplicity of VDR ligands,together with the cell type-specificity of VDR activation,must be taken into consideration in assessing the validity of VDR being a potential druggable target for NASH treatment.To this end,we have evaluated the relationship between VDR activation and various contributing factors,such as gut microbiota,bile acid,fatty acids,and insulin,in addition to vitamin D,with an expectation that a potential drug might be identified that can elicit VDR activation in a tissue-and/or cell type-specific manner and therefore achieving therapeutic benefits in NASH.

Association of single nucleotide polymorphism of vitamin D receptor gene start codon and the suscepbility to prostate cancer in Han nationality in Hubei, China

Aim: To investigate the single nucleotide polymorphism of vitamin D receptor (VDR) gene start codon in the Han nationality in Hubei and its relationship to the susceptibility to prostate cancel (PCa). Methods: The VDR genotypes were determined by poly-merase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 80 patients with PCa and 96 normal male controls from the Han nationality in Hubei, using endonuclease Fok. Direct sequencing was done in part of the PCR products. Results: The frequency distribution of Fok I alleles in this cohort all followed the Hardy-Weinberg equilibrium. The distribution of genotypes and alleles had no significant difference between PCa patients and the controls (P>0.05). Conclusion: There was no significant relationship between Fok I polymorphism of VDR gene start codon and PCa in the Han nationality in Hubei.

Vitamin D receptor expression in human bone tissue and dose-dependent activation in resorbing osteoclasts

The effects of vitamin D on osteoblast mineralization are well documented. Reports of the effects of vitamin D on osteoclasts, however, are conflicting, showing both inhibition and stimulation. Finding that resorbing osteoclasts in human bone express vitamin D receptor （VDR）, we examined their response to different concentrations of 25-hydroxy vitamin D3 [25（OH）D3] （100 or 500 nmol·L^-1） and 1,25-dihydroxy vitamin D3 [1,25（OH）2D3] （0.1 or 0.5 nmol·L^-1） metabolites in cell cultures. Specifically, CD14＋ monocytes were cultured in charcoal-stripped serum in the presence of receptor activator of nuclear factor kappa-B ligand （RANKL） and macrophage colony-stimulating factor （M-CSF）. Tartrate-resistant acid phosphatase （TRAP） histochemical staining assays and dentine resorption analysis were used to identify the size and number of osteoclast cells, number of nuclei per cell and resorption activity. The expression of VDR was detected in human bone tissue （ex vivo） by immunohistochemistry and in vitro cell cultures by western blotting. Quantitative reverse transcription-PCR （qRT-PCR） was used to determine the level of expression of vitamin D-related genes in response to vitamin D metabolites. VDR-related genes during osteoclastogenesis, shown by qRT-PCR, was stimulated in response to 500 nmol·L^-1 of 25（OH）D3 and 0.1-0.5 nmol·L^-1 of 1,25（OH）2D3, upregulating cytochrome P450 family 27 subfamily B member I （CYP27B1） and cytochrome P450 family 24 subfamily A member I （CYP24A1）. Osteoclast fusion transcripts transmembrane 7 subfamily member 4 （tm7sf4） and nuclear factor of activated T-cell cytoplasmic 1 （nfatcl） where downregulated in response to vitamin D metabolites. Osteoclast number and resorption activity were also increased. Both 25（OH）D3 and 1,25（OH）2D3 reduced osteoclast size and number when co-treated with RANKL and M-CSF. The evidence for VDR expression in resorbing osteoclasts in vivo and low-dose effects of 1,25（OH）2D3 on osteoclasts in vitro may therefore provide insight into the effects of clinical vitamin D treatments, further providing a counterpoint to the high-dose effects reported from in vitro experiments.

Association between gene polymorphisms of vitamin D receptor and pulmonary tuberculosis susceptibility:a meta-analysis

The vitamin D receptor （VDR） gene is a primary candidate gene for tuberculosis susceptibility, but results of previous studies are somewhat contradictory and underpowered. Thus, it is essential to further explore the association between VDR gene polymorphisms and risk of pulmonary tuberculosis （PTB）. Methods： A systematic review and meta-analysis about the association between Fok[, TaqI, Apal and Bsm[ polymorphisms and PTB susceptibility was conducted. Statistical Package for Social Science （Version 13.0） and Review Manager （Version 4.2, The Cochrane Collaboration） were used to analyze the data reported in studies. Results： A total of 13 studies with 2 262 cases and 2 833 controls were involved in the FokI polymorphism, and the results showed FokI polymorphism was associated with PTB susceptibility （allele f vs F： OR=1.12, 95% CI=[1.02, 1.23]; the additive effect model ff vs FF： OR=1.40, 95%CI=[1.10, 1.77]; the recessive genetic model firs Ff＋FF： OR=1.39, 95%CI=[1.12, 1.71]）. No significant associations were observed between TaqI （15 studies with 3 031 cases and 3 132 controls）, ApaI （7 studies with 1 495 cases and 1 922 controls）, BsmI （6 studies with 919 cases and 1 250 controls） variants and PTB susceptibility. Conclusion： We found variant Fokl polymorphism of VDR gene may play a risky role in PTB development, and the genetic model was presumed to be recessive.

Expression of vitamin D receptor and cathelicidin in human corneal epithelium cells during fusarium solani infection

AIMTo observe the expression of vitamin D receptor (VDR) in human specimen and immortalized human corneal epithelium cells (HCEC) when challenged with fusarium solani. Moreover, we decided to discover the pathway of VDR expression. Also, we would like to detect the expression of cathelicidin antimicrobial peptide (CAMP) in the downstream pathway of VDR.METHODSImmunohistochemistry was used to examine the VDR expression in HCEC from healthy and fungal keratitis patients. Real time quantitative polymerase chain reaction (qPCR) was performed to observe the messenger ribonucleic acid (mRNA) change of VDR when immortalized HCEC were challenged with fusarium solani for different hours. CAMP was detected at both mRNA and protein levels.RESULTSWe found out that the VDR expression in fusarium solani keratitis patients' specimen was much more than that in healthy people. The mRNA and protein expression of VDR increased when we stimulated HCEC with fusarium solani antigen (P&#x0003c;0.01) and it could be inhibited by toll like receptor 2 (TLR2) monoclonal antibody. The CAMP expression was decreased because of fusarium solani antigen stimulation (P&#x0003c;0.01).CONCLUSIONThe VDR expression can be increased via TLR2/1-VDR pathway while the CAMP expression is decreased by the stimulation of fusarium solani antigen.

Plasma Vitamin D Levels And Vitamin D Receptor Polymorphisms Are Associated with Survival of Non-small Cell Lung Cancer

Objective：Vitamin D and its receptor（VDR） involve in multiple cellular processes and play an important role in the initiation and progression of malignancy.Thus we hypothesized that plasma vitamin D levels and single nucleotide polymorphisms（SNPs） in VDR may be of prognostic significance in non-small cell lung cancer（NSCLC）.Methods：We examined plasma 25-hydroxyvitamin D [25（OH）D] levels in 87 patients diagnosed with NSCLC using enzyme-linked immunosorbent assay（ELISA） and genotyped seven potentially functional SNPs in VDR in 568 NSCLC patients on Illumina Golden Gate platform.Results：Patients with higher plasma 25（OH）D levels had worse survival than patients with lower ones（P for trend = 0.048）.The SNPs of rs1544410 and rs739837 were independently associated with NSCLC survival（adjusted HR = 1.61,95% CIs = 1.06-2.45 for rs739837 AA vs AC/CC and adjusted HR = 1.51,95% CIs = 1.06-2.16 for rs1544410 AG/AA vs GG）.A joint effect was observed between rs1544410 and rs739837 and the risk of death elevated as the number of unfavourable genotypes patients carried increased（P for trend = 0.003）.There were no significant associations between VDR polymorphisms and plasma 25（OH）D levels.Conclusion：Our findings indicate that plasma 25（OH）D levels and genetic variants of VDR may serve as prognostic markers for NSCLC in this Chinese population.

Polymorphisms of the Vitamin D Receptor Gene and SexDifferential Associations with Lipid Profiles in Chinese Han Adults

Objective To explore the association of single nucleotide polymorphisms(SNPs)of the vitamin D receptor gene(VDR)with circulating lipids considering gender differences.Methods Of the Han Chinese adults recruited from a health examination center for inclusion in the study,the circulating lipids,25-hydroxyvitamin D(25OHD),and other parameters were measured.The VDR SNPs of Cdx2(rs11568820),Fok1(rs2228570),Apa1(rs7975232),and Taq1(rs731236)were genotyped with a qPCR test using blood DNA samples,and their associations with lipids were analyzed using logistic regression.Results In the female participants(n=236 with dyslipidemia and 888 without dyslipidemia),multiple genotype models of Fok1 indicated a positive correlation of B(not A)alleles with LDLC level(P<0.05).In the male participants(n=299 with dyslipidemia and 564 without dyslipidemia),the recessive model of Cdx2 and the additive and recessive models of Fok1 differed(P<0.05)between the HDLC-classified subgroups,respectively,and Fok1 BB and Cdx2 TT presented interactions with 25OHD in the negative associations with HDLC(P<0.05).Conclusion In the Chinese Han adults included in the study,the Fok1 B-allele of VDR was associated with higher LDLC in females,and the Fok1 B-allele and the Cdx2 T-allele of VDR were associated with lower HDLC in males.The interaction of VD and Fok1 BB or Cdx2 TT in males synergistically decreased HDLC levels.

Association of Vitamin D Receptor Gene Polymorphisms with Metabolic Syndrome in Rural Areas of China

Metabolic Syndrome (MS) is a combination of multiple complex diseases, whose etiology is complicated and has many influencing factors Randomized controlled trials have shown that vitamin D supplementation could delay the ameliorate symptoms of multiple chronic disease Therefore, it is reasonable to postulate that the expression levels of vitamin D and its related gene variants might be correlated with MS.

Association of vitamin D and polymorphisms of its receptor with antiviral therapy in pregnant women with hepatitis B

BACKGROUND The interruption of mother-to-child transmission(MTCT)is considered important to decrease the individual and population morbidity of hepatitis B virus(HBV)infection as well as the global burden of hepatitis B.Serum vitamin D(VD)is associated with hepatitis B.AIM To assess whether baseline VD levels and single nucleotide polymorphisms of the VD receptor gene(VDR SNPs)are associated with the efficacy of tenofovir disoproxil fumarate(TDF)in the prevention of MTCT in pregnant women with high HBV viral loads.METHODS Thirty-eight pregnant women who were at high risk for MTCT of HBV(those with an HBV DNA level≥2×10^(5)IU/mL during 12-24 wk of gestation)receiving antiviral therapy of TDF between June 1,2019 and June 30,2021 in Mianyang were included in this retrospective study.The women received 300 mg TDF once daily from gestational weeks 24-28 until 3 mo after delivery.To further characterize the clinical relevance of maternal serum HBV DNA levels,we stratified patients according to HBV DNA level as follows:Those with levels<2×10_(5)(full responder group)vs those levels≥2×10^(5)IU/mL(partial responder group)at delivery.Serum levels of 25-hydroxyvitamin D[25(OH)D],liver function markers,virological parameters,VDR SNPs and other clinical parameters were collected to analyze their association with the efficacy of TDF.The Mann-Whitney U test or t test was used to analyze the serum levels of 25(OH)D in different groups.Multiple linear regressions were utilized to analyze the determinants of the maternal HBV DNA level at delivery.Univariate and multivariate logistic regression analyses were employed to explore the association of targeted antiviral effects with various characteristics at baseline and delivery.RESULTS A total of 38 pregnant women in Mianyang City at high risk for MTCT of HBV were enrolled in the study.The MTCT rate was 0%.No mother achieved hepatitis B e antigen or hepatitis B surface antigen(HBsAg)clearance at delivery.Twenty-three(60.5%)participants were full responders,and 15(39.5%)participants were partial responders according to antiviral efficacy.The present study showed that a high percentage(76.3%)of pregnant women with high HBV viral loads had deficient(<20 ng/mL)or insufficient(≥20 but<31 ng/mL)VD levels.Serum 25(OH)D levels in partial responders appeared to be significantly lower than those in full responders both at baseline(25.44±9.42 vs 17.66±5.34 ng/mL,P=0.006)and delivery(26.76±8.59 vs 21.24±6.88 ng/mL,P=0.044).Serum 25(OH)D levels were negatively correlated with maternal HBV DNA levels[log(10)IU/mL]at delivery after TDF therapy(r=-0.345,P=0.034).In a multiple linear regression analysis,maternal HBV DNA levels were associated with baseline maternal serum 25(OH)D levels(P<0.0001,β=-0.446),BMI(P=0.03,β=-0.245),baseline maternal log10 HBsAg levels(P=0.05,β=0.285)and cholesterol levels at delivery(P=0.015,β=0.341).Multivariate logistic regression analysis showed that baseline serum 25(OH)D levels(OR=1.23,95%CI:1.04-1.44),maternal VDR Cdx2 TT(OR=0.09,95%CI:0.01-0.88)and cholesterol levels at delivery(OR=0.39,95%CI:0.17-0.87)were associated with targeted antiviral effects(maternal HBV DNA levels<2×10^(5) at delivery).CONCLUSION Maternal VD levels and VDR SNPs may be associated with the efficacy of antiviral therapy in pregnant women with high HBV viral loads.Future studies to evaluate the therapeutic value of VD and its analogs in reducing the MTCT of HBV may be justified.

Vitamin D receptor gene Tru9I polymorphism and risk for incidental sporadic colorectal adenomas

AIM： Recent laboratory and epidemiological studies suggest that vitamin D is a potential agent for colorectal cancer prevention. Its function is partially mediated by the vitamin D receptor （VDR）. The aim of this study was to investigate whether a novel G （allele ‘U’g〉A （allele ‘u’ polymorphism （Tru9I） in the VDR intron 8 region is associated with risk for colorectal adenoma in a colonoscopy-based case-control study. METHODS： Genotyping for a total of 391 subjects was carried out through PCR and restriction fragment length polymorphism. RESULTS： The frequencies of ‘U’ and ‘u’ alleles were 89.3% and 10.7%, respectively. The ‘Uu’ and ‘uu’ genotypes were associated with decreased risk for adenoma （OR, 0.71; 95%CI, 0.40-1.25）. The inverse association was more pronounced for multiple adenomas and adenomas that were larger had moderate or greater dysplasia, or were sessile： the odds ratios （ORs） were, 0.51 （95%CI, 0.21-1.24）, 0.37 （95%CI, 0.11-1.28）, 0.68 （95%CI, 0.33- 1.41）, and 0.36 （95%CI, 0.13-0.97） respectively. In joint/ combined analyses, inverse associations were more obvious among those who had at least one ‘u’ allele and also were younger （OR, 0.60; 95%CI, 0.26-1.37）, women （OR, 0.38; 95%CI, 0.17-0.88）, did not smoke （OR, 0.39; 95%CI, 0.13-1.23）, or took NSAID （OR, 0.38; 95%CI, 0.12-1.25）, but no evidence existed for interactions with calcium or vitamin D intake.CONCLUSION： Our findings suggest that the VDR TrugI polymorphism may be associated with lower risk for colorectal adenoma, particularly in interaction with various risk factors, but not with calcium or vitamin D.