Integrative role of vitamin D related and Interleukin-28B genes polymorphism in predicting treatment outcomes of Chronic Hepatitis C.
ABSTRACT: BACKGROUND:Improving prediction of treatment outcomes in chronic hepatitis C (CHC) genotype 4 (G4) is necessary to increase sustained viral response (SVR) rates. Vitamin D related and interferon stimulated genes are good candidates as they are recently crosstalk altering interferon response. Thus single nucleotide polymorphisms (SNPs) within some of these genes and multiple stepwise regression analysis including other independent predictors (IL28B(rs12979860), serum 25OH-vitamin D, serum alfa-fetoprotein (AFP)) were performed on a cohort of 200 Egyptian CHC patients treated with Pegylated interferon-alpha (Peg-IFN) plus ribavirin. METHODS:SNPs in cytochrome P-450 (CYP2R1)(rs10741657AG), vitamin D receptor (VDR)(rs2228570AG, rs1544410CT), oligoadenylate synthetases-like (OASL)(rs1169279CT) and adenosine deaminases acting on RNA (ADAR)(rs1127309TC) genes were analyzed by real-time PCR. RESULTS:The carrier state of A allele in VDR rs2228570 and CYP2R1 rs10741657 genes were independently associated with SVR [OR 6.453 & 3.536, p < 0.01 respectively]. Combining carriers of A allele in CYP2R1 and VDR genes with IL28B C/C genotype increased the probability of SVR from 80 % to reach 87.8 %, 93 % and 100 %. No relation was found between VDR rs1544410CT, ADAR rs1127309TC, OASL rs1169279CT polymorphisms and treatment outcome. Combining VDR rs2228570 A/A genotype with IL28B C/C genotype increased the probability of SVR from 82 % to reach 100 % and from 29 % to reach 80 % in C/T+ T/T IL28B genotype in none F4 liver disease patients. CONCLUSION:Vitamin D related (VDR rs2228570 and CYP2R1 rs10741657) and IL28B rs12979860 genes polymorphisms accurately assure SVR in naïve CHC G4 patients treated with low cost standard therapy.
Project description: To examine the effect of most common studied single nucleotide polymorphisms (SNP) on serum 25-hydroxyvitamin D (25OHD) levels in Saudi Arabian population. A cross-sectional observational study was carried out between July 2014 and October 2015, at King Fahd Hospital of the University (KFHU), Al-Khobar, Kingdom of Saudi Arabia. After informed consent, blood samples from 283 subjects living in the Eastern province were collected for 25-OHD measurement and genetic analysis of SNPs in vitamin D receptor (VDR) [rs2228570 and rs1544410], Cytochrome, P450 family 2 (CYP2R1) [rs10741657 and rs1993116], and Group-specific components (GC) [rs2282679 and rs4588]. Vitamin D deficiency was found in 87.6% and insufficiency in 7.7%. The percentages of the different alleles of the 6 SNPs tested ranged between 0-62.5%. There was significant difference between the AA, AG, and GG alleles of VDR rs2228570. The carries of GG allele was associated with increased risks of vitamin D insufficiency (p less than 0.002) and deficiency (p less than or equal to 0.005). The CYP2R1 rs10741657 gene showed that AG and GG allele carriers had significant risk of vitamin D deficiency. AG allele (normal versus Insufficiency p less than 0.02 and normal versus deficiency p less than 0.08) and GG allele normal versus deficiency (p less than 0.002) and insufficiency versus deficiency (p less than 0.001). For group-specific components (GC rs4588), there was only significant difference between the normal and deficiency for the AC allele (p less than 0.0001).The presence of GG allele of the SNP rs2228570 of VDR gene, SNPs rs4588 of GC gene and CYP2R1 rs10741657 gene was associated with vitamin D deficiency.
Project description:To explore subclinical fatty liver disease (FLD) in donors as a possible mechanism leading to FLD in recipients of living donor liver transplantation (LDLT), we extracted thirty donor-recipient pairs' serum DNA and explored the presence of CYP2R1 single nucleotide polymorphism (SNP) rs10741657 and vitamin D receptor (VDR) SNP rs2228530 A/G alleles using real-time polymerase chain reaction. We measured the serum 25(OH)D concentrations and investigated the CYP2R1 and VDR genotypes of the donors and recipients before and after LDLT for comparison with the histological findings from the donors on wedge biopsy, the recipients' removed native liver, and selective liver biopsy after LDLT. There was a significant difference in low serum 25(OH)D concentration between the donors and recipients before LDLT and in the recipients before versus after LDLT (13.90 ± 8.85 versus 47.9 ± 14.88 versus 11.82 ± 10.36, P < 0.001), and significant difference in FLD was detected on wedge biopsy from the donors and the native liver from the recipients as well as the native liver and follow-up biopsy from the recipients (P < 0.001). CYP2R1 and VDR genotype were predominant, both for the AG and for the GG alleles. For the donor VDR SNP rs2228570, low serum 25(OH)D was significantly different between genotypes AA and AG (P = 0.024) as well as between genotypes AA and AG plus GG (P = 0.042). Our data suggest that donors' VDR rs2228570 AA alleles may play a major role in low serum 25(OH)D regarding pathological FLD in recipients after LDLT.
Project description:As recent studies have described an association between vitamin D and allergic rhinitis, we hypothesized that vitamin D pathway-related genes may be candidate genes for susceptibility to allergic rhinitis. Thus, we sought to evaluate whether polymorphisms in the vitamin D receptor (VDR) and CYP2R1 genes are associated with mite-sensitized persistent allergic rhinitis (PER) in a Han Chinese population. A hospital-based case-control study consisting of 519 patients with mite-sensitized PER and 447 healthy controls was conducted. Five single nucleotide polymorphisms (SNPs) in VDR and CYP2R1 were selected for genotyping. The genotype and allele frequencies of rs9729, rs2228570, rs1544410, and rs731236 in VDR as well as rs2060793 in CYP2R1 were not significantly associated with susceptibility to mite-sensitized PER. After stratification analyses, however, both the CT and CT/TT genotypes of rs2228570 in VDR exhibited a significantly decreased risk (CT: adjusted odds ratio (OR)=0.58, 95% confidence intervals (CI)=0.37-0.91;adjusted OR=0.61, 95% CI=0.40-0.93) of mite-sensitized PER, while the AA genotype of rs2060793 in CYP2R1 exhibited a significantly increased risk (adjusted OR=1.85, 95% CI=1.03-3.34) of PER in the age subgroup of <16 years old. Both the AG and AG/GG genotypes of rs731236 in VDR exhibited a significantly decreased risk (AG: adjusted OR=0.43, 95% CI=0.21-0.89;adjusted OR=0.46, 95% CI=0.23-0.94) of PER in the female subgroup. Analysis of the locus-locus interactions of VDR and CYP2R1 revealed two models that involved combined SNPs of VDR and CYP2R1 were statistically significant (P<0.05). Our data suggest that age and gender may have an impact on the association of three SNPs (rs2228570, rs731236, and rs2060793) in genes of the vitamin D pathway with the risk of mite-sensitized PER in this Chinese population. The VDR and CYP2R1 variants may be involved in genetic interactions in the pathogenesis of PER.
Project description:Chlamydia trachomatis is the most common sexually transmitted bacterium worldwide. Its often asymptomatic course of infection increases chances of transmission, and increases risk of late complications. Genetic variations in the host immune system are known to impact the course of infections. Recent studies have shown a positive impact of vitamin D on the regulation of the immune system. This study assesses the impact of eight polymorphisms in five genes [VDR (rs1544410 G > A, rs2228570 C > T), CYP27B1 (rs10877012 G > T), DHCR7 (rs7944926 G > A, rs3829251 G > A), GC (rs3755967) and CYP2R1 (rs10741657 G > A, rs2060793 G > A)] on susceptibility to Chlamydia infections in humans. These polymorphisms could influence protein expression or function, and thus influence the immune system. Samples of women visiting the STD outpatient clinic in South Limburg were genotyped using the Roche Lightcycler 480. In this study, we did not observe statistically significant differences between the genotype distributions of these polymorphisms in women with or without a Chlamydia infection. This suggests that VDR, CYP27B1, DHCR7, GC and CYP2R1 do not affect the susceptibility to Chlamydia infections. However, due to its pleiotropic nature in the immune system a role for the vitamin D pathway may not be excluded from the whole clinical course of Chlamydia infections (e.g. late complications), and further research is required.
Project description:Vitamin D receptor (VDR) modulates host immune responses to infections such as hepatitis C virus (HCV) infection, including interferon signaling. This study aimed to investigate the associations of VDR polymorphisms with advanced liver fibrosis and response to pegylated interferon (PEG-IFN)-based therapy in patients with chronic HCV infection. In total, 554 Thai patients with chronic HCV infection treated with a PEG-IFN-based regimen were enrolled. Six single-nucleotide polymorphisms (SNPs) were genotyped: the IL28B C > T (rs12979860) SNP and five VDR SNPs, comprising FokI T > C (rs2228570), BsmI C > T (rs1544410), Tru9I G > A (rs757343), ApaI C > A (rs7975232), and TaqI A > G (rs731236). In total, 334 patients (60.3%) achieved sustained virological response (SVR), and 255 patients (46%) were infected with HCV genotype 1. The bAt (CCA) haplotype, consisting of the BsmI rs1544410 C, ApaI rs7975232 C, and TaqI rs731236 A alleles, was associated with poor response (in terms of lack of an SVR) to PEG-IFN-based therapy. The IL28B rs12979860 CT/TT genotypes (OR = 3.44, 95% CI [2.12-5.58], p < 0.001), bAt haplotype (OR = 2.02, 95% CI [1.04-3.91], p = 0.03), pre-treatment serum HCV RNA (logIU/mL; OR = 1.73, 95% CI [1.31-2.28], p < 0.001), advanced liver fibrosis (OR = 1.68, 95% CI [1.10-2.58], p = 0.02), and HCV genotype 1 (OR = 1.59, 95% CI [1.07-2.37], p = 0.02) independently predicted poor response. Patients with the bAt haplotype were more likely to have poor response compared to patients with other haplotypes (41.4% vs 21.9%, p = 0.03). The FokI rs2228570 TT/TC genotypes (OR = 1.63, 95% CI [1.06-2.51], p = 0.03) and age ?55 years (OR = 2.25; 95% CI [1.54-3.32], p < 0.001) were independently associated with advanced liver fibrosis, assessed based on FIB-4 score >3.25. VDR polymorphisms were not associated with pre-treatment serum HCV RNA. In Thai patients with chronic HCV infection, the bAt haplotype is associated with poor response to PEG-IFN-based therapy, and the FokI rs2228570 TT/TC genotypes are risk factors for advanced liver fibrosis.
Project description:Experimental and epidemiological evidence shows a beneficial role of vitamin D in cancer. In vitro evidence is consistent with a similar protective function in glioma; however, no study has yet examined the potential role of vitamin D in glioma.We evaluated the association between common genetic variants in the vitamin D pathway and glioma risk and patient outcome in 622 newly diagnosed glioma cases and 628 healthy controls enrolled in a clinic-based case-control study. Subjects were genotyped for 7 candidate and tagging single nucleotide polymorphisms in the vitamin D receptor and 8 additional variants in NADSYN1, GC, CYP24A1, CYP2R1, and C10ORF88 linked in genome-wide association studies to serum concentrations of vitamin D. Unconditional logistic regression was used to estimate age- and gender-adjusted odds ratios and 95 % confidence intervals for glioma risk according to vitamin D genotypes. Proportional hazards regression was used to estimate hazard ratios for glioma-related death among 320 patients diagnosed with high-grade tumors. P values were uncorrected for multiple comparisons.Risk of astrocytic tumors was associated with variant alleles in rs3829251 (NADSYN1), rs10741657 (CYP2R1), rs2228570 (Fok1, VDR), and rs731236 (Taq1, VDR). No risk associations were found among oligodendroglial tumors. Survival associations were observed according to variant status for rs1544410 (Bsm1, VDR) and rs6013897 (CYP24A1).This exploratory analysis provides limited evidence of a role for genetic variation in vitamin D pathway genes with glioma risk and survival.
Project description:Vitamin D exerts immunomodulatory effects on the host response against infection with hepatitis C virus (HCV). This study was performed to assess the putative influence of polymorphisms in vitamin D-related genes on the response to antiviral therapy in patients with chronic hepatitis C (CHC).Single nucleotide polymorphisms (SNPs) in CYP27B-1260 gene promoter (rs10877012AC) and in vitamin D receptor (VDR) gene rs2228570TC, rs1544410CT, rs7975232AC and rs731236AT were analyzed in a cohort of 238 Caucasian CHC patients treated with pegylated interferon (Peg-IFN) plus ribavirin (RBV). Multivariate analyses were performed to exclude confounding effects of well-known baseline predictors of response to therapy (HCV genotype and load, IL28B genotype, age, and GGT and serum cholesterol).Three SNPs at the VDR gene (rs1544410, rs7975232 and rs731236) were in strong linkage disequilibrium, with the CCA haplotype predicting therapeutic failure [Odds ratio 2.743; (95% C.I. 1.313-5.731), p?=?0.007]. The carrier state of the VDR rs2228570 T allele was inversely related to the probability of therapeutic failure [Odds ratio 0.438; 95 C.I. (0.204-0.882), p?=?0.021]. No relation existed between CYP27B-1260 rs10877012 polymorphism and response to therapy. The area under the operating curve (AUROC) based on the model including all variables significantly related to the response to therapy was 0.846 (95% confidence interval?=?0.793-0.899).VDR gene polymorphisms are independently related to the response to Peg-IFN+RBV therapy in chronic hepatitis C and could be used as complementary biomarkers of response when included in a prediction algorithm in association with demographic, virologic, biochemical and genetic traits.
Project description:Introduction:Sarcoidosis is a rare multisystem granulomatous disease with unknown etiology. The interplay of vitamin D deficiency and genetic polymorphisms in genes coding for the proteins relevant for metabolism of vitamin D is an important, but unexplored area. The aim of this study was to investigate the association between single nucleotide polymorphisms (SNPs) in CYP2R1 (rs10741657), CYP27B1 (rs10877012), DBP (rs7041; rs4588), and VDR (rs2228570) genes and sarcoidosis, as well as the association between these SNPs and 25(OH)D levels in sarcoidosis patients. Material and methods:For that purpose we genotyped 86 sarcoidosis patients and 50 healthy controls using the PCR-RFLP method. Results:Subjects carrying the CC genotype of CYP27B1 rs10877012 have 10 times lower odds of suffering from sarcoidosis. Moreover, DBP rs4588 AA genotype was shown to be a susceptibility factor, where carriers of this genotype had eight times higher odds for developing sarcoidosis. In addition, the A allele of the DBP gene (rs4588) was associated with lower levels of 25(OH)D in sarcoidosis patients. Conclusions:These results suggest that patients with vitamin D deficiency should be regularly tested for genetic modifiers that are related to sarcoidosis in order to prevent development of serious forms of sarcoidosis.
Project description:Emerging evidence suggests a role for 7-dehydrocholesterol reductase (DHCR7) in the crosstalk between cholesterol and vitamin D. Our aim was to evaluate the impact of vitamin D-related polymorphisms and DHCR7 levels in the association between vitamin D deficiency and altered lipid profile in rheumatoid arthritis (RA). Serum 25(OH)-vitamin D, DHCR7 levels and vitamin D-related polymorphisms (VDR-rs2228570, CYP27A1-rs933994, CYP2R1-rs10741657 and DHCR7-rs12785878) were analyzed in 211 RA patients,94 controls and in a prospective cohort of 13 RA patients undergoing TNF?-blockade. Vitamin D was decreased in RA (p?<?0.001), correlated to HDL-cholesterol (r?=?0.217, p?<?0.001) and total-/HDL-cholesterol ratio (r?=?-0.227, p?=?0.004). These correlations were restricted to the VDR-rs2228570 status. Vitamin D deficiency was associated with lower HDL-cholesterol (p?=?0.028), higher tender (p?=?0.005) and swollen (p?=?0.002) joint counts, higher DAS28 (p?=?0.018) and HAQ (p?=?0.024) in AG/AA-patients but not in their GG-counterparts. The associations among DHCR7, vitamin D and lipid profile followed a seasonal pattern, decreased DHCR7 (p?=?0.008) and vitamin D (p?<?0.001) and increased total-cholesterol (p?=?0.025) being found in winter/spring. Increasing vitamin D upon TNF?-blockade paralleled RA clinical improvement (r?=?-0.610, p?=?0.027) and DHCR7 elevation (r?=?0.766, p?=?0.002). In conclusion, vitamin D-related polymorphisms and DHCR7 are pivotal to understand the complex, seasonal associations between vitamin D and lipid profile in RA.
Project description:Environmental factors such as diet, intake of vitamin D supplements and exposure to sunlight are known to influence serum vitamin D concentrations. Genetic epidemiology of vitamin D is in its infancy and a better understanding on how genetic variation influences vitamin D concentration is needed. We aimed to analyse previously reported vitamin D-related polymorphisms in relation to serum 25(OH)D concentrations in 201 healthy Danish families with dependent children in late summer in Denmark. Serum 25(OH)D concentrations and a total of 25 SNPs in GC, VDR, CYP2R1, CYP24A1, CYP27B1, C10or88 and DHCR7/NADSYN1 genes were analysed in 758 participants. Genotype distributions were in Hardy-Weinberg equilibrium for the adult population for all the studied polymorphisms. Four SNPs in CYP2R1 (rs1562902, rs7116978, rs10741657 and rs10766197) and six SNPs in GC (rs4588, rs842999, rs2282679, rs12512631, rs16846876 and rs17467825) were statistically significantly associated with serum 25(OH)D concentrations in children, adults and all combined. Several of the SNPs were in strong linkage disequilibrium, and the associations were driven by CYP2R1-rs10741657 and rs10766197, and by GC-rs4588 and rs842999. Genetic risk score analysis showed that carriers with no risk alleles of CYP2R1-rs10741657 and rs10766197, and/or GC rs4588 and rs842999 had significantly higher serum 25(OH)D concentrations compared to carriers of all risk alleles. To conclude, our results provide supporting evidence that common polymorphisms in GC and CYP2R1 are associated with serum 25(OH)D concentrations in the Caucasian population and that certain haplotypes may predispose to lower 25(OH)D concentrations in late summer in Denmark.