ApaI AA Research Articles

VDR gene polymorphism in susceptibility to urolithiasis among the Asian population: A systematic review and meta-analysis

Urolithiasis is one of the most prevalent urinary diseases worldwide. Several studies have reported VDR gene polymorphisms to have a contributing genetic factor in susceptibility to urolithiasis and suggested its possibility of being a good candidate marker for urolithiasis. However, results across numerous studies centred on the relationship between the VDR gene polymorphism and urolithiasis have been inconclusive. To perform a meta-analysis concerning the association between the risk of urolithiasis and VDR gene polymorphismsviz., ApaI, BsmI, FokI, and TaqI among the Asian population. A comprehensive electronic search was conducted to identify published studies that investigates the relationship between four polymorphisms (ApaI, BsmI, FokI and TaqI) in the VDR gene and the risk of urinary stone disease using electronic databases. VDR ApaI and FokI polymorphisms were found to be associated with urolithiasis risk. Results from pooled analysis indicated ApaI aa genotype to be associated with urolithiasis compared to AA or Aa genotypes. In addition, the minor f allele of FokI variant was identified to be the risk allele in susceptibility to urolithiasis while F allele to be protective. Moreover, from the subgroup analysis, the ff genotype of FokI and aa genotype of ApaI were associated with higher risk of urolithiasis among the East Asian but not among the Southwest Asians.

Vitamin D Receptor Gene Polymorphisms and Association with Vitiligo in Indonesian Population.

Vitiligo is an acquired depigmenting skin disorder due to the loss of melanocyte function in the epidermis and hair follicles. The pathogenesis of vitiligo is multifactorial, with genetics being a predisposing factor. Previous studies had varying results regarding whether or not polymorphisms of vitamin D receptor (VDR) gene are associated with the risk of vitiligo in specific populations. This study investigated the association between three frequently analyzed VDR gene polymorphisms (ApaI, BsmI, TaqI) and susceptibility to vitiligo in Indonesian population. Thirty-four vitiligo patients and 34 age- and sex-matched healthy subjects aged ≥18 years old were recruited in the Dermatology and Venereology Outpatient Clinic of Dr. Hasan Sadikin General Hospital, Bandung, Indonesia. Genomic deoxyribonucleic acid (DNA) was extracted from the peripheral blood using a DNA isolation kit. VDR gene polymorphisms (ApaI, BsmI, and TaqI) were investigated using the polymerase chain reaction-restriction-fragment length polymorphism method. The differences of genotype distributions and allele frequencies were statistically compared between case and control groups using Chi-square test. VDR gene polymorphisms were identified in 68 participants, consisting of Aa (n = 14), aa (n = 20), Bb (n = 15), bb (n = 19), and TT (n = 34) genotypes in the case group. In the control group, Aa (n = 6), aa (n = 28), Bb (n = 17), bb (n = 17), and TT (n = 34) genotypes were identified. However, only subjects with ApaI Aa genotype polymorphism had a 3.267-fold increased risk of developing vitiligo. This study showed that ApaI Aa genotype polymorphism of the VDR gene increases the risk of vitiligo in Indonesian population.

Association Between Circulating 25-Hydroxy Vitamin D Receptor and Molecular Response in Multiple Myeloma.

<b>Background and Objective:</b> Vitamin D Receptor (VDR) regulate several body processes related to metabolism, immunological function and oncogenesis. Low vitamin D levels are recognized as associated with a higher incidence of hematologic malignancies and poor outcomes. This study aims to determine whether vitamin D levels and VDR contribute to multiple myeloma (MM). <b>Materials and Methods:</b> This study enrolled twenty-five patients diagnosed with MM. Ages and gender were matched between patients and healthy groups. Serum Protein Electrophoresis (SPEP) was detected for all patients. Also, serum 25-hydroxy vitamin D levels were recorded. The PCR products were submitted to Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) and Sanger sequencing to detect VDR gene polymorphism including (FokI, ApaI and Tru9I). <b>Results:</b> This study revealed that an M spike was detected in five patients newly diagnosed with MM. According to vitamin D levels 84% of patients had a vitamin D deficiency. In the RFLP technique, FokI CT, ApaI AA and Tru9I GG genotypes were highly distributed in patients. Additionally, the MM group had a significant frequency of the T allele in the FokI (44.0%), the A allele in the ApaI (68.0%) and the A allele in the Tru9I (30.0%). <b>Conclusion:</b> The SPEP is an easy-to-perform laboratory test that can be used to detect and quantify monoclonal proteins. Low vitamin D level of less than 20 ng mL<sup></sup><sup>1</sup> is associated with an increased prevalence of MM and a worse response to treatment. In addition, VDR gene polymorphisms may be a molecular marker of MM risk.

Association of vitamin D receptor polymorphisms with vitamin D and calcium levels in Turkish multiple sclerosis patients.

Aim: The present study was conducted to assess the impact of gene (vitamin D receptor [VDR]polymorphisms) - environment (serum vitamin D and calcium levels) interaction on multiple sclerosis (MS) risk. Materials & methods: FokI, BsmI, TaqI and ApaI genotyping were performed in 149 MS patients and 127 controls. We measured serum vitamin D and calcium levels. Results: No significant difference between VDR polymorphisms and MS risk was detected. In patients with FokI ff, BsmI Bb, TaqI Ttand ApaI AA genotypes, vitamin D levels were statistically higher. Serum calcium levels were significantly lower in patients with FokI FF, Ff, all BsmI and TaqI genotypesand ApaI AA and Aa genotypes. Conclusion: No significant association was found between VDR polymorphisms with MS risk.

The role of vitamin D receptor polymorphisms in the course of chronic hepatitis C infection.

BackgroundVitamin D and its receptor (VDR) exert important immunoregulatory functions that contribute to liver homeostasis. The aim of this study was to investigate the influence of FokI, ApaI, BsmI and TaqI VDR polymorphisms on cirrhosis development and laboratory variables in patients with chronic hepatitis C (CHC).MethodsA total of 48 patients were enrolled in this retrospective, observational study and underwent genotype analysis; their medical records were examined to obtain relevant data.ResultsThe cumulative rate of progression to cirrhosis during the course of CHC was 31.3% after a median period of 11 years from diagnosis. Importantly, in multivariate analysis, FokI ff (adjusted hazard ratio [aHR] 13.6, 95% confidence interval [CI] 2.51-73.73; P=0.002) and ApaI aa (aHR 4.69, 95%CI 1.13-19.43; P=0.033) genotypes were independently associated with progression to cirrhosis. The presence of the aa genotype was also associated with higher liver stiffness measurements measured by transient elastography compared to the AA/Aa genotype (12.3kPa interquartile range [IQR] 9.6-17.3 vs. 7.1kPa IQR 5.6-11.1; P=0.012). In addition, higher HCV RNA and lower serum albumin levels were observed in patients with the tt genotype of the TaqI polymorphism compared to TT/Tt carriers, and in patients with the aa genotype compared to AA/Aa carriers. In haplotype analysis, no association was found between any haplotype and disease progression.ConclusionsIn patients with CHC, laboratory parameters are influenced by VDR polymorphisms and the development of cirrhosis is related to homozygosity for the dominant trait of ApaI and FokI variants.

Association of Interleukin-10 Vitamin D Receptor and Cytochrome P450 1A1 Gene Polymorphisms with Renal Cell Carcinoma Risk

The current study examined the relationship between renal cell carcinoma-related risk and gene polymorphisms in the interleukin-10, vitamin D receptor and cytochrome P450 1A1 genes. Using the preferred reporting items for systematic reviews and meta-analyses criteria, the link between gene polymorphisms and renal cell carcinoma was studied by utilizing the Web of Science, Embase, PubMed and Wanfang databases. The CC and TT genotypes along with the interleukin-10-819C/T C-allele were found to be substantially associated with renal cell carcinoma risk in the Chinese residents. Furthermore, significant relationships between the vitamin D receptor, FokI FF genotype and FokI F allele, ApaI A allele, ApaI AA and aa genotypes and renal cell carcinoma risk were observed in Asian populations. The cytochrome P450 1A1 MspI (rs4646903) polymorphism was substantially linked to an elevated risk of renal cell carcinoma in the T allele, TT genotype. However, no significant relationships were found between renal cell carcinoma risk and the single nucleotide polymorphisms interleukin-10-1082A/G, vitamin D receptor TaqI and cytochrome P450 1A1 Ile462Val (rs1544410).

Effects of vitamin D receptor gene polymorphisms on the prognosis of COVID-19.

Vitamin D deficiency has emerged as another potential risk factor for coronavirus disease (COVID-19) due to the immunomodulatory effects of 25 hydroxyvitamin D [25 (OH)D]. Vitamin D receptor (VDR) gene polymorphisms such as Fok I, Bsm I, Apa I, and Taq I are also associated with different courses of viral infections. This study aimed to evaluate the association between the VDR gene polymorphism at Fok I, Taq I, Bsm I, and Apa I genotypes and the prognosis of COVID-19 in respect to vitamin D deficiency. Two-hundred ninety-seven patients with COVID-19 were enrolled. Serum 25 (OH)D levels were measured. Four variant regions of the VDR gene, FokI, BsmI, ApaI, and TaqI were determined. Eighty-three percent of subjects had vitamin D deficiency, and 40.7% of the whole group had severe deficiency. Median 25 (OH)D level was 11.97 ng/ml. Vitamin D levels were not related to inflammatory markers, disease severity, admission to intensive care unit (ICU), and mortality. While disease severity was related to Fok I Ff genotype, it was Taq TT genotype for ICU admission. Moreover, the ApaI aa genotype was common among the patients who were died. None of the deceased subjects had the Fok I FF genotype. 25 (OH)D levels were not related to the severity and mortality of COVID-19. VDR gene polymorphisms are independently associated with the severity of COVID-19 and the survival of patients.

Association of Vitamin D Receptor Gene Polymorphisms with Metabolic Syndrome in Chinese Children

PurposeTo investigate the association between vitamin D receptor (VDR) gene polymorphisms and vitamin D deficiency, overweightness/obesity, and metabolic syndrome (MetS) in a cohort of Han children residing in Hangzhou, China.Patients and MethodsThis study assessed 106 overweight/obese and 86 healthy (control) children. Five single-nucleotide polymorphisms (SNPs) in the VDR gene, namely, TaqI (rs731236 T > C), ApaI (rs7975232 C > A), BsmI (rs1544410 G > A), FokI (rs2228570 G >A), and Cdx2 (rs11568820 G > A), were genotyped by sequencing the total polymerase chain reaction products. The distributions of different genotypes and alleles were compared among different groups.ResultsThe serum 25-hydroxyvitamin D (25(OH)D) concentration was significantly lower in overweight/obese children, while the AA genotype of ApaI SNP exhibited higher frequencies in the overweight/obese group than in the control. Furthermore, children with the ApaI AA genotype showed higher levels of Glu-60min, Glu-90min, Glu-120min and triglyceride. The AA genotype of FokI SNP was significantly associated with MetS. However, no association was observed between the five VDR SNPs and the risk of vitamin D deficiency.ConclusionVDR ApaI polymorphisms appear to be correlated with overweightness/obesity and glucose intolerance. FokI polymorphisms may be linked to a higher susceptibility toward MetS in Chinese children.

Association of sunshine vitamin receptor gene polymorphisms (rs 2228570) and (rs7975232) with the type 2 diabetes mellitus in Iraqi patients from the middle Euphrates region

BackgroundDiabetes mellitus is a significant global health issue. Polymorphisms of Vitamin D receptor gene such as rs 2228570 could be linked with type 2 DM. MethodsA case-control analysis was performed on 400 patients and 400 controls. This research was conducted in Iraqi patients for the correlation between (rs2228570) and (rs7975232) with T2DM. After extraction of DNA, FokI and ApaI are used as restriction enzymes in the RFLP method to detect these two polymorphisms. Insulin level, serum 25 hydroxyvitamin D, HDL, TG, VLDL, and total cholesterol were measured. BMI has been calculated in all subjects. The odds ratio for type 2 DM risk was calculated. ResultsThe ff, Ff and f allele of rs 2228570 was significantly associated with an increased risk of developing T2DM [OR = 4.30, p = 0.000], [OR = 3.12, p = 0.001] and [OR = 3.24, p = 0.000] respectively. The SNP is correlated with T2DM in the various inheritance models, dominant [OR = 4.0, p = 0.001] and recessive [OR = 2.90 p = 0.000]. Under codominant pattern revealed that the (BMI, insulin level and 25 hydroxyvitamin D) analyzed showed significant differences among genotypes in patients group.There were no significant differences between all genetic models and alleles frequencies of the ApaI (rs 7975232) and the risk of T2DM (p > 0.05). ApaI AA genotype was associated with a higher HDL level (p < 0.05). ConclusionOur results revealed that the FokI rs2228570 SNP increases the risk of T2DM, and it is associated with low levels of vitamin D, while no significant between the risk of T2DM and ApaI rs 7975232 genotype.

Vitamin D receptor ApaI polymorphism associated with progression of liver disease in Vietnamese patients chronically infected with hepatitis B virus

BackgroundVitamin D derivatives and their receptor (VDR) are potent modulators of immune responses in various diseases including malignancies as well as in metabolic and infectious disorders. The impact of vitamin D receptor polymorphisms on clinical outcomes of hepatitis B virus (HBV) infection is not well understood. This study aims to investigate the potential role of VDR polymorphisms (TaqI, FokI, ApaI, and BsmI) in Vietnamese HBV infected patients and to correlate these polymorphisms with the progression of HBV-related liver disease.MethodsFour hundred forty-three HBV infected patients of the three clinically well-defined subgroups chronic hepatitis B (CHB, n = 183), liver cirrhosis (LC, n = 89) and hepatocellular carcinoma (HCC, n = 171) and 238 healthy individuals (HC) were enrolled. VDR polymorphisms were genotyped by DNA sequencing and in-house validated ARMS assays. Logistic regression models were applied in order to determine the association of VDR polymorphisms with manifest HBV infection as well as with progression of related liver diseases mulin different genetic models.ResultsThe VDR ApaI CA genotype was less frequent in HCC than in CHB patients in different genetic models (codominant model, OR = 0.5, 95%CI = 0.3–0.84, P = 0.004; dominant model, OR = 0.46, 95%CI = 0.27–0.76, P = 0.0023). In the recessive model, the genotype ApaI AA was found more frequently among HCC compared to CHB patients (OR = 2.56, 95%CI = 1.01–6.48, P = 0.04). Similarly, the ApaI CA genotype was less frequent in HCC than in non-HCC group codominant model, OR = 0.6, 95%CI = 0.4–0.98, dominant model, P = 0.04 and OR = 0.6, 95%CI = 0.38–0.90, P = 0.017). The ApaI genotypes CA and AA was significantly associated with higher levels of liver enzymes, bilirubin, and HBV DNA (P < 0.05). No association between TaqI, FokI and BsmI polymorphisms and any clinical outcome as well as liver disease progression was found.ConclusionsAmong the four investigated VDR polymorphisms, ApaI is associated with clinical outcome and liver disease progression in Vietnamese HBV infected patients.

Vitamin D status and vitamin D receptor gene polymorphism in Saudi children with acute lower respiratory tract infection.

There is a significant association exists between vitamin D deficiencies, low respiratory tract infections, and certain types of VDR gene polymorphism. Various studies are being conducted to prove any such link between the different clinical conditions due to disturbed vitamin D regulation and VDR gene polymorphisms. The present study analyzed the presence of vitamin D receptor (VDR) gene polymorphisms (ApaI and TaqI) in Saudi pediatric patient suffering from acute lower respiratory tract infection (ALRTI) cases. Fifty children (50) with ALRTI admitted at King Saud University Medical City, Riyadh/Saudi Arabia were included in addition to seventy-three (73) apparently healthy children who were considered as the control group. Genomic DNA from whole blood was extracted and subjected to polymerase chain reaction (PCR) targeting TaqI and ApaI VDR polymorphisms. RFLP-PCR genotyping was performed to determine the allelic frequency within the VDR gene. In the whole sample, the allelic frequency of ApaI polymorphism in the VDR gene was 58.5%, 17.9%, and 23.6% for AA, Aa, and aa respectively (p = 0.11), while it was 48%, 19%, and 33% for TT, Tt, and tt respectively (p = 0.33) with regards to the frequency of TaqI polymorphism in the VDR gene. VDR ApaI Aa and aa genotypes and VDR TaqI Tt and tt genotypes were not associated with increased risk of ALRTI in children (OR 0.87, 95% CI 0.33-2.28, p = 0.77; OR 0.56, 95% CI 0.23-1.4, p = 0.21; OR 1.15, 95% CI 0.44-2.99, p = 0.77; OR 0.73, 95% CI 0.32-1.68, p = 0.46 respectively). To conclude, neither vitamin D status nor VDR gene polymorphisms such as ApaI and TaqI is associated with increased susceptibility to ALRTI. Linkage disequilibrium was not detected between ApaI and TaqI VDR gene polymorphisms as in the case of serum vitamin D status in ALRTI patients versus apparent healthy children.

Association of Methylenetetrahydrofolate Reductase, Vitamin D Receptor, and Interleukin-16 Gene Polymorphisms With Renal Cell Carcinoma Risk.

In this meta-analysis, we investigated the association of methylenetetrahydrofolate reductase, vitamin D receptor, and interleukin-16 gene polymorphisms with the risk of renal cell carcinoma. We searched the PubMed and Cochrane Library databases up to July 1, 2017, and included 12 eligible case–control studies in our analysis. The vitamin D receptor ApaI A allele, ApaI AA and aa genotypes, BsmI B allele, and Fok1 FF genotype were all associated with the risk of renal cell carcinoma in Asian populations. However, methylenetetrahydrofolate reductase (rs1801133 and rs1801131), vitamin D receptor (TaqI and Fok1), and interleukin-16 (rs4778889 and rs11556218) gene polymorphisms were not associated with the risk of renal cell carcinoma. Our study indicates that the vitamin D receptor ApaI A allele, ApaI AA and aa genotypes, BsmI B allele, and Fok1 FF genotype are associated with renal cell carcinoma risk.

Association of vitamin D receptor gene TaqI, FokI and ApaI variants with arteriovenous fistula failure in hemodialysis patients.

We investigated the influence of the vitamin D receptor gene TaqI (rs731236), ApaI (rs7975232), and FokI (rs2228570) polymorphisms in arteriovenous fistula failure in hemodialysis patients. This study was carried out with 54 patients who experienced two or more fistula failures in the late period after arteriovenous fistula operation and 58 control patients with no history of arteriovenous fistula failure in 3 years or longer. The polymerase chain reaction-restriction fragment length polymorphism method was used to determine the vitamin D receptor TaqI, FokI, and ApaI polymorphisms. For vitamin D receptor gene TaqI and Fok1 polymorphisms, no significant association was found between the two groups ( p > 0.05). However, a statistically significant association was determined for ApaI polymorphism between the two groups ( p = 0.02). In patients, ApaI AA, AC, and CC genotype frequencies were found as 21 (38.9%), 32 (59.3%), and 1 (1.8%), respectively. However, genotype frequencies of AA, AC, and CC in the control group were 29 (50%), 22 (37.9%), and 7 (12.1%), respectively. In all three polymorphisms, no significant difference was found between the two groups in terms of allele frequencies ( p > 0.05). Vitamin D receptor ApaI AC genotype may be a possible cardiovascular risk factor for the development of arteriovenous fistula failure.

RETRACTED ARTICLE: Associations between VDR Gene Polymorphisms and Osteoporosis Risk and Bone Mineral Density in Postmenopausal Women: A systematic review and Meta-Analysis

Results on the relationships between vitamin D receptor (VDR) gene polymorphisms and postmenopausal osteoporosis (PMOP) susceptibility and bone mineral density (BMD) are conflicting. The aim of the study is to identify more eligible studies that calculated pooled OR and WMD with 95% CI to assess their associations. Overall, there were significant correlations between VDR ApaI, VDR FokI and PMOP susceptibility. Subgroup analysis showed that VDR ApaI polymorphism significantly decreased the osteoporosis risk in Caucasian postmenopausal women. In Asian populations, VDR BsmI and VDR FokI were associated with an increased risk of PMOP. As to the associations between VDR polymorphisms and BMD, Caucasian PMOP women carrying the ApaI aa genotype were at risk of high BMD in femoral neck, and low femoral neck BMD was observed in Caucasian PMOP women with FokI Ff genotype. PMOP women with the Cdx2 GA genotype had a lower lumbar spine BMD in overall and Caucasian populations compared with PMOP women with GG genotype. Different VDR gene polymorphisms have different impacts on PMOP risk and BMD.

Effect of pharmacogenetic markers of vitamin D pathway on deferasirox pharmacokinetics in children.

Patients with β-thalassemia major have extremely low vitamin D levels, owing to reduced intestinal absorption, subicteric tint, and/or iron-induced higher pigmentation. We investigated whether some polymorphisms within the VDR, CYP24A1, CYP27B1, and GC genes could play a role in deferasirox pharmacokinetics in a cohort of pediatric patients. Eighteen children with β-thalassemia were enrolled. Drug plasma concentrations at the end of dosing interval (Ctrough) and after 0, 2, 4, 6, and 24 h of drug administration were measured by a HPLC-UV method. Allelic discrimination for VDR (TaqI, FokI, BsmI, Cdx2, and ApaI), CYP24A1 (22776, 3999 and 8620), CYP27B1 (2838 and -1260), and GC (1296) single nucleotide polymorphisms was performed by real-time PCR. CYP24A1 8620 AG/GG group negatively predicted Ctrough in regression analysis (P=0.012). ApaI AA genotype resulted as a negative predictor of Ctrough (P=0.025) and area under the concentration curve (P=0.007); FoKI CC genotype remained as area under the concentration curve positive predictor (P=0.008) and TC/CC group as half-life (t1/2) (P=0.003) and volume of distribution (Vd) (P=0.011) negative one; TaqI TC/CC was retained as a negative predictor of drug maximum concentration (Cmax) (P=0.004). Moreover, GC 1296 TG/GG seemed able to predict lower time to reach drug maximum concentration (Tmax) (P=0.033). Our preliminary experience suggested the potential usefulness of vitamin D pharmacogenetic to better understand deferasirox interindividual variability, also in pediatric patients.

Vitamin D pathway gene polymorphisms as predictors of hepatitis C virus-related mixed cryoglobulinemia.

Mixed cryoglobulinemia (MC) is the most frequent extrahepatic hepatitis C virus (HCV) complication. Vitamin D is a modulator of several biological processes, including immune and skeletal systems and MC presence and systemic vasculitis were associated independently with low levels of vitamin D. Considering the impact of vitamin D, we aimed to evaluate the role of some single nucleotide polymorphisms (SNPs) of vitamin D pathway genes in the prediction of MC in HCV patients treated with pegylated interferon and ribavirin. We investigated SNPs in IL-28B, CYP27B1, CYP27A1, CYP24A1, VDBP, and VDR genes through real-time PCR. VDR gene SNPs were related to baseline viral load: VDR BsmI AA (P=0.018), TaqI CC (P=0.009), and ApaI AA (P=0.004) showed a lower baseline HCV count. Among vitamin D pathway gene polymorphisms, VDR FokI T>C was a factor associated with the presence of MC in the study population (P=0.011): related to C allele carriers (TT vs. TC/CC), we obtained a P-value of 0.003. In the logistic regression analysis to assess which demographic, clinical, or genetic factors could predict the presence of cryoglobulin, the TT/CC IL-28B rs8099917/rs12979860 haplotype [P<0.001; odds ratio (OR) 3.516 (1.951-6.336)], baseline viral load [P<0.001; OR 1.000 (0.999-1.001)], and VDR FokI TC/CC genotypes [0.044; OR 0.463 (0.218-0.981)] remained in the final regression model. These data could help physicians identify patients with a higher probability of developing MC extrahepatic complications.

Correlations between Polymorphisms of Estrogen 1, Vitamin D Receptors and Hormonal Profile in Infertile Men

Estrogen receptor alpha (ESR1) polymorphisms (XbaI and PvuII) and vitamin D receptor (VDR) polymorphisms (FokI, BsmI, ApaI and TaqI) are the most frequently studied regarding the correlations with the infertility in males, but the results are controversial.The purpose of this study is to evaluate possible correlations between hormonal markers, VDR and ESR1 genotypes and semen analysis, in order to bring new data for a better understanding of male infertility. 42 infertile men and 28 controls were enrolled. The polymorphisms of VDR gene (ApaI, TaqI, BsmI and FokI) and ESR1 (XbaI and PvuII) were performed by PCR-RFLP, along with hormonal markers. An important correlation between PvuII polymorphism and infertility status was revealed. A significant difference between control and infertility group regarding the presence of BsmI (A>G) and ApaI (G>T) polymorphisms was observed in infertile group, prolactin and DHEA were found to correlate significantly statistic with BsmI GG genotype, whereas ApaI AA genotype correlates with prolactin and SHBG levels. By a multivariate analysis, we demonstrated a cumulative effect of some genetic variants in the hormonal status of infertile patients. Therefore, we show that specific genetic variants of ESR1 and VDR genes may jointly influence human spermatogenesis.

Meta-analysis on vitamin D receptor and cancer risk: focus on the role of TaqI, ApaI, and Cdx2 polymorphisms.

Vitamin D plays a significant role in our health, including cancer incidence and mortality. Vitamin D receptor (VDR) single-nucleotide polymorphisms (SNPs) may affect its activity, influencing the risk of cancer. Several studies have investigated VDR SNPs, but the association with the risk of cancer is controversial. Here, we present a meta-analysis to assess the association of TaqI, ApaI, and Cdx2 SNPs with the risk of cancer. A systematic literature search was performed following a predefined protocol and using validated search strategies. This meta-analysis shows the summary odd ratio (SOR) overall, by cancer sites and by ethnicity. Up to January 2014, we identified 73 independent studies with 35 525 cases and 38 675 controls. The meta-analysis of Cdx2 gg versus GG showed a significant 12% increased risk for all cancers [SOR=1.12; 95% confidence interval (CI): 1.00–1.25]. The other SNPs analyzed did not show an overall significant association with the risk of cancer: SOR=0.98 (95% CI: 0.90–1.07) and 1.06 (95% CI: 0.95–1.19) for TaqI tt versus TT and ApaI aa versus AA, respectively. TaqI shows a significant 43% increased risk for colorectal cancer (SOR=1.43; 95% CI: 1.30–1.58 for tt vs. TT). Strong frequency variations are present among different ethnic groups. This meta-analysis showed an overall increased risk of cancer associated with Cdx2 SNP and a specific higher risk of colorectal cancer associated with the TaqI polymorphism. The VDR genotype might become more relevant when clustered in a specific haplotype, associated with other SNPs of genes involved in vitamin D metabolism, or for specific tumors and/or patient characteristics.

Ethambutol plasma and intracellular pharmacokinetics: A pharmacogenetic study

We evaluated ethambutol plasma and intracellular pharmacokinetic according to single nucleotide polymorphisms in ABCB1, OATP1B1, PXR, VDR, CYP24A1 and CYP27B1 genes. Mycobacterium tubercolosis infected patients were enrolled. Standard weight-adjusted antitubercular treatment was administered intravenously for 2 weeks and then orally. Allelic discrimination was performed by real-time PCR. Ethambutol plasma and intracellular concentrations were measured by UPLC-MS/MS methods. Twenty-four patients were included. Considering weeks 2 and 4, median plasma Ctrough were 73ng/mL and 247ng/mL, intracellular Ctrough were 16,863ng/mL and 13,535ng/mL, plasma Cmax were 5627ng/mL and 2229ng/mL, intracellular Cmax were 133,830ng/mL and 78,544ng/mL. At week 2, ABCB1 3435 CT/TT (p=0.023) and CYP24A1 8620 AG/GG (p=0.030) genotypes for plasma Ctrough, BsmI AA (p=0.036) for intracellular Ctrough and BsmI AA (p<0.001) and ApaI AA (p=0.048) for intracellular Cmax, remained in linear regression analysis as predictive factors. Concerning week 4 only ABCB1 3435 CT/TT (p=0.035) and Cdx2 AG/GG (p=0.004) genotypes for plasma Ctrough and BsmI AA (p=0.028) for plasma Cmax were retained in final regression model. We reveal, for the first time, the possible role of single nucleotide polymorphisms on ethambutol plasma and intracellular concentrations; this may further the potential use of pharmacogenetic for tailoring antitubercular treatment.

Abstract A39: Meta-analysis on vitamin D Receptor polymorphisms and colorectal cancer risk

Abstract Epidemiological studies have suggested a reduced risk of several cancers associated with an adequate vitamin D (VD) status. Previous meta-analyses evaluating serum vitamin D and cancer risk showed a consistent inverse relationship between serum 25-hydroxyvitamin D levels and colorectal cancer. Single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) are important regulators of the vitamin D pathway and they may indirectly modulate cancer risk. Several studies have investigated VDR SNPs, but the results on their associations with cancer risk are controversial. We carried a meta-analysis to investigate the association of the major VDR SNPs with colorectal cancer risk (CRC). A systematic literature search was performed following a pre-defined protocol and using validated search strategies up to April 2014. This meta-analysis shows the summary odd ratio (SOR) overall and by ethnicity, obtained with random effect models and investigating heterogeneity. The meta-analysis included for BsmI 13 studies with 8,709 and 10,010 controls, for FokI 16 studies with 8,877 cases and 10,548 controls, and for ApaI, Cdx2 or TaqI 10 studies with 6,443 cases and 6,915 controls. We found a significant increased risk between the TaqI tt genotype and CRC: SOR= 1.43 (95%CI: 1.30-1.58), evaluating eight studies. Moreover we found similar results for non Caucasians (SOR= 1.47; 95%CI: 1.28-1.7). Furthermore BsmI showed a significant risk reduction (SOR=0.89; 95%CI: 0.80-0.98) for BB genotype versus bb and borderline significant for Bb vs bb (SOR=0.94; 95%CI: 0.87-1.01). FokI, ApaI and Cdx2 polymorphisms did not show any significant association for CRC. For FokI we estimated a SOR=1.05 (95%CI: 0.84-1.31) for ff vs FF genotype. Five studies evaluated ApaI and Cdx2 with SOR=1.21 (95%CI: 0.82-1.78) and SOR=1.24 (95%CI: 0.94-1.63), respectively for ApaI aa vs AA, and Cdx2 gg vs GG. We also found a significant 6-7% reduction of cancer risk at any site respectively for carriers of Bb genotype (SOR= 0.94; 95%CI: 0.90-0.99) and for carriers of BsmI BB genotype (SOR; 95%CI: 0.93; 0.89-0.98) compared to bb carriers. BsmI B allele has a very wide range from 0.5% to 46% (with a outlier deviating from Hardy-Weinberg equilibrium up to 74%). FokI f allele was from 25% to 48%, among control subjects and for three studies, a significant departure from Hardy-Weinberg equilibrium was observed. The TaqI t allele frequency is relatively broad ranging from 4% to 41%. Interestingly in Asian populations the t allele appear to be quite rare and several studies did not present homozygote tt carriers but only subjects with tT genotype. ApaI a allele frequency ranges from 23% to 50%. Cdx2 g in Caucasian and Asian populations ranges from 21% to 34%; interestingly in a study, evaluating the risk for other cancer site in African-American, the a allele ranges from 73% to 79%. No indication of publication bias was found. In conclusion, in our meta-analysis TaqI tt genotype showed an increased risk for colorectal cancer. BsmI might affect VD activities especially in Caucasians. FokI, ApaI and Cdx2 SNPs did not show a significant cancer risk association. A differential effect due to ethnicity is suggested. The VDR genotype might become more relevantly clustered in specific haplotype, for specific tumor biology, subjects characteristics or with other genes involved in the vitamin D metabolisms, especially for VD binding protein. Citation Format: Sara Gandini, Patrizia Gnagnarella, Sara Raimondi, Elena Tagliabue, Davide Disalvatore, Davide Serrano. Meta-analysis on vitamin D Receptor polymorphisms and colorectal cancer risk. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A39.