Association between the c.910A>G genetic variant of the XRCC1 gene and susceptibility to esophageal cancer in the Chinese Han population

Esophageal cancer (EC) is a common malignancy worldwide. The X-ray repair cross-complementing 1 gene (XRCC1) is one of the most important candidate genes for influencing susceptibility to EC. This study aimed to investigate the effect of XRCC1 genetic variants on susceptibility to EC. A total of 383 EC patients (males: 239, females: 144, mean age: 56.62) and 387 cancer-free controls (males: 251, females: 136, mean age: 58.23) were enrolled in this study. The c.910A>G genetic variant of the XRCC1 gene was determined by polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing methods. The allele and genotype frequencies indicated statistical differences between EC patients and cancer-free controls. The c.910A>G genetic variant was statistically associated with increased susceptibility to EC [GG vs AA: odds ratio (OR)=1.79, 95% confidence interval (CI)=1.12-2.86, P=0.014; GG vs AG/AA: OR=1.76, 95%CI=1.13-2.75, P=0.013; G vs A: OR=1.25, 95%CI=1.01-1.55, P=0.041]. The allele G and genotype GG could contribute to the increased susceptibility to EC. Our findings suggest that the c.910A>G genetic variant is associated with susceptibility to EC in the Chinese Han population, and might be used as a molecular marker for detecting susceptibility to EC.     

CHRNA5 polymorphism and susceptibility to lung cancer in a Chinese population

Polymorphisms in the nicotinic acetylcholine receptor subunit CHRNA5 gene have been associated with lung cancer positive susceptibility in European and American populations. In the present hospital-based, case-control study, we determined whether polymorphism in rs503464 of CHRNA5 is associated with lung cancer risk in Chinese individuals. A single nucleotide polymorphism in CHRNA5 rs503464, c.-166T>A (hereafter T>A), was identified using TaqMan-MGB probes with sequencing via PCR in 600 lung cancer cases and 600 healthy individuals. Genotype frequencies for rs503464 (T>A) were in Hardy-Weinberg equilibrium for the control population. However, genotype frequencies were significantly different between cases and controls (P < 0.05), while allele frequencies were not significantly different between groups. Compared to homozygous genotypes (TT or AA), the risk of lung cancer in those with the heterozygous genotype (TA) was significantly lower (OR = 0.611, 95%CI = 0.486-0.768, P = 0.001). Using genotype AA as a reference, the risk of lung cancer for those with genotype TA was increased 1.5 times (OR = 1.496, 95%CI = 1.120-1.997, P = 0.006). However, no difference in risk was observed between T allele carriers and A allele carriers (OR = 0.914, 95%CI = 0.779-1.073, P = 0.270). Stratification analysis showed that the protective effect of TA was more pronounced in those younger than 60 years, nonsmokers, or those without a family history of cancer, as well as in patients with adenocarcinoma or squamous cell carcinoma in clinical stages III or IV (P < 0.05). Therefore, the heterozygous genotype c.-166T>A at rs503464 of CHRNA5 may be associated with reduced risk of lung cancer, thus representing a susceptibility allele in Chinese individuals.     

Predictive role of miR-146a rs2910164 (C>G), miR-149 rs2292832 (T>C), miR-196a2 rs11614913 (T>C) and miR-499 rs3746444 (T>C) in the development of hepatocellular carcinoma

We conducted a case-control study to evaluate the association of miR-146a rs2910164 (C>G), miR-149 rs2292832 (T>C), miR-196a2 rs11614913 (T>C) and miR-499 rs3746444 (T>C) polymorphisms with the risk of hepatocellular carcinoma. A total of 274 patients with HCC were collected between January 2013 and December 2014. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was taken to determine the polymorphism of miR-146a C>G, miR-149 T>C, miR-196a2 T>C and miR-499 T>C. By comparing with control groups, patients with HCC were more likely to be males (OR=2.01, 95% CI=1.38-2.95), have older age (OR=1.52, 95% CI=1.09-2.13), have a history of alcohol drinking (OR=2.09, 95% CI=1.49-2.93), and be infected with HBV (OR=32.98, 95% CI=19.70-55.46) and HCV (OR=56.26, 95% CI=23.28-152.98) infection. By conditional regression analysis, individuals carrying the TC and CC genotypes of miR-196a2 T>C were found to be associated with an elevated risk of HCC compared to the TT genotype, and the adjusted odds ratio were 1.50 (1.03-2.17) and 2.86 (1.60-5.16), respectively. Moreover, the TC+CC genotype was correlated with an increased risk of HCC (OR=1.69, 95% CI=1.19-2.41) compared to the wide-type genotype. In conclusion, our results suggested that miR-196a2 T>C polymorphism is associated with HCC risk in Chinese population.     

The Interaction Between Allelic Variants of CD86 and CD40LG: A Common Risk Factor of Allergic Asthma and Rheumatoid Arthritis

Purpose

Allergic asthma (AA) and rheumatoid arthritis (RA) are immune tolerance-related diseases, and immune tolerance is known to be influenced by costimulatory molecules. In this study, we sought to identify common genetic susceptibility in AA and RA.

Methods

Two hundred cases of AA, 184 cases of RA, and 182 healthy controls were recruited at the Seoul National University Hospital, Seoul, Korea. Eight single nucleotide polymorphisms (SNPs) in five genes coding costimulatory molecules, namely, -318C>T, +49A>G, and 6230G>A in CTLA4, IVS3+17T>C in CD28, -3479T>G and I179V in CD86, -1C>T in CD40, and -3458A>G in CD40LG were scored, and genetic interactions were evaluated by multifactor dimensionality reduction (MDR) analysis.

Results

MDR analysis revealed a significant gene-gene interaction between -3479T>G CD86 and -3458A>G CD40LG for AA. Subjects with the T/T genotype of -3479T>G CD86 and the A/A genotype of -3458A>G CD40LG were found to be significantly more likely to develop AA than those with the T/T genotype of -3479T>G CD86 and A/- genotype of -3458A>G CD40LG (adjusted OR, 6.09; 95% CI, 2.89-12.98; logistic regression analysis controlled by age). Similarly those subjects showed a significant risk of developing RA (adjusted OR, 39.35; 95% CI, 15.01-107.00, logistic regression analysis controlled by age).

Conclusions

Our findings suggest that a genetic interaction between CD86 and CD40LG favors the development of both AA and RA.     

Correlation between the interactions of ABCA4 polymorphisms and smoking with the susceptibility to age-related macular degeneration

Objective: Our study was aimed to analyze the relationship between retina-specific ATP-binding cassette, sub-family A, member 4 (ABCA4) gene polymorphisms and gene-environment interactions with age-related macular degeneration (AMD) susceptibility. Methods: 98 AMD patients and 110 healthy controls, matched in age and sex, were enrolled in this study. ABCA4 polymorphisms (2633C>A, 5646G>A and 6389T>A) were determined by direct sequencing. Differences of genotype and allele distributions were analyzed by χ² test. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were adopted to represent the relative risk of AMD. Gene-environment interactions were analyzed using crossover analysis. Results: 2633C>A polymorphism had no obvious correlation with AMD risk. Genotype AA and allele A in 5646G>A polymorphism significantly increased the risk of AMD (OR=4.753, 95% CI=1.249-18.085; OR=1.944, 95% CI=1.209-3.126). 6389T>A polymorphism AA genotype had no significant correlation with AMD risk, but the A allele distinctly enhanced the AMD risk (OR=1.681, 95% CI=1.071-2.639). Afterwards, we analyzed the interactions between ABCA4 polymorphisms and smoking on AMD. Smoking had interactions with all of 2633C>A (CC+CA), 5646G>A and 6389T>A polymorphisms, and the interactions were significantly correlated with AMD. Conclusions: 2633C>A (CC+CA) genotype, 5646G>A and 6389T>A polymorphisms of ABCA4 gene and smoking are susceptible factors for AMD, and the interactions of ABCA4 polymorphisms with smoking increased the risk of AMD.     

IL-4 Receptor α Polymorphisms May Be a Susceptible Factor for Work-Related Respiratory Symptoms in Bakery Workers

Purpose

The IL-4 and IL-4 receptor α (IL-4Rα) genes are the key candidate genes for atopy and asthma susceptibility. Exposure to wheat flour can cause IgE sensitization and respiratory symptoms in bakery workers. Therefore, we hypothesized that IL-4 and IL-4Rα single nucleotide polymorphisms (SNPs) may be involved in the pathogenic mechanism of baker''s asthma.

Methods

Clinical and genetic data from 373 bakery workers were analyzed. A survey questionnaire, spirometry, and skin prick tests with wheat flour were performed. Serum-specific IgE, IgG1, and IgG4 to wheat flour were determined using ELISA. Five candidate IL-4 (-729 T>G, 589 T>C, and 33 T>C) and IL-4Rα (Ile75Val A>G and Gln576Arg A>G) SNPs were genotyped and analyzed.

Results

Workers with the G allele of IL-4Rα Ile75Val A>G had a significantly higher prevalence of work-related lower respiratory symptoms than those with the AA genotype (P=0.004, 16.0% vs. 2.9%). In the skin prick test, workers with the AA genotype of IL-4Rα Gln576Arg A>G had a significantly higher positive rate to wheat flour (P=0.015, 8.2% vs. 1.1%) than those with AG/GG genotype. No significant associations were found in the three genetic polymorphisms of IL-4. For the predicted probabilities, workers with the AA genotype of Gln576Arg A>G had a higher prevalence of IgG1 and IgG4 in response to wheat flour, according to increased exposure intensity (P=0.001 for IgG1 and P=0.003 for IgG4).

Conclusions

These findings suggest that the IL-4Rα Ile75Val and Gln576Arg polymorphisms may be associated with work-related respiratory symptom development.     

Tumor growth reduction is regulated at the gene level in Walker 256 tumor-bearing rats supplemented with fish oil rich in EPA and DHA

We investigated the effect of fish oil (FO) supplementation on tumor growth, cyclooxygenase 2 (COX-2), peroxisome proliferator-activated receptor gamma (PPARγ), and RelA gene and protein expression in Walker 256 tumor-bearing rats. Male Wistar rats (70 days old) were fed with regular chow (group W) or chow supplemented with 1 g/kg body weight FO daily (group WFO) until they reached 100 days of age. Both groups were then inoculated with a suspension of Walker 256 ascitic tumor cells (3×10⁷ cells/mL). After 14 days the rats were killed, total RNA was isolated from the tumor tissue, and relative mRNA expression was measured using the 2^-ΔΔCT method. FO significantly decreased tumor growth (W=13.18±1.58 vs WFO=5.40±0.88 g, P<0.05). FO supplementation also resulted in a significant decrease in COX-2 (W=100.1±1.62 vs WFO=59.39±5.53, P<0.001) and PPARγ (W=100.4±1.04 vs WFO=88.22±1.46, P<0.05) protein expression. Relative mRNA expression was W=1.06±0.022 vs WFO=0.31±0.04 (P<0.001) for COX-2, W=1.08±0.02 vs WFO=0.52±0.08 (P<0.001) for PPARγ, and W=1.04±0.02 vs WFO=0.82±0.04 (P<0.05) for RelA. FO reduced tumor growth by attenuating inflammatory gene expression associated with carcinogenesis.     

Association between 8473T>C polymorphism in the cyclooxygenase-2 gene and the risk of nasopharyngeal carcinoma

Background: No studies have examined the relationship between COX-2 8473T>C polymorphism and the risk of nasopharyngeal carcinoma in Chinese population. Material and methods: 296 patients with nasopharyngeal carcinoma and 300 age and gender-matched healthy controls recruited were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Cancer risk associated with the genotypes was estimated as odds ratios (ORs) and 95% confidence intervals (95% CIs) using unconditioned logistic regression. Results: There was significant difference in the distribution of COX-2 8473T>C polymorphism genotype between nasopharyngeal carcinoma patients and healthy controls (P=0.027). When the TT genotype was used as the reference group, the CC genotype was associated with significantly decreased risk for nasopharyngeal carcinoma (adjusted OR=0.67, 95% CI=0.33-0.83; P=0.01). Under the recessive model of inheritance, the CC genotype was associated with significantly decreased risk for nasopharyngeal carcinoma (adjusted OR=0.43, 95% CI=0.37-0.81; P=0.007). Furthermore, the C allele was associated with significantly decreased risk for nasopharyngeal carcinoma (adjusted OR=0.48, 95% CI=0.39-0.85; P=0.009). Conclusion: These data suggested that COX-2 8473T>C polymorphism was associated with reduced risk of nasopharyngeal carcinoma.     

Surfactant protein B gene polymorphisms is associated with risk of bronchopulmonary dysplasia in Chinese Han population

Objective: To investigate the relationship between Surfactant protein B (SP-B) gene polymorphisms and bronchopulmonary dysplasia (BPD) development in preterm infants of China Han ethnic population. Methods: SP-B gene polymorphisms were studied in 134 neonates who were born at < 32 weeks of gestation, with the diagnosis of BPD and in a control group of 168 preterm infants without BPD. Genotyping for SP-B was performed by polymerase chain reaction (PCR) and gene sequencing. Results: In this study, three of the SNP genotypes, -18C/A, 1580C/T and 4564T/C were common identified in SP-B gene. The -18C/A genotype was found to be significantly associated with BPD (χ² = 10.741, P < 0.01), with P < 0.01 for the dominant model (OR = 1.712, 95% CI = 1.228-2.3894) and the allelic model (OR = 1.787, 95% CI = 1.276-2.502). The 1580C/T genotype was found to be associated with BPD (χ² = 7.014, P < 0.05), with P < 0.05 for the dominant model (OR = 0.752, 95% CI = 0.593-0.954) and P < 0.01 for the allelic model (OR = 0.706, 95% CI = 0.548-0.909). The 4564T/C genotypes and alleles were found not to be associated with BPD (χ² = 3.399 and 3.227, P > 0.05). Conclusion: SP-B -18C/A and 1580C/T polymorphisms are associated with BPD. The 1580C/T polymorphism was protective while the -18C/A polymorphism increased the risk for BPD. SP-B 4564T/C polymorphism is not associated with BPD.     

Cytokine TGF-β1, TNF-α, IFN-γ and IL‐6 Gene Polymorphisms and Localization of Premalignant Gastric Lesions in Immunohistochemically H. pylori-negative Patients

Background: Cytokines and their gene variants are proven to play a role in pathogenic gastritis and carcinogenesis. The study assesses associations of the cytokine gene polymorphisms with extension of atrophic gastritis/intestinal metaplasia (AGIM) in patients without Helicobacter pylori infection on immunohistochemistry study.Methods: 224 adult consecutive patients undergoing an upper digestive endoscopy were included and grouped according to localization of AGIM: 37 patients with antrum-limited AGIM, 21 corpus-limited AGIM, 15 extended-AGIM (antrum and corpus) and 151 patients had no AGIM. Medical records of the patients were checked and a structured direct interview was applied in order to collect clinical data, including digestive symptoms. In all cases, IFN-γ +874T>A, TGF-β1 +869T>C, TNF‐α-308G>A and -238G>A, and IL-6 -174C>G polymorphisms were genotyped.Results: The mean age was significantly higher in the AGIM group, while the comorbidies were similar among patients with different localization of lesions or in patients without AGIM. There were no significant differences in digestive symptoms, nor in the consumption of non-steroidal anti-inflammatory drugs or proton pump inhibitor with the different extensions of AGIM. There was a significant association between oral anticoagulant consumption and localization of AGIM (P = 0.042), frequency being higher among patients with corpus-limited AGIM than those with no AGIM (P = 0.007, adjusted P = 0.041). TGF-β1 +869T>C was less frequent among patients with corpus-limited AGIM (n=7, 33.3%) and extended AGIM (n=5, 33.3%) than in antrum-limited AGIM (n=25, 67.6%). There were no other significant differences regarding variant and wild genotype frequencies of IFN-γ +874T>A (86.5%, 81.0%, 86.7%, p=0.814), TNF‐α-308G>A (35.1%, 28.6%, 53.3%, p=0.48) and IL-6 -174C>G (70.3%. 61.9%, 73.3% p=0.656) among patients with antrum-limited, corpus-limited or extended AGIM. TGF-β1 +869T>C was associated with a decreased risk for corpus-affected AGIM (adjusted odds ratio: 0.42, 95% confidence interval: 0.19-0.93, P = 0.032). The dominant inheritance models no revealed significant association for IFN-γ +874T>A, TNF‐α-308G>A and IL-6 -174C>G gene polymorphism and the risk of localization of AGIM.Conclusion: TGF-β1 +869T>C gene polymorphism is associated with a decreased risk for corporeal localization of premalignant lesions, while IFN-γ +874T>A, TNF-α-308G>A and IL-6 -174C>G are not associated with the risk for AGIM in immunohistochemically H. pylori negative patients.     

Correlation between interleukin-18 promoter -607C/A polymorphism and susceptibility to ischemic stroke

Single nucleotide polymorphisms in the promoter region of interleukin-18 (IL-18), an inflammatory cytokine, have been linked to susceptibility to many diseases, including cancer and immune dysfunction. Here, we explored the potential association between the IL-18 -607C/A (rs1946518) promoter region polymorphism and susceptibility to ischemic stroke (IS). This locus was amplified from peripheral blood samples of 386 IS patients (cases) and 364 healthy individuals (controls) by the polymerase chain reaction with sequence-specific primers. Significant differences were observed by the χ² test in the -607C/A (rs1946518) genotype and allele frequencies between cases and controls (P < 0.05). Furthermore, after excluding for age, gender, smoking status, and hypertension, logistic regression indicated that IS susceptibility of -607C carriers increased 1.6 times (OR = 1.601, 95%CI = 1.148-2.233, P = 0.006) compared to -607A carriers. Additionally, similar increases in IS risk were noted for male patients or patients less than 65 years old. In conclusion, IL-18 -607C/A (rs1946518) promoter polymorphism is associated with IS susceptibility, and the C allele may confer increased IS risk.     

Genetic association of cyclooxygenase-2 gene polymorphisms with Parkinson’s disease susceptibility in Chinese Han population

Objective: The aim of this study was to explore the genetic association of cyclooxygenase-2 (COX2) gene promoter region polymorphisms with Parkinson’s disease (PD) susceptibility in Chinese Han population. Methods: The genotyping of COX2 gene polymorphisms was conducted by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 122 patients with PD and 120 healthy persons. The association strength of gene polymorphism with disease was measured by odds ratio (OR) and 95% confidence interval (95% CI) calculated using χ² test which also evaluated the Hardy-Weinberg equilibrium (HWE) of gene polymorphism in controls. The linkage disequilibrium and haplotype were also analyzed as evidence in the analysis of association. Results: On condition that the genotypes distributions of COX2 -1290A>G, -1195G>A, -765G>C in the control group all conformed to HWE, however, only the homozygous genotype AA of -1195G>A polymorphism showed an association with PD (OR=0.432, 95% CI=0.196-0.950). In addition, in haplotype analysis, G-A-C haplotype frequency in cases was significantly lower than the controls, compared with the common haplotype A-G-G (P=0.031, OR=0.375, 95% CI=0.149-0.940). Conclusions: COX2 -1195G>A polymorphism might play a protective role in the onset of PD and G-A-C haplotype in this three promoter region polymorphisms also showed a negative association.     

Association of ERCC gene polymorphism with osteosarcoma risk

BackgroundThe relationship between ERCC gene polymorphism and osteosarcoma risk / overall survival of osteosarcoma is still conflicting, and this meta-analysis was performed to assess these associations.Material and methodsThe association studies were identified from PubMed, and eligible reports were included and calculated using meta-analysis method.ResultsFour studies were included for the association of ERCC gene polymorphism with osteosarcoma risk, and nine studies were recruited into this meta-analysis for the relationship between ERCC gene polymorphism and overall survival of osteosarcoma. The meta-analysis indicated that ERCC1 rs3212986 (8092 C>A) gene polymorphism, ERCC1 rs11615 (19007 T>C) gene polymorphism, ERCC2 rs1799793 (A>G) gene polymorphism, ERCC2 rs13181 (Lys751Gln) gene polymorphism were not associated with osteosarcoma risk. ERCC1 rs2298881 (C>A) gene polymorphism, ERCC1 rs3212986 (8092 C>A) gene polymorphism, ERCC1 rs11615 (19007 T>C) gene polymorphism, ERCC2 rs1799793 (Asp312Asn) gene polymorphism were not associated with overall survival of osteosarcoma. Interestingly, ERCC2 rs13181 A allele and GG genotype were associated with overall survival of osteosarcoma, but AA genotype not (A allele: OR = 0.78, 95% CI: 0.65–0.93, P = 0.007; GG genotype: OR = 1.32, 95% CI: 1.05–1.65, P = 0.02; AA genotype: OR = 0.69, 95% CI: 0.45–1.04, P = 0.08).ConclusionERCC2 rs13181 A allele and GG genotype were associated with overall survival of osteosarcoma.     

TNF-α -857C>T Genotype is Predictive of Clinical Response after Treatment with Definitive 5-Fluorouracil/cisplatin-based Chemoradiotherapy in Japanese Patients with Esophageal Squamous Cell Carcinoma

Background: Genotypes of tumor necrosis factor alpha (TNF-α) and its surface receptors, TNFRSF1A and TNFRSF1B, have been examined in terms of the progression, metastasis, clinical efficacy, and prognosis of various cancers; however, little is known about their effects on clinical outcome in patients with esophageal squamous cell carcinoma (ESCC). In this study, TNF-α and TNFRSF1A genotypes were retrospectively evaluated in terms of predicting clinical response, long-term survival, and severe acute toxicities in 46 male Japanese ESCC patients treated with definitive 5-fluorouracil (5-FU)/cisplatin (CDDP)-based chemoradiotherapy (CRT).Methods: A course consisted of the continuous infusion of 5-FU at 400 mg/m²/day for days 1-5 and 8-12, the infusion of CDDP at 40 mg/m²/day on days 1 and 8, and radiation at 2 Gy/day on days 1-5, 8-12, and 15-19, with a second course being repeated after a 2-week interval. The TNF-α -1031T>C (rs1799964), -863C>A (rs1800630), -857C>T (rs1799724), -308G>A (rs1800629), -238G>A (rs361525), TNFRSF1A -609G>T (rs4149570), and 36A>G (rs767455) genotypes were evaluated.Results: The TNF-α -857C>T genotype was found to be predictive of clinical response, i.e., complete response or not (P = 0.010, Fisher''s exact test), but had no effect on long-term survival (CC^-857 vs. CT^-857 + TT^-857, P = 0.072, Fisher''s exact test, P = 0.070, Log-rank test).Conclusions: The TNF-α -857C>T genotype was found to be predictive of clinical response and was more likely to predict long-term survival in Japanese ESCC patients receiving definitive 5-FU/CDDP-based CRT. Further clinical investigations with a larger number of patients or experiments in vitro should be performed to assess the predictive value of this genotype following CRT.     

PIK3CA polymorphisms associated with susceptibility to hepatocellular carcinoma

Purpose: Our study was carried out to explore the relationship of PIK3CA rs17849071 and rs17849079 polymorphisms with the susceptibility to hepatocellular carcinoma (HCC) in Chinese Han population. Methods: 150 HCC patients and 152 healthy individuals were recruited in the case and control groups respectively. The genotypes of PIK3CA rs17849071 and rs17849079 polymorphisms were detected with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The linkage disequilibrium and haplotypes were analyzed with Haploview software. Differences in frequencies of genotypes, alleles, and haplotypes between the case and control groups were checked with χ² test. The controls were matched with the cases in age and gender. The relative risk of HCC was represented by odds ratio (OR) and 95% confidence interval (95% CI). Results: Significant difference in frequencies of GG genotype and G allele in PIK3CA rs17849071 polymorphism existed between the two groups (P=0.040; P=0.028), indicating that rs17849071 was closely related to the increased risk of HCC (OR=2.919, 95% CI=1.007-8.460; OR=1.642, 95% CI=1.051-2.564). Furthermore, TT genotype also significantly increased the susceptibility to HCC (OR=3.438, 95% CI=1.050-11.250) and so was T allele (OR=1.521, 95% CI=1.052-2.199). The haplotype analysisshowed that G-T haplotypes were higher in cases than that of controls (P=0.030), which suggested that G-T might be a susceptible haplotype to HCC. Conclusions: The PIK3CA rs17849071 and rs17849079 polymorphisms may increase the risk of HCC either independently or synergistically.     

Twelve novel HGD gene variants identified in 99 alkaptonuria patients: focus on ‘black bone disease' in Italy

Alkaptonuria (AKU) is an autosomal recessive disorder caused by mutations in homogentisate-1,2-dioxygenase (HGD) gene leading to the deficiency of HGD enzyme activity. The DevelopAKUre project is underway to test nitisinone as a specific treatment to counteract this derangement of the phenylalanine-tyrosine catabolic pathway. We analysed DNA of 40 AKU patients enrolled for SONIA1, the first study in DevelopAKUre, and of 59 other AKU patients sent to our laboratory for molecular diagnostics. We identified 12 novel DNA variants: one was identified in patients from Brazil (c.557T>A), Slovakia (c.500C>T) and France (c.440T>C), three in patients from India (c.469+6T>C, c.650–85A>G, c.158G>A), and six in patients from Italy (c.742A>G, c.614G>A, c.1057A>C, c.752G>A, c.119A>C, c.926G>T). Thus, the total number of potential AKU-causing variants found in 380 patients reported in the HGD mutation database is now 129. Using mCSM and DUET, computational approaches based on the protein 3D structure, the novel missense variants are predicted to affect the activity of the enzyme by three mechanisms: decrease of stability of individual protomers, disruption of protomer-protomer interactions or modification of residues in the region of the active site. We also present an overview of AKU in Italy, where so far about 60 AKU cases are known and DNA analysis has been reported for 34 of them. In this rather small group, 26 different HGD variants affecting function were described, indicating rather high heterogeneity. Twelve of these variants seem to be specific for Italy.     

The Association between GWAS-identified BARD1 Gene SNPs and Neuroblastoma Susceptibility in a Southern Chinese Population

A previous genome-wide association study (GWAS) has found that some common variations in the BARD1 gene were associated with neuroblastoma susceptibility especially for high-risk subjects, and the associations have been validated in Caucasians and African-Americans. However, the associations between BARD1 gene polymorphisms and neuroblastoma susceptibility have not been studied among Asians, not to mention Chinese subjects. In the present study, we investigated the association of three BARD1 polymorphisms (rs7585356 G>A, rs6435862 T>G and rs3768716 A>G) with neuroblastoma susceptibility in 201 neuroblastoma patients and 531 controls using TaqMan methodology. Overall, none of these polymorphisms was significantly associated with neuroblastoma susceptibility. However, stratified analysis showed a more profound association between neuroblastoma risk and rs6435862 TG/GG variant genotypes among older children (adjusted OR=1.55, 95% CI=1.04-2.31), and children with adrenal gland-originated disease (adjusted OR=2.94, 95% CI=1.40-6.18), or with ISSN clinical stages III+IV disease (adjusted OR=1.75, 95% CI=1.09-2.84). Similar results were observed for the variant genotypes of rs3768716 A>G polymorphism among these three subgroups. Our results suggest that the BARD1 rs6435862 T>G and rs3768716 A>G polymorphisms may contribute to increased susceptibility to neuroblastoma, especially for the subjects at age ≥12 months, with adrenal gland-originated or with late clinical stage neuroblastoma. These findings need further validation by prospective studies with larger sample size with subjects enrolled from multicenter, involving different ethnicities.     

IFN-γ +874 A>T (rs2430561) gene polymorphism and risk of pulmonary tuberculosis: a meta-analysis

IntroductionThe role of interferon gamma (IFN-γ) +874 A>T (rs2430561) gene polymorphism has been evaluated in different ethnicities with pulmonary tuberculosis (PTB) infection, and inconsistent results have been reported. In this study, a meta-analysis was performed to determine the precise association between IFN-γ +874 A>T gene polymorphism and PTB susceptibility.Material and methodsA total of 21 studies comprising 4281 confirmed PTB cases and 5186 healthy controls were included in this meta-analysis by searching the PubMed (Medline), EMBASE, and Google Scholar web-databases.ResultsWe observed reduced risk of PTB in allelic contrast (T vs. A: p = 0.001; OR = 0.818, 95% CI: 0.723–0.926), homozygous (TT vs. AA: p = 0.017; OR = 0.715, 95% CI: 0.543–0.941), heterozygous (AT vs. AA: p = 0.002; OR = 0.782, 95% CI: 0.667–0.917), dominant (TT+AT vs. AA: p = 0.002; OR = 0.768, 95% CI: 0.652–0.906), and recessive (TT vs. AA+AT: p = 0.042; OR = 0.802, 95% CI: 0.649–0.992) genetic models. In ethnicity-wise subgroup analysis, reduced risk of PTB was found in the Caucasian population. However, we did not find an association with any of the genetic models in the Asian population.ConclusionsIn conclusion, the IFN-γ +874 A>T gene polymorphism is significantly associated with reduced risk of PTB, showing a protective effect in the overall and in the Caucasian population. However, this polymorphism is not associated with PTB risk in the Asian population.     

Interleukin-10 -1082A/G polymorphism is associated with the development of acute pancreatitis in a Chinese population

We conducted a case-control study to investigate the association between IL-10 gene polymorphism (-1082A/G, -819T/C, and -592A/C) and risk of acute pancreatitis in a Chinese population. A total of 240 patients with proven acute pancreatitis and 240 control subjects were collected between May 2012 and January 2015. Genotyping of the IL-10-1082A/G, -819T/C, and -592A/C gene polymorphisms was conducted by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. By univariate logistic regression analysis, patients with acute pancreatitis were more likely to have higher BMI (OR=2.12, 95% CI=1.45-3.12; P<0.001) and have a habit of alcohol drinking (OR=2.01, 95% CI=1.37-2.95; P<0.001). There were significant differences in the genotype distributions of IL-10-1082A/G between patients with acute pancreatitis and control subjects (χ²=9.97, P=0.007). By multiple logistic regression analysis, we found that individuals with the GG genotype of IL-10-1082A/G were associated with an increased risk of acute pancreatitis when compared with the AA genotype (OR=2.32, 95% CI=1.20-4.59; P=0.007). In dominant and recessive models, the IL-10-1082A/G gene polymorphism was significantly correlated with an elevated risk of acute pancreatitis, and the adjusted Ors (95% CI) were 1.50 (1.03-2.20) and 1.99 (1.06-3.79), respectively. However, no significant different was found between IL-10-819T/C and -592A/C gene polymorphisms and susceptibility to acute pancreatitis. In conclusion, we suggest that IL-10-1082A/G gene polymorphisms contribute to the development of acute pancreatitis in codominant, dominant and recessive models.