Polymorphisms Of Codon Research Articles

Association of Polymorphisms in IL-10, TGF-β1, IFN-γ, and TNF-α Genes with the Susceptibility to Chronic Obstructive Pulmonary Disease in Kerman, Iran

Background: One of the principal cigarette smokes (CS) mediated diseases is chronic obstructive pulmonary disease (COPD). Methods: In the current case-control study, the relationship between the polymorphisms of interleukin-10 (IL-10), transforming growth factor-β1 (TGF-β1 ) codon 10, TGF-β1 codon 25, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) in 213 individuals with COPD and susceptibility to the disease, with 100 healthy age and gender-matched people as a control group, was investigated using PCR-ARMS (polymerase chain reaction-amplification refractory mutation system). Moreover, the combination of the polymorphisms of TGF-β1 codon 10.25 regarding this susceptibility was studied in the same condition. Results: There was a significant difference between polymorphism of TGF-β1 codon 10 (+869 T/C), codon 25 (G+915C), and susceptibility to the disease (OR=0.50; (95 %CI=0.24-1.07, p=0.05), ORCC =5.31; (95% CI: 1.22-23.2); p=0.02), thus polymorphism of IL-10 and TGF-β1 increased the risk of susceptibility to COPD but the polymorphisms of TNF-α (G-308A) and IFN-γ (+847 T/A) did not show any association. Conclusion: All in all, it is recommended that the patients carrying the above-said genotypes should be paid proper attention, especially those who are exposed to chemicals at their workplaces, pollution, and cigarette smoke.

DNAR-04. BOTH P53 CODON 72 ARG/ARG AND PRO/ARG GENOTYPES IN GLIOBLASTOMA MULTIFORME PATIENTS HAVE A BETTER PROGNOSIS IN BEVACIZUMAB TREATMENT

Abstract BACKGROUND In glioblastoma multiforme (GBM), bevacizumab increased progression-free survival but it has failed to improve overall survival (OS) in controlled trials. This study, therefore, aimed to retrospectively analyze the polymorphisms of p53 codon 72 and the clinical characteristics of GBM specimens from Taiwanese patients. METHODS The polymorphisms of p53 codon 72 in 99 patients with GBM treated at Taichung Veterans General Hospital in Taiwan from 2007 to 2017 were analyzed using direct DNA sequencing and PCR-RFLP analysis. RESULTS We found that among these GBM patients, the polymorphisms of p53 codon 72 were not directly associated with the overall survival of GBM, both the Arg/Arg and Arg/Pro genotypes were associated with significant benefits in terms of overall survival in patients treated with CCRT plus bevacizumab compared to patients treated with CCRT alone. CONCLUSIONS This pilot study suggests that both the Arg/Arg and Arg/Pro genotypes of p53 codon 72 polymorphism may have value as independent prognostic or predictive parameters for bevacizumab treatment response and failure. Relatedly, the results of the study further demonstrate the utility of stratifying GBM patientsaccording to bevacizumab sensitivity.

DNAR-15. POLYMORPHISM AT P21 CODON 31 PROVIDED A PREDICTION FOR BEVACIZUMAB THERAPY IN GLIOBLASTOMA MULTIFORME

Abstract Glioblastoma (GBM) is a common, malignant brain tumor. While it rarely metastasizes to distant organs, the diffuse invasion of glioma cells within the brain makes it difficult to resect. P21 (Waf-1) is a cyclin-dependent kinase inhibitor that plays an essential role in cell growth arrest, terminal differentiation, and apoptosis. Thus, the existence of natural variants of p21 could be linked to specific cancer. The purpose of this study was to identify the polymorphism variants of p21 codon 31 (Ser31Arg) and to explore its role in the therapy of glioblastoma multiforme. A total of unrelated 99 GBM subjects, were enrolled in the study, and genomic DNA was obtained from each tumor sample for genotyping. Genotyping was performed by polymerase chain reaction (PCR) restriction fragment length polymorphism method (PCR-RFLP analysis. Odds ratios (Ors) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression analysis. We found that among these GBM patients, the distribution of codon 31 polymorphisms was 20.2% for Serine homozygotes (Ser/Ser), 32.3% for arginine homozygotes (Arg/Arg), and 47.5% for Serine/arginine heterozygotes (Ser/Arg). Although the polymorphisms of p21 codon 31 were not directly associated with the overall survival of GBM, both the Arg/Arg and Arg/Ser genotypes were associated with significant benefits in terms of overall survival in patients treated with CCRT plus bevacizumab compared to patients treated with CCRT alone. Our findings suggest that the p21 Ser31Arg polymorphism may play an important role in the pathogenesis and initiation of GBM. Moreover, the polymorphism seems to contribute to a significant prediction at early diagnosis for bevacizumab therapy.

Occurrence of Strongylid Nematode Parasites on Horse Farms in Berlin and Brandenburg, Germany, With High Seroprevalence of Strongylus vulgaris Infection.

The infection of horses with strongylid nematodes is highly prevalent, with multi-species infections being the rule. Strongylus spp. and in particular Strongylus vulgaris are amongst the most pathogenic strongyle equine parasites. Presumably due to regular strategic anthelmintic treatments in combination with long prepatencies, prevalence of these worms was severely reduced in past decades. In this study, 484 horses from 48 farms in Berlin/Brandenburg, Germany were sampled between May 2017 and January 2018. Mini-FLOTAC and combined sedimentation/flotation were used to analyse faecal samples and larval cultures were carried out from individual strongyle infected horses for molecular testing for Strongylus spp. infection. Additionally, for Strongylus vulgaris, antibodies against a recombinant larval antigen were quantified in an ELISA. Strongyle type eggs were detected in 66.7% of the individual faecal samples. Nematode DNA was amplifiable from 311 samples and S. vulgaris and Strongylus edentatus were detected in four (1.3%) and 10 (6.3%) of these, respectively, the latter using a novel high-resolution-melt PCR targeting S. edentatus, Strongylus equinus, and Strongylus asini. On the farm level, prevalence for Strongylus spp. by PCR was 12.5%. Applying a conservative cut-off (sensitivity 0.43, specificity 0.96), 21.2% of all serum samples were positive for antibodies against S. vulgaris larvae (83.3% prevalence on farm level). Newly developed pyrosequencing assays to analyse putatively benzimidazole resistance associated polymorphisms in codons 167, 198, and 200 of the isotype 1 β-tubulin gene of S. vulgaris did not detect such polymorphisms in the four positive samples. Low age and increasing access to pasture were risk factors for egg shedding and seropositivity for S. vulgaris. Time since last treatment increased whereas use of moxidectin and ivermectin for the last treatment decreased the risk for strongyle egg shedding. Noteworthy, horses under selective treatment had significantly higher odds to be seropositive for anti-S. vulgaris antibodies than horses treated four times per year (odds ratio 4.4). The serological findings suggest that exposure to S. vulgaris is considerably higher than expected from direct diagnostic approaches. One potential explanation is the contamination of the environment by a few infected horses, leading to the infection of many horses with larvae that never reach maturity due to regular anthelmintic treatments.

Absence of Polymorphisms in Codons 167, 198 and 200 of All Seven β-Tubulin Isotypes of Benzimidazole Susceptible and Resistant Parascaris spp. Specimens from Australia.

Benzimidazoles resistance is widespread in strongyle parasitic nematodes and associated with polym orphisms in the codons 167, 198 and 200 of isotype 1 β-tubulin (tbb-1). In ascarids, benzimidazole (BZ) resistance has rarely been reported and in none of these cases were any of these polymorphisms detected. Here, available genome and transcriptome data from WormBase ParaSite were used to compare the complete β-tubulin reservoirs of Parascaris univalens, Ascaris suum and Ascaris lumbricoides. Adult Parascaris spp. specimens collected in Australia from horses after BZ treatment (susceptible, n = 13) or surviving BZ treatment and collected after ivermectin treatment (resistant, n = 10) were genotyped regarding codons 167, 198 and 200 using Sanger sequencing. Phylogenetic analyses clearly showed that there are no one-to-one ascarid orthologs of strongyle tbb-1 genes. In the reference genomes, as well as phenotypically susceptible and resistant Parascaris spp. from Australia, six out of seven β-tubulin genes showed a BZ-susceptible genotype (F167, E198, F200). The only exception were the testis-specific β-tubulin D genes from all three ascarid species that encode tyrosine at codon 200. This was observed independently of the BZ-susceptibility phenotype of Parascaris spp. These data suggest that different mechanisms lead to BZ resistance in ascarid and strongyle nematodes.

Association between the DNA Repair Gene Polymorphisms and Lung Cancer in Turkish Population

Introduction: DNA repair enzymes continuously monitor DNA to correct damaged nucleotide residues generated by exposure to environmental mutagenic and cytotoxic compounds or carcinogens. Our objective was to investigate the association among XRCC1 (Arg399Gln and Arg194Trp), XRCC3 (Thr241Met), XPD-ERCC2 (Lys751Gln), APE1 (Asp241Glu), PARP-ADPRT (Val762Ala) DNA repair gene polymorphisms and lung cancer in Turkish population. Materials and Methods: Our patient group consists of 90 patients with lung cancer and the control group had 100 healthy individuals all of those smoking. DNA was extracted using the whole blood samples. PCR- RFLP technique was used to investigate the polymorphisms on target genes. Results: There was no significant difference in the genotype distributions of XPD Lys751Gln, XRCC1 Arg194Trp, XRCC3 Thr241Met, APE1 Asp241Glu between lung cancer patients and controls for each polymorphism (p > 0.05). However, there was a significant difference between the genotype distributions of XRCC1 Arg399Gln, and PARP Val762Ala in patients and the control group (p > 0.05). Discussion: Only the polymorphisms of XRCC1 codon 399 and PARP Val762Ala alleles are associated with the risk of lung cancer. Other genotypes were not related to lung cancer.

Polymorphisms in Plasmodium falciparum dihydropteroate synthetase and dihydrofolate reductase genes in Nigerian children with uncomplicated malaria using high-resolution melting technique

In 2005, the Nigerian Federal Ministry of Health revised the treatment policy for uncomplicated malaria with the introduction of artemisinin-based combination therapies (ACTs). This policy change discouraged the use of Sulphadoxine-pyrimethamine (SP) as the second-line treatment of uncomplicated falciparum malaria. However, SP is used as an intermittent preventive treatment of malaria in pregnancy (IPTp) and seasonal malaria chemoprevention (SMC) in children aged 3–59 months. There have been increasing reports of SP resistance especially in the non-pregnant population in Nigeria, thus, the need to continually monitor the efficacy of SP as IPTp and SMC by estimating polymorphisms in dihydropteroate synthetase (dhps) and dihydrofolate reductase (dhfr) genes associated with SP resistance. The high resolution-melting (HRM) assay was used to investigate polymorphisms in codons 51, 59, 108 and 164 of the dhfr gene and codons 437, 540, 581 and 613 of the dhps gene. DNA was extracted from 271 dried bloodspot filter paper samples obtained from children (< 5 years old) with uncomplicated malaria. The dhfr triple mutant I51R59N108, dhps double mutant G437G581 and quadruple dhfr I51R59N108 + dhps G437 mutant haplotypes were observed in 80.8%, 13.7% and 52.8% parasites, respectively. Although the quintuple dhfr I51R59N108 + dhps G437E540 and sextuple dhfr I51R59N108 + dhps G437E540G581 mutant haplotypes linked with in-vivo and in-vitro SP resistance were not detected, constant surveillance of these haplotypes should be done in the country to detect any change in prevalence.

Association between p53 and p21 genes polymorphisms and ulcerative colitis in an Iranian population

Ulcerative colitis is an inflammatory disease characterized by ongoing mucosal and submucosal changes, starting from the rectum and spreading to proximal regions. The p53 gene is considered as the most important tumor suppressor gene, encoding for a 53 k Dalton phosphoprotein, whose natural function is to protect the genome against damages by activation of the P21 protein. The P21 protein, in turn, causes cell cycle arrestment at the G1/S phase through inhibition of the CDK1 and CDK2 activity, and thus, permits DNA repair.In this study, we investigated the association of the p53 codon 72 and p21 codon 31 polymorphisms with ulcerative colitis in the north of Iran using RFLP-PCR assay. A total number of 174 patients with intestinal ulcers and 82 healthy controls were genotyped for p53 codon 72 and p21 codon 31 polymorphisms.The Arg/Arg genotype of p53 gene codon 72 was associated with an increased risk for ulcerative colitis (OR, 4.074; 95% CI,5.874–1.800), compared with the Pro/Pro genotype. Also, the Ser/Ser genotype of p21 gene codon 31 was associated with an increased risk of ulcerative colitis (OR, 3.175; 95% CI, 4.875–1.700), compared with the Arg/Arg genotype. Also, we found a significant relationship between ulcerative colitis with age, metastasis, and cancer stage, but no relationship with gender was found )Chi-Square p < 0.05).The findings suggest that genetic polymorphisms of the p53 gene codon 72 and p21 gene codon 31 were significantly associated with ulcerative colitis and could be used as a prognostic marker for ulcerative colitis and gastrointestinal malignancies.

Both p53 codon 72 Arg/Arg and pro/Arg genotypes in glioblastoma multiforme are associated with a better prognosis in bevacizumab treatment

BackgroundIt has previously been shown that bevacizumab, when added to chemotherapy, improved overall survival in several cancers. In glioblastoma multiforme (GBM), bevacizumab increased progression-free survival and it is widely used for tumor recurrence, though it has failed to improve overall survival (OS) in controlled trials. However, an effective biomarker for predicting the prognosis of bevacizumab treatment has yet to be identified. This study, therefore, aimed to retrospectively analyze the polymorphisms of p53 codon 72 and the clinical characteristics of GBM specimens from Taiwanese patients.MethodsThe polymorphisms of p53 codon 72 in 99 patients with GBM treated at Taichung Veterans General Hospital in Taiwan from 2007 to 2017 were analyzed using direct DNA sequencing and PCR-RFLP analysis.ResultsWe found that among these GBM patients, the distribution of codon 72 polymorphisms was 28.3% for proline homozygotes (Pro/Pro), 38.4% for arginine homozygotes (Arg/Arg), and 33.3% for proline/arginine heterozygotes (Pro/Arg). Although the polymorphisms of p53 codon 72 were not directly associated with the overall survival of GBM, both the Arg/Arg and Arg/Pro genotypes were associated with significant benefits in terms of overall survival in patients treated with CCRT plus bevacizumab compared to patients treated with CCRT alone.ConclusionsThis pilot study suggests that both the Arg/Arg and Arg/Pro genotypes of p53 codon 72 polymorphism may have value as independent prognostic or predictive parameters for bevacizumab treatment response and failure. Relatedly, the results of the study further demonstrate the utility of stratifying GBM patients according to bevacizumab sensitivity.

Impact of mannose-binding lectin 2 gene polymorphisms on disease severity in noncystic fibrosis bronchiectasis in children.

Mannose-binding lectin (MBL) is a complement protein involved in the innate immune system, and is associated with some chronic respiratory diseases including noncystic fibrosis (non-CF) bronchiectasis in adults. The aim of this study was to investigate the frequency of MBL2 gene polymorphisms in children with non-CF bronchiectasis, and the effect of MBL deficiency on disease severity. Fifty children with non-CF bronchiectasis (bronchiectasis group) and 50 healthy controls (control group) were included. The demographic findings, number of acute pulmonary exacerbations in the previous year, airway cultures, pulmonary function tests, and radiologic scores of the bronchiectasis group were recorded. DNA extraction was performed in both groups and MBL2 gene polymorphisms in codons 52, 54, 57 in exon 1 and H/L, Y/X in the promoter region were studied using real-time polymerase chain reaction. Haplotypes were made by genotypes, and MBL serum expression was classified according to the genotypes in the literature. The bronchiectasis group consisted of 23 (46%) patients with primary ciliary dyskinesia, 5 (10%) with primary immunodeficiency diseases, and 22 (44%) with idiopathic bronchiectasis. There were no statistically significant differences between the bronchiectasis and control groups in terms of allele and genotype frequencies of polymorphisms in codons 52, 54, 57 in exon 1 and promoter H/L. However, the YX heterozygote genotype was more frequent in the control group (82%) compared with the bronchiectasis group (50%) (P = .002). The frequency of patients with intermediate serum MBL expression genotype was higher in the bronchiectasis group (20%) than in the control group (0%) (P = .001). In the bronchiectasis group, there were no significant differences in growth, annual pulmonary exacerbation rates in the last year, pulmonary function tests, radiologic scores, and microbiologic findings between low, intermediate, and high-expressing genotypes. In children with non-CF bronchiectasis, MBL genotype was different from healthy controls. MBL deficiency associated only with MBL genotype was not related to disease severity in this group of patients.

Molecular detection of benzimidazole resistance levels associated with F167Y and F200Y polymorphisms in Haemonchus contortus of goats from Mozambique.

Benzimidazole (BZ) resistance of Haemonchus contortus has been associated with single nucleotide polymorphisms (SNPs) in codons 200 (F200Y) and 167 (F167Y) and, to a lesser extent, in codon E198A, of the β-tubulin isotype 1 gene. The present study was undertaken to survey the status of BZ resistance in naturally infected goats in smallholder farms in southern Mozambique by real-time PCR (qPCR) using TaqMan® assays. H. contortus-infective larvae (L3; n = 432) from 12 populations were individually genotyped for F200Y and F167Y SNPs to detect BZ resistance. For the F200Y SNP, the results revealed an overall mean percentages of 18.8% homozygous resistant (RR), 47.8% homozygous susceptible (SS) and 33.4% heterozygous (RS) H. contortus. For the F167Y SNP, the overall mean percentages were 1.6% RR, 94.9% SS and 3.5% RS. The percentage of resistant alleles (%R) for the F200Y and F167Y SNPs was 35.7 and 3.4%, respectively. Genotype combinations of the two mutations indicate resistant percentages ranging from 0.0 to 52.9%. From the four herds with high RR individuals, three farms dewormed the animals monthly, while the fourth farm dewormed the animals every 3months. In farms where animals were dewormed every 6months, low percentages of RR individuals were found, whereas no RR individuals were discovered in herds where animals were dewormed annually. These results suggest that the F200Y SNP is more significant in BZ resistance development of the surveyed population compared with the F167Y SNP.

Standardization and application of a modified RFLP-PCR methodology for analysis of polymorphisms linked to treatment resistance in Ancylostoma braziliense

BackgroundSingle nucleotide polymorphisms (SNPs) in codons 167, 198 and 200 of the beta-tubulin isotype 1 gene are associated with benzimidazoles resistance in many helminths. Codon 167 mutation has never been described in hookworms; however, polymorphisms in codons 198 and 200 have been described for Ancylostoma caninum and Necator americanus. These mutations have never been investigated in Ancylostoma braziliense; therefore, it is not known if they are present in this species and whether they are correlated with treatment resistance. The RFLP-PCR technique has been used to analyze these polymorphisms in some nematodes, but depending on the species, these alterations do not create or eliminate any restriction enzyme cleavage site, making it impossible to use this technique. Here, we describe the standardization and application of a modified RFLP-PCR technique for detecting polymorphisms in individual A. braziliense worms recovered from naturally infected dogs in two Brazilian states.ResultsThe molecular techniques used were sensitive, specific, and easy to apply. To our knowledge, we report for the first time the presence of a polymorphism at codon 198 of the beta-tubulin gene of A. braziliense (1/81; 95% CI: 0–3.69%).ConclusionsIt is not known whether the presence of the mutation in codon 198 of the beta-tubulin gene of A. braziliense has importance for this parasite. However, based on studies of other helminths, it is possible that this polymorphism is directly related to the resistance to benzimidazoles. This may be a major concern, since this nematode has considerable relevance as a parasite of canids and felids and as one of the agents of cutaneous larva migrans in humans. Standardized methodologies will be useful for screening for polymorphisms in the beta-tubulin gene of canine hookworms in a broader population. The method could also be adapted for the analysis of other SNPs in other nematode species.

Prion protein testis specific (PRNT) gene polymorphisms and transcript level in ovine spermatozoa: Implications in freezability, fertilization and embryo production

An essential role of prion protein testis specific (PRNT) and prion protein 2 dublet (PRND) genes in the male reproductive function has been highlighted, although a deeper knowledge for the mechanisms involved is still lacking. Our goal was to determine the importance of the PRNT haplotypic variants and mRNA expression levels in ovine spermatozoa freezability and ability for fertilization and embryo developmental processes. Their association with the PRND gene polymorphisms was also analyzed. DNA from rams belonging to three Portuguese sheep breeds (n = 28) was screened by single-strand conformation polymorphism (SSCP) analysis to identify the PRNT and PRND polymorphisms. Semen collected from these rams was cryopreserved and fertility traits evaluated. The SSCP analyses revealed polymorphisms in the codons 6, 38, 43 and 48 of the PRNT coding region - respectively c.17C > T (p.Ser6Phe, which disrupts a consensus arginine-X-X serine/threonine motif); c.112G > C (p.Gly38 > Arg); and synonymous c.129T > C and c.144A > G. The polymorphisms in codons 6, 38 and 48 occur simultaneously while the one in codon 43 occurs independently. Six haplotypes were identified in the PRNT coding region, resulting in three different amino acid polymorphic variants (6S-38G-43C-48V, S6F-G38R-43C-48V and 6F-38R-43C-48V). The PRNT gene mRNA transcript level in spermatozoa was related to the identified haplotypic variants, either considering the codons 6-38-48 (P ≤ 0.0001) or the codon 43 alone (P ≤ 0.0001) or altogether (P ≤ 0.0001). An interaction between PRNT haplotypes and PRND genotypes on PRNT transcript level was also identified (P = 0.0003). Rams carrying the 17C-112G-144A PRNT haplotype had sperm with the highest post-thawed individual motility (P ≤ 0.03). Combined PRNT and PRND polymorphic variation influenced the post-thawed individual motility (P = 0.01). The male PRNT haplotypic, either considering the codons 6-38-48 and 43 altogether or the codon 43 alone, interfered (P ≤ 0.04) in embryo production rates. In conclusion, our data confirm that the PRNT gene is highly polymorphic in sheep and that the PRNT and PRND genotypes are associated. The identified polymorphisms of PRNT coding region seems to interfere on the ram spermatozoa mRNA transcript level and on male fertility, specifically in sperm freezability and ability for embryo development.

Genotypic profile of benzimidazole resistance associated with SNP F167Y and F200Y beta-tubulin gene in Brazilian populations of Haemonchus contortus of goats.

Benzimidazoles are the most common anthelminthic used for control of gastrointestinal nematodes of goats in the Brazilian semi-arid region. Resistance to these compounds in the nematode Haemonchus contortus has been associated with single nucleotide polymorphisms (SNP) in codons 167 (F167Y) and 200 (F200Y) on the β-tubulin isotype 1 gene. To determine the resistance profile to benzimidazoles of populations of H. contortus of goats of Brazilian semi-arid region, larvae of 29 populations of these nematodes were individually genotyped by real time PCR using a Taqman assay. The percentage of larvae homozygous (RR) for SNP F200Y was relatively low (18.9%), particularly when compared to SNP F167Y (32.7%), indicating that the latter has more relevance in this region. However, the associations between these two SNP demonstrate percentages of resistance ranging from 34.7% to 100% between populations, being the highest percentages for homozygous individuals resistant for the mutation 167 and susceptible to mutation 200 (RR-F167Y/F200Y-SS: 26.7%), followed by combination of heterozygous for both mutations (F167Y-SR/F200Y-SR: 22.8%). These results indicate high levels of resistance in populations of H. contortus of goats in the Brazilian semi-arid region, and thus ineffective antiparasitic control with the use of benzimidazoles in the region.

Allelic polymorphism in codon 72 of p53 gene: prognosis value, survival rates, and their association with breast cancer.

There are controversial findings to establish relationship between genotype polymorphism of codon 72 of P53 gene, its prognosis value, and survival rate of the patients in breast cancer. For the first time this study has shown such relationship in Sabzevar, Iran. A descriptive analytical case-control study was conducted on 160 people (80 patients and 80 controls). DNA was extracted and codon 72 of the p53 gene was amplified. The genotype of the p53 gene was determined by electrophoresis, samples were sequenced, and all patients were followed up for 30 months. The frequency of heterozygote arginine/proline was 49 (30.6%) and 51(31.9%) in the patients and controls, respectively. Homozygote arginine/arginine had frequency of 29 (18.1%) in the patients while it was 15 (9.4%) in controls. Homozygote of proline/proline was two (1.3%) in the patients and 14 (8.8%) in controls. The sequencing results were consistent to PCR and electrophoresis results. This is the first study in the region which shows relationship between genotype polymorphism, survival rate, and its prognosis value in breast cancer. The authors showed that homozygote proline/proline in controls was significantly higher compared with that in the patients. They may therefore, conclude that detection of allelic polymorphisms of codon 72 of the p53 gene including arginine/arginine could be a risk factor predisposition for breast cancer and valuable tool for determining prognosis, progress, and treatment purposes.

Analysis of polymorphisms in codons 11, 72 and 248 of TP53 in Brazilian women with breast cancer.

The association between TP53 gene polymorphisms and breast cancer (BC) in Brazilian women is a controversial topic. In this cross-sectional study, we evaluated the association between clinical pathological variables and three polymorphisms (TP53*11, TP53*72, and TP53*248) in BC patients and controls. Genomic DNA was extracted from the blood cells of 393 participants; the cancer-free control subjects were 26-72 years old (41 ± 11.03) and the BC patients were 28-80 years old (51 ± 10.70). We used standard polymerase chain reaction-restriction fragment length polymorphism and confirmed the results by genetic sequencing. In TP53*11, there was 100% homozygous Glu distribution in both groups. TP53*72 showed genotypic distribution: in the control group, there was 16.10% homozygous Pro, and 42.44% heterozygous and 41.46% homozygous Arg; in the BC group, there was 15.43% homozygous Pro, and 42.55% heterozygous and 42.02% homozygous Arg. The relative frequency of each allele was 0.37% for Pro and 0.63% for Arg in the control group, and 0.37% for Pro and 0.63% for Arg in the BC group. The nuclear grade (P = 0.0084) and adapted histological grade (P = 0.0265) were associated with TP53*72. The distribution of the codon 72 genotypes did not deviate from Hardy-Weinberg equilibrium in either group. In TP53*248, there was 100% homozygous Arg distribution in both groups. In codon 72, the Arg allele is the most prevalent in Brazilian women. TP53*72 may be associated with susceptibility to BC, although more studies are required to evaluate the profile of Brazilian women with BC.

The prion-related protein (testis-specific) gene (PRNT) is highly polymorphic in Portuguese sheep.

The objective of this study was to search for polymorphisms in the ovine prion-related protein (testis-specific) gene (PRNT). Sampling included 567 sheep from eight Portuguese breeds. The PRNT gene-coding region was analyzed by single-strand conformation polymorphism and sequencing, allowing the identification of the first ovine PRNT polymorphisms, in codons 6, 38, 43 and 48: c.17C>T (p.Ser6Phe, which disrupts a consensus arginine-X-X-serine/threonine motif); c.112G>C (p.Gly38>Arg); c.129T>C and c.144A>G (synonymous) respectively. Polymorphisms in codons 6, 38 and 48 occur simultaneously in 50.6% of the animals, 38.8% presenting as heterozygous. To study the distribution of the polymorphism in codon 43, a restriction fragment length polymorphism analysis was performed. Polymorphic variant c.129C, identified in 89.8% of the animals with 32.8% presented as heterozygous, was considered the wild genotype in Portuguese sheep. Eight different haplotypes which have comparable distribution in all breeds were identified for the PRNT gene. In conclusion, the PRNT coding region is highly polymorphic in sheep, unlike the prion protein 2 dublet gene (PRND), in which we previously found only one synonymous substitution (c.78G>A), in codon 26. The absence or reduced number of PRND heterozygotes (c.78G>A) was significantly associated with three PRNT haplotypes (17C-112G-129T-144A,17CT-112GC-129CT-144AG and 17T-112C-129C-144G), and the only three animals found homozygous at c.78A had the 17C-112G-129C-144A PRNT haplotype. These results constitute evidence of an association between polymorphic variation in PRND and PRNT genes, as has already been observed for PRND and prion protein gene (PRNP).

APOE and cerebral amyloid angiopathy in community-dwelling older persons

Both cerebral amyloid angiopathy and Alzheimer's disease pathology involve abnormal β-amyloid processing. We aim to elucidate the relationship of the apolipoprotein E (APOE) genotypes with amyloid angiopathy in the presence of variable amounts of Alzheimer's pathology. Data came from 1062 autopsied subjects from 2 community-based studies of aging. Common neuropathologies including Alzheimer's disease and amyloid angiopathy were assessed using uniform methods. APOE was genotyped by sequencing the 2 polymorphisms in codons 112 and 158 of exon 4. We examined the associations of APOE with amyloid angiopathy using ordinal logistic regression analyses, controlling for demographics and subsequently Alzheimer's and other common pathologies. Moderate to severe amyloid angiopathy was identified in 35.2% (n = 374) of the subjects; 15.3% (n = 162) of the subjects were APOE ε2 carriers; and 26.1% (n = 277) ε4 carriers. Adjusting for demographics, the presence of ε4 allele, but not ε2, was associated with more severe amyloid angiopathy. After further adjustment for Alzheimer's pathology, both ε2 (odds ratio 1.707, 95% confidence interval 1.236–2.358, p = 0.001) and ε4 (odds ratio 2.284, 95% confidence interval 1.730–3.014, p < 0.001) were independently associated with amyloid angiopathy. The results were confirmed by path analysis. Furthermore, APOE ε4 carriers, but not ε2 carriers, were more likely to have capillary amyloid angiopathy. Accounting for capillary involvement did not alter the APOE associations with amyloid angiopathy. We conclude that both APOE ε2 and ε4 alleles are associated with more severe cerebral amyloid angiopathy, and the direct effect of ε2 is masked by the allele's negative association with comorbid Alzheimer's pathology. APOE ε4, but not ε2, is associated with capillary amyloid angiopathy.

The association of mannose-binding lectin genetic polymorphisms with the risk of rheumatoid arthritis: a meta-analysis

Objective: To better understand the risks of rheumatoid arthritis (RA) and certain subsets conferred by mannose-binding lectin (MBL2) polymorphisms in different races. Materials and methods: Eighteen articles (4810 cases and 4585 controls) were identified from the latest literature search carried out in May 2014 using PubMed, Web of Science, Wanfang Database (Chinese) and Chinese National Knowledge Infrastructure. Three single nucleotide polymorphisms of codon 52, 54 and 57, exonic and extended genotypic variance in MBL2 were synthesized. Results: Codon 54 mutation of MBL2 was unlikely to be a risk factor for RA in overall population, but turned out to be deleterious in East Asian (four studies with 523 cases and 647 controls, pooled OR:1.63, 95% CI: 1.23–2.17). Codon 54 mutation increased the risk of seropositive and erosive RA by 44% and 162%, respectively (three studies with 281 cases and 358 controls, 95% CI: 1.01–2.05; 3 studies with 180 cases and 499 controls, 95% CI: 1.77–3.88). Furthermore, those risks were relatively stronger when restricted in East Asian (two studies with 147 cases and 244 controls, pooled OR: 1.85, 95% CI: 1.19–2.87; 2 studies with 170 cases and 291 controls, pooled OR: 2.78, 95% CI: 1.85–4.20). No remarkable associations were detected regarding codon 52, 57, exon 1 and extended genotype of MBL2. Conclusions: Polymorphism of codon 54 in MBL2 may predispose to RA, especially seropositive or erosive RA, which East Asian appears to be more vulnerable.

DNA repair genes XPD and XRCC1 polymorphisms and risk of end-stage renal disease in Egyptian population

DNA repair gene polymorphisms may affect DNA repair capacity and modulate susceptibility to end-stage renal disease (ESRD). We aimed to determine the association of polymorphisms in xeroderma pigmentosum complementation group D (XPD) and X-ray cross-complementing group 1 (XRCC1) with ESRD development. Polymorphisms in XPD codons 312 and 751 and XRCC1 codon 399 were genotyped in 98 patients undergoing hemodialysis and 102 healthy controls using polymerase chain reaction and restriction fragment length polymorphism. Patients having XRCC1-399 Arg/Gln genotype or XRCC1-399 Gln/Gln genotype had a significantly higher risk of ESRD than those with XRCC1-399 Arg/Arg [odds ratio (OR): 2.48; 95% confidence intervals (CI): 1.36–4.52; p = 0.004 and OR: 4.05; 95% CI: 1.19–13.73; p = 0.03, respectively]. We also found a significantly higher frequency of the XRCC1 399Gln allele in patients with ESRD than in controls (OR: 2.22; 95% CI: 1.16–4.25; p = 0.02). Combination of the Arg/Gln or Gln/Gln genotypes of XRCC1 Arg399Gln polymorphism with Asp/Asn or Asn/Asn genotypes of XPDAsp312Asn or with the Lys/Gln or Gln/Gln genotypes of XPD Lys751Gln was significantly associated with the development of ESRD. Haplotypes association showed that association of Gln allele of XRCC1 Arg399Gln polymorphism with the Asn allele of XPDAsp312Asn polymorphism (p = 0.004) or Gln allele of XRCC1 Arg399Gln polymorphism with the Gln allele of XPD Lys751Gln polymorphism (p = 0.003) was highly significantly associated with the development of ESRD. This study revealed that XRCC1 Arg399Gln polymorphism may confer increased risk for the development of ESRD. Furthermore, larger studies should be conducted to confirm these results.