AA Allele Research Articles

Inherited variations in human pigmentation-related genes modulate cutaneous melanoma risk and clinicopathological features in Brazilian population

Ultraviolet light exposure and cutaneous pigmentation are important host risk factors for cutaneous melanoma (CM), and it is well known that inherited ability to produce melanin varies in humans. The study aimed to identify single-nucleotide variants (SNVs) on pigmentation-related genes with importance in risk and clinicopathological aspects of CM. The study was conducted in two stages. In stage 1, 103 CM patients and 103 controls were analyzed using Genome-Wide Human SNV Arrays in order to identify SNVs in pigmentation-related genes, and the most important SNVs were selected for data validation in stage 2 by real-time polymerase-chain reaction in 247 CM patients and 280 controls. ADCY3 c.675+9196T>G, CREB1 c.303+373G>A, and MITF c.938-325G>A were selected for data validation among 74 SNVs. Individuals with CREB1 GA or AA genotype and allele “A” were under 1.79 and 1.47-fold increased risks of CM than others, respectively. Excesses of CREB1 AA and MITF AA genotype were seen in patients with tumors at Clark levels III to V (27.8% versus 13.7%) and at III or IV stages (46.1% versus 24.9%) compared to others, respectively. When compared to others, patients with ADCY3 TT had 1.89 more chances of presenting CM progression, and those with MITF GA or AA had 2.20 more chances of evolving to death by CM. Our data provide, for the first time, preliminary evidence that inherited abnormalities in ADCY3, CREB1, and MITF pigmentation-related genes, not only can increase the risk to CM, but also influence CM patients’ clinicopathological features.

Association of GHR Polymorphisms with Milk Production in Buffaloes.

Simple SummaryThe present study reported two missense mutations in the buffalo GHR gene: A novel (c.380G>A) and (c.836T>A) which was described in previous studies. These two single nucleotide polymorphisms (SNPs) were found to be associated with milk yield, fat %, protein %, and 305 day-milk, fat and protein yield, with higher performance for AA haplotype animals. Therefore, selection of buffaloes with AA haplotype would more likely improve milk production traits. Consequently, this would allow breeders to take more precise selection decisions, leading to significantly higher productivity and profitability within the Egyptian buffalo herds.For its role in the mediation of growth hormone (GH) galactopoietic effect, growth hormone receptor (GHR) was considered a functional candidate gene for milk performance in cattle. However, its genetic variation and potential effect have not been investigated in Egyptian buffaloes. This study aimed to screen GHR for polymorphisms and study their associations with milk traits in Egyptian buffaloes. Polymerase chain reaction, single-strand conformation polymorphism, and sequencing were used to identify mutations in 4 exons (E4–E6 and E8) of the GHR gene in 400 Egyptian buffaloes. No polymorphisms were found in E4, while 2 SNPs (c.380G>A/p.Arg127Lys and c.387C>T/p.Gly129) in E5, one silent mutation (c.435A>G/p.Pro145) in E6, and another missense mutation (c.836T>A/p.Phe279Tyr) in E8 were detected. The c.380G>A SNP in the extracellular domain was associated with milk yield, fat %, protein %, and 305-day milk, fat and protein yield, with higher levels in animals carrying the mutant A allele. The c.836T>A SNP in the transmembrane domain was associated with milk yield, fat %, protein %, and 305-day milk, fat and protein yield, with higher milk yield and lower fat %, protein %, fat and protein yield in the mutant A allele-animals. Interestingly, animals with the two mutant AA alleles produced higher milk yield, fat %, protein %, fat and protein yield, accompanied with upregulated expressions of GHR, GH, insulin-like growth factor 1 (IGF1), prolactin (PRL), prolactin receptor (PRLR), β-casein (encoded by CSN2 gene), and diacylglycerol acyltransferase-1 (DGAT1) genes and proteins in milk somatic cells. Therefore, selection of Egyptian buffaloes with mutant AA haplotypes for the novel c.380G>A SNP and the well-known c.836T>A SNP could improve milk yield and quality in buffaloes.

Single Nucleotide Polymorphism Analysis in HIV and Kaposi's Sarcoma Disease by Microarray Technique.

Emergence of Kaposi's Sarcoma in the cases other than HIV, following the use of immunosuppressant drugs, demonstrates that it is related to weak immunity. The fact that this malignancy does not occur in every HIV-positive patient suggests that genetic predisposition may also be effective. Replacement of one of the base pairs of adenine, guanine, cytosine, and thymine that constitute the DNA sequence in the human genome with another base pair can affect susceptibility to disease, response to treatment, and immunity. The purpose of this study is to analyze the Single Nucleotide Polymorphism that could predispose to Kaposi's sarcoma of an HIV-infected patient and to identify which nucleotides such SNPs correspond to, using the microarray technology. The blood samples of individuals, one of whom was diagnosed with Kaposi's Sarcoma HIV (+) visiting the outpatient clinic of infectious diseases polyclinic of Harran University Research and Practice Hospital and of a healthy individual with no Kaposi's Sarcoma, were used in the study. Following the DNA isolation of the blood samples taken from the respective individuals, a SNP analysis was conducted on the microarray device. 204,000 SNPs obtained were scanned later on in the databases in an attempt to identify the SNPs related to Kaposi's Sarcoma. In the 204,000 SNP screenings, we scrutinized the SNPs that differ in the case of Kaposi's Sarcoma [KS (+) and HIV (+)] on the basis of Control [KS(-) and HIV(-)] and HIV+ [KS(-)], and two SNPs of the ENDRA gene, three SNPs of the ADRA1A gene, six SNPs of the STIM1 gene, four SNPs of the EFNB2 gene, and one SNP of the CD209 gene were found to be different. However, when it comes to all SNPs (all the 204.000 SNPs) screened in terms of allele, it was observed that the AA and BB alleles were lower in the patient with Kaposi's Sarcoma [KS (+) and HIV (+)] compared to other groups and AB alleles were found to be higher than others in the patient with Kaposi's sarcoma [KS] (+) and HIV (+)]. In the microarray study we have conducted, 204,000 SNPs were screened for Control (HIV-) HIV (+) and HIV (+) patient with Kaposi's Sarcoma. It was found that 32,362 of those SNPs had different alleles in the Kaposi's Sarcoma [KS + HIV (+)] patient, while they had the same ones in the control [KS (-) and HIV (-)] and HIV + [KS (-)] group. 16 of the 32,362 SNPs took place among the genes related to Kaposi's Sarcoma. In the cases of Kaposi's Sarcoma with suspected diagnosis, it can be used as a beneficial laboratory test.

Relationship between interleukin-13 rs20541 single nucleotide polymorphisms and therapeutic efficacy in children with asthma.

ObjectiveTo investigate the relationship between therapeutic efficacy in children with asthma and interleukin-13 (IL-13) rs20541 polymorphisms.MethodsFifty children with moderate-to-severe asthma were assigned to the GG, GA, and AA groups according to the IL-13 gene locus rs20541 polymorphism. The patients received budesonide inhalation suspension 1 mg twice daily combined with fluticasone propionate 80 µg/inhalation. The improvement of clinical symptoms (gasping, coughing, and wheezing), improvement of lung function, and adverse reactions were observed.ResultsLung function did not significantly differ among three groups before treatment. After treatment, the time to symptom relief was significantly shorter in the GG group than that in the other two groups. The forced expiratory volume in one second and percent predicted peak expiratory flow were also significantly better in the GG group than in the other two groups.ConclusionBudesonide inhalation suspension combined with fluticasone propionate is an effective treatment regimen for moderate-to-severe asthma. Polymorphism of the IL-13 rs20541 locus may be correlated with therapeutic efficacy. Patients carrying the GG allele were more responsive than their counterparts with the GA or AA allele.

Genetic analysis of SLC47A1, SLC22A1, SLC22A2, ATM gene polymorphisms among diabetics in an Indian population

Background: Metformin is a first-line therapy for type 2 diabetes mellitus. However, the glycaemic response to metformin is likely to be affected by polymorphisms of transporter genes. Therefore, the study was done with the aim to assess demographic distribution of transporter genotypes involved in disposition and action of metformin.Methods: This cross-sectional, observational, single centre, clinical study was conducted in 80 diabetic patients recruited from medicine OPD. Descriptive analysis was done for distribution of the four transporter genotypes viz. SLC47A1 (rs2289669), ATM (rs11212617), SLC22A2 (rs316019) and SLC22A1 (rs622342). Genotyping was determined by DNA extraction, agarose gel electrophoresis, estimation of DNA concentration, polymerase chain reaction, DNA sequencing, sequencing analysis.Results: Transporter genotype analysis showed that for SLC47A1 (rs2289669) transporter, 31.25% and 26.25% were homozygous for AA and GG allele respectively, while 42.5% were heterozygous (AG). For ATM (rs11212617), SLC22A2 (rs316019) and SLC22A1 (rs622342) transporter, 45% and 10%, 1.25% and 80%, 58.75% and 7.50% were homozygous for AA and CC allele respectively; while 45%, 18.75%, 33.75% were heterozygous (AC) respectively. Interethnic differences in the genotype and allele frequencies of SLC22A1 (rs622342) and ATM (rs11212617) gene polymorphism were observed when compared with other major populations.Conclusions: In the genotypic distribution of four transporter genotype study showed that there was an ethnic variation in allelic distribution of allele A and C of ATM (rs11212617) and SLC22A1 (rs622342) while AA genotype of SLC22A2 (rs316019) was rare genotype and allele ‘A’ was major allele found in our study. The study data observed would justify further pharmacogenetic studies to evaluate the role of gene polymorphism in the therapeutic efficacy of metformin.

Clinical, Diagnostic and Prognostic Significance of Farnesyl Diphosphate Synthase Gene Polymorphism in Patients with Osteoarthritis: Decreased Bone Density and Overweight

A comprehensive study of 96 patients with osteoarthritis (OA) revealed that AA homozygotes prevail, the frequency of which is significantly higher than heterozygotes or homozygotes with the SS genotype (53.1 ± 5.1 %, 41.7 ± 5.0 % and 5, 2 ± 2.3 %, respectively; p <0.05). The frequency of homozygotes with the AA genotype significantly (almost 8–10 times; p <0.001) prevails over the frequency of SS homozygotes. The generalized WOMAC index in the patient groups was 48.8 ± 1.8 % and was large in AA homozygotes with a tendency to prevail in the severity structure of the manifestations of stiffness. Among homozygotes, AA have an increased body mass (BM) or obesity of 83.3 ± 4.8 %, among heterozygotes - 75.0 ± 6.8 %, among homozygotes of SS - 80.0 ± 19.1 % of people. The apelin content in the blood plasma of patients with OA depending on the BM and the variant polymorphism of the FDPS gene is characterized by the fact that with homozygosity SS, in the case of an increase in BM, the apelin content decreases, while with AA homozygosity it does not change significantly. The relationship between the FDPS gene polymorphism and the OA stage is characterized by the prevalence of more severe radiological signs of articular cartilage degradation among homozygous AA alleles.

Polymorphisms of Drug-Metabolizing Enzymes and Transporters Contribute to the Individual Variations of Erlotinib Steady State Trough Concentration, Treatment Outcomes, and Adverse Reactions in Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer Patients.

BackgroundErlotinib is presently the first line treatment for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) active mutation. An increasing number of evidences show that the treatment efficacy and toxicities are considerably heterogeneous among individuals. Hence, it is necessary to find biological predictors for further individualized treatment of erlotinib in NSCLC patients.MethodsOur present study enrolled 87 cases of NSCLC patients who had been administrated erlotinib with a fixed dose (150 mg/d). Eleven polymorphisms in seven genes of drug-metabolizing enzymes and transporters were genotyped and the steady state trough concentrations were also determined.ResultsThere were significant variances in the steady-state erlotinib trough plasma concentrations, ranging from 315.6 ng/ml to 4479.83 ng/ml. Erlotinib steady state trough concentration was remarkably lower in current smoking patients. The steady state trough concentration of GG in rs1048943 of CYP1A1 was significantly higher than that of AA allele carriers. The polymorphism of CYP1A2 was significantly associated with the severity of skin rash, and the development of diarrhea was associated with SNPs in ABCB1 and CYP3A5. We also observed that GG allele in CYP1A1 was accompanied with a longer PFS in our study.ConclusionA large variability of erlotinib steady state trough concentration was found among Chinese Han population. SNPs in CYP1A1 appeared to influence the steady state trough concentration of erlotinib. Correlation between CYP1A2 polymorphisms and severity of skin rash was observed, together with the correlation between the development of diarrhea and SNPs in ABCB1 and CYP3A5.

The Impact of TRAIL (C1595T and G1525A) and DR4 (rs20576) Gene Polymorphisms on Systemic Lupus Erythematosus.

Apoptosis dysregulation is a distinct hallmark of several disorders like systemic lupus erythematosus(SLE). In fact, SLE has two special features for apoptosis: irregular apoptosis and decline in clearing of apoptotic bodies. Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) is a death ligand that causes toapoptosis via attaching to its receptors such as death receptor-4 (DR4). The present study aimed to evaluate the effects of TRAIL G1525A and C1595T and DR4 A683C(rs20576) gene polymorphisms on SLE development. 160 SLE patients and 160 healthy individuals as the control group participated in the study. Genotype analysis was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). With regard to TRAIL (C1595T) polymorphism, the frequency of CT genotype was significantly higher in the case group than the control with 3-fold increase in SLE development risk (P = 0.0001). Furthermore, the frequency of the TT genotype also was higher in the case group than the control group with 3.2-fold increase in SLE development risk. The allelic distribution analysis defined the T allele as a risk factor for SLE development (P = 0.0001). The frequency of AA genotype and allele A ofTRAIL (G1525A) polymorphismalso was statistically higher in the case group than the control group (P = 0.0001). There was no significant association between DR4 rs20576 polymorphism and SLE development. TRAIL C1595T and G1525A gene polymorphisms are suggested as the risk factors for SLE development, although the results showed no association between DR4 rs20576 polymorphism and SLE.

Glutathione S-transferasesP1 AA (105Ile) allele increases oral cancer risk, interacts strongly with c-Jun Kinase and weakly detoxifies areca-nut metabolites

The Glutathione S-transferases (GSTs) protects cellular DNA against oxidative damage. The role of GSTP1 polymorphism (A313G; Ile105Val) as a susceptibility factor in oral cancer was evaluated in a hospital-based case-control study in North-East India, because the habit of chewing raw areca-nut (RAN) with/without tobacco is common in this region. Genetic polymorphism was investigated by genotyping 445 cases and 444 controls. Individuals with the GSTP1 AA-genotype showed association with the oral cancer (OR = 3.1, 95% CI = 2.4–4.2, p = 0.0002). Even after adjusting for age, sex and habit the AA-genotype is found to be significantly associated with oral cancer (OR = 2.4, 95% CI = 1.7–3.2, p = 0.0001). A protein-protein docking analysis demonstrated that in the GG-genotype the binding geometry between c-Jun Kinase and GSTP1 was disrupted. It was validated by immunohistochemistry in human samples, showing lower c-Jun-phosphorylation and down-regulation of pro-apoptotic genes in normal oral epithelial cells with the AA-genotype. In silico docking revealed that AA-genotype weakly detoxifies the RAN/tobacco metabolites. In addition, experiments revealed a higher level of 8-Oxo-2′-deoxyguanosine induction in tumor samples with the AA-genotype. Thus, habit of using RAN/tobacco and GSTP1 AA-genotype together play a significant role in predisposition to oral cancer risk by showing higher DNA-lesions and lower c-Jun phosphorylation that may inhibit apoptosis.

Association of TERT, OGG1, and CHRNA5 Polymorphisms and the Predisposition to Lung Cancer in Eastern Algeria.

Lung cancer remains the most common cancer in the world. The genetic polymorphisms (rs2853669 in TERT, rs1052133 in OGG1, and rs16969968 in CHRNA5 genes) were shown to be strongly associated with the risk of lung cancer. Our study's aim is to elucidate whether these polymorphisms predispose Eastern Algerian population to non-small-cell lung cancer (NSCLC). To date, no study has considered this association in the Algerian population. This study included 211 healthy individuals and 144 NSCLC cases. Genotyping was performed using TaqMan probes and Sanger sequencing, and the data were analyzed using multivariate logistic regression adjusted for covariates. The minor allele frequencies (MAFs) of TERT rs2853669, CHRNA5 rs16969968, and OGG1 rs1052133 polymorphisms in controls were C: 20%, A: 31%, and G: 29%, respectively. Of the three polymorphisms, none shows a significant association, but stratified analysis rs16969968 showed that persons carrying the AA genotype are significantly associated with adenocarcinoma risk (pAdj = 0.03, ORAdj = 2.55). Smokers with an AA allele have a larger risk of lung cancer than smokers with GG or GA genotype (pAdj = 0.03, ORAdj = 3.91), which is not the case of nonsmokers. Our study suggests that CHRNA5 rs16969968 polymorphism is associated with a significant increase of lung adenocarcinoma risk and with a nicotinic addiction.

Prevalence of K-RAS mutations and CA125 tumor marker in patients with ovarian carcinoma.

Background:Ovarian carcinoma is one of the leading causes of cancer-related death among females. K-ras codon 12 mutations are commonly occurring mutations in different types of cancers and leads to resistance against anti-EGFR therapeutics. Hence, determination of mutations in k-ras gene is crucial for predicting response to anti-EGFR therapies. This study aimed to evaluate the prevalence of k-ras gene mutations and CA125 tumor marker in patients with ovarian carcinoma in Tabriz city.Methods:Genomic DNA was extracted from 67 tissues pertained to women with ovarian carcinoma. Mutations in codon 12 and 13 of k-ras gene were analyzed by Nested PCR and RFLP methods. Titer of CA125 tumor marker was determined by ELISA.Results:Among the 67 patients, 7 patients (10.4%) had mutation in k-ras codon 12 while none of them had mutation in k-ras codon 13. Based on the results, the frequency of various genotypes were 89.55%, 10.44%, and 0%, for GG, GA, and AA alleles, respectively. The p-value for stage I and Grade I tumors were 0.022 and 0.04, respectively, indicating a statistically significant correlation between codon 12 mutation and stage I and Grade I tumors. Furthermore, we found significant correlations among CA125 tumor marker titers and histological grade (p<0.000) and stage (p<0.000). The mean serum CA125 tumor marker levels in malignant carcinomas were 499.84 U/ml.Conclusion:The results in this study indicated high prevalence of k-ras codon 12 mutations and high titer of CA125 tumor marker in patients with ovarian carcinoma in the study region.

Role of Glutathione S-transferase (GSTM1, GSTT1) and CYP1A1 (cytochrome p450) Gene Polymorphisms in Susceptibility to Acute Myeloid Leukemia

Background: Acute myeloid leukemia (AML) may originate from the combination of genetic susceptibility factors and environmental exposure. The aim of this study was to investigate the association of GSTM1 and GSTT1 null genotypes and CYP1A1*2A allele with susceptibility to AML in an Iranian population. Method: In this case-control study, 200 patients with AML and 200 normal individuals as controls were included. GSTM1 and GSTT1 null genotypes were amplified using multiplex PCR and CYP1A1*2A polymorphisms were genotyped by PCR-RFLP. Result: The frequency of GSTM1 null genotype was significantly higher in the control group compared to the case group. The frequency of GSST1 null genotype was significantly lower in the controls. No association was observed between the studied CYP1A1*2A variant and the risk of acute myeloid leukemia. The combination of GSTT1 null genotype and CYP1A1 *2A AA and AC alleles further increased the risk of AML. Conclusion: GSTT1 null genotype can increase the risk of AML, particularly when combined with CYP1A1*2A allele. GSTM1 null genotype can also play a protective role and reduce the risk of AML. However, further studies are required on a larger number of patients.

The genetic component of chronic respiratory diseases in workers of foundry productions

Review of the literature shows that currently there is an accumulation of data on the genetic determination of individual susceptibility to adverse industrial factors. Material of the research were high molecular DNA samples isolated from epithelial mouth scrapings in 99 foundry workers. Study of polymorphic variants of interleukin genes was performed by means of the analysis ofproducts of amplification of specific regions of the genome. Homozygous genotype TNF-a (-308A/G) was established to increase the relative risk of shaping of chronic respiratory diseases: with AA alleles - by 6.4 times and GG alleles - by 2.4 times, while the heterozygous genotype (AG) decreases - by 1. 9 times. Polymorphism of gene IL-1β (+3953 T / C) had no significance for the development of respiratory disease. Genotyping interleukins, involved in the inflammatory responses of the bronchopulmonary tract, can be considered as an element ofprimary prevention in industries with a high risk for shaping of respiratory diseases.

The Study of Polymorphisms Rs3020434, Rs11742635, Rs124577644, Rs12637801, Rs2861221, and Rs17677069 in Women with Familial Uterine Myoma

Study Objective To find genetic markers of family forms of myomas for the optimization of diagnostics, management of patients, and prediction of the risk of recurrence. Design Canadian Task Force: Level II-2. Setting Department of Operative Gynecology, V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Ministry of Health of the Russian Federation. Patients or Participants 106 patients with uterine myoma scheduled for hysterectomy or myomectomy were organized into 3 groups: group 1 with family history of myoma; group 2 without such history; group 3 - patients who did not have information about their anamnesis. 24 women represented the control group. Interventions Patients underwent hysterectomy or myomectomy for symptomatic uterine myoma. Individual fibroids and blood of all patients were collected during the surgery. DNA extraction and genotyping of six loci (rs3020434, rs11742635, rs124577644, rs12637801, rs2861221, rs17677069) of the ESR1, FBN2, CELF4, KCWMB2 genes was undertaken. Measurements and Main Results 130 patients were included in the study (51, 36, and 19 women in the first, second, and third groups respectively and 24 patients in the control group). While rare alleles of polymorphisms rs3020434 (TT), rs11742635 (TT), rs2861221 (GG) and rs17677069 (GG) were not found in patients with familial myoma; common forms of these polymorphisms were found in this group and included: CC allele of rs3020434 polymorphism in 73 % (p=0.003), GG variant of rs11742635 in 82 % (p=0.008), and CC allele of rs2861221 and AA allele of rs17677069 in 82 % of these women (p=0.02 and p=0.001, respectively). Conclusion Rare alleles of rs3020434, rs11742635, rs2861221, and rs17677069 polymorphisms can potentially be protective variants in the development of family forms of uterine myoma. Common alleles identified could increase the risk of development of familial myoma. It may be possible to use these alleles as genetic markers for predicting the development of myoma in women with a family history of this disease.

Association of HLA class II alleles/haplotypes and amino acid variations in the peptide binding pockets with rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune, inflammatory disease, caused by environmental and genetic factors. To elucidate the association of human leukocyte antigen (HLA)-DRB1*/DQB1* alleles/haplotypes and the variations of polymorphic amino acid changes in peptide binding pockets in RA patients from south India. HLA typing was performed in 176 RA patients and 176 healthy controls by polymerase chain reaction-sequence-specific primers method. Strong susceptible association for alleles such as DRB1*04:01(odds ratio [OR]=3.66), 04:06 (OR=3.81), 03:01 (OR=2.93), 06:01 (OR=2.53) and protective association for alleles such as DRB1*13:01 (OR=0.17), 14:01 (OR=0.15), 05:02 (OR=0.17), and 05:03 (OR=0.338) were observed in RA patients. The 2-locus haplotypes such as 04-02:01 (OR=3.844), 04-06:01 (OR=6.57), 07-03:01 (OR=6.16), 07-06:01 (OR=3.42), 12-06:01 (OR=5.24), 15-03:01 (OR=4.69) with susceptible and DRB1*14-DQB1*05:03 (OR=0.078) with protective associations were observed in RA patients. The acid-base analysis revealed that the basic group BB allele was positively associated (OR=2.372) and the acidic group AA allele was negatively associated (OR=0.086). The analysis on shared epitopes has revealed that the combination QKRAA+, (Q)RRAA+ or (Q)RRAA- was positively associated with RA (OR=2.78). The amino acid variation at HLA-DQβ molecule revealed susceptible associations for residues E86 and L87 (P1); E74 (P3); A13 , Y26 , I/S28 , T28 , I71 and E74 (P4); L9 , T30 , D37 and D57 (P9), whereas, the amino acids A86 and T87 (P1); S74 (P3); G13/26 , A71 and S74 (P4); H30 and T37 , S57 (P9), showed protective associations. Alleles DRB1*04:06 and*04:01 showed strong susceptible and DRB1*13:01 and *14:01 showed protective associations in RA patients. The amino acid variations in DQβ molecules revealed significant molecular markers for susceptibility to and protection from RA in south India.

Genetic susceptibility of Iraqis for obesity and type 2 diabetes: LEPR gene polymorphisms

Prevalence of obesity and diabetes over world encouraged researchers to expand their studies about genetic predisposition factors which increase individuals' risk for diseases. LEPR gene encodes for leptin receptor which regulates body weight, energy expenditure and insulin sensitivity by binding with adipose derived hormone (leptin). Therefore we sequenced LEPR's promoter, coding exons, exon-intron boundaries and 3′UTRin 45 Iraqi individuals (24 were diagnosed with type 2 diabetes and 21 were not). Seventeen polymorphisms have been detected in this study, 6 in promoter region, 5 in coding exons, 5 in introns (2 were novel) and I Ins/Del in 3′UTR. Type 2 diabetic carriers of rs1137101 in exon 6 were 75% in comparison to non-diabetics (52.4%). Also 50% and 33.3% from diabetic patients and non-diabetics, respectively were carrying p.S343S in exon 9. GC allele in exon 14 increased the BMI of diabetics to 34.6 ± 7.8 but it was 32.4 ± 4.4 in patients with GG allele and both of them were higher in type 2 diabetics than other group (30.2 ± 5.2 and 29.9 ± 2.5, respectively). BMI of diabetic patients with AA allele (P1019P) in exon 20 was 35.7 ± 4 but it was 32.7 ± 5.9 in patients with GG allele, the same was in non-diabetics which was 33.3 ± 4 and 30 ± 3.7, respectively. Also CTTTA insertion allele increased the BMI of diabetics to 35.7 ± 4 in comparison to CTTTA deletion allele as well as 33.3 ± 4 and 29.6 ± 3.5 in other group, respectively. We have concluded that LEPR polymorphisms may increase the risk of developing type 2 diabetes in individuals with BMI ≥ 30 and in general LEPR is a candidate gene for susceptibility to obesity and its outcomes.

Tumor necrosis factor-α 308G/A and cardiac valves replacement surgery with cardiopulmonary bypass associated acute kidney injury in Chinese Han population

Objective To investigate the effect of polymorphism of tumor necrosis factor-α (TNF-α) 308G/A on the risk of cardiac valves replacement surgery with cardiopulmonary bypass associated acute kidney injury in Chinese Han. Methods A total of 223 consecutive patients who underwent cardiac valves replacement surgery with cardiopulmonary bypass at our institution were prospectively enrolled. Patients were genotyped for TNF-α308G/A (rs1800629). According to the A allele, they were divided into two groups: TNF1 (GG) and TNF2 (GA+ AA), and compared the incidence of postoperative acute kidney injury. Results Genotyping revealed for TNF-α308G/A, 14 patients were carriers of the AA allele (6%), 93 patients GG (42%), and 116 patients GA (52%). The genotype frequency conformed to the hardy-weinberg equilibrium. Demographic characteristics and procedural data revealed no significant differences between genotypes. The incidence of postoperative kidney injury was 33%in TNF1 and 28% in TNF2 respectively. No association between TNF-α308G/A genotypes and the KDIGO criteria could be detected. Conclusion TNF-α308G/A polymorphism is not associated with acute renal injury after cardiac valves replacement surgery with cardiopulmonary bypass. Key words: Tumor necrosis factor-α308G/A polymorphism; Cardiopulmonary bypass; Cardiac valves replacement; Acute kidney injury

Functional rs6265 polymorphism in the brain‐derived neurotrophic factor gene confers protection against neurocognitive dysfunction in posttraumatic stress disorder among Chinese patients with hepatocellular carcinoma

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that plagues trauma survivors. Evidence shows that brain-derived neurotrophic factor (BDNF) may be involved in the occurrence and development of PTSD. Here we tried to demonstrate whether BDNF gene polymorphisms are correlated with neurocognitive function following PTSD in patients with hepatocellular carcinoma (HCC). This study included 102 patients withHCC complicated with PTSD, 146 HCC patients, and 152 healthy volunteers. Initially, we evaluated the neurocognitive function of the study subjects. Next, we measured BDNF G11757C and rs6265 polymorphisms by polymerase chain reaction-restriction fragment length polymorphism. The correlation of BDNF polymorphisms and BDNF level with HCC complicated with PTSD was evaluated. The results revealed that HCC complicated with PTSD showed decreased serum BDNF level and Mini-mental state examination (MMSE) score. Serum BDNF level of HCC and HCC complicated with PTSD was positively correlated with MMSE score. GA + AA allele and A allele of rs6265 increased the risk of PTSD among patients with HCC. GA and AA genotypes of rs6265 were correlated with the decreased MMSE score of HCC complicated with PTSD. Haplotype GA of rs6265 and G11757C increased the risk of PTSD for HCC, while haplotype CG decreased this risk. Lastly, the logistic regression analysis suggested that low BDNF level was a contributor to HCC complicated with PTSD, while GG genotype of rs6265 served as a protective factor. Collectively, this study defines the GG genotype of BDNF rs6265 polymorphism as a protector to HCC complicated with PTSD. In addition, these results provided a promising target for PTSD prevention in patients with HCC.

GSTP1 as a potential predictive factor for adverse events associated with platinum-based antitumor agent-induced peripheral neuropathy.

Glutathione S-transferase (GST) exhibits antidotal effects on numerous drugs, including platinum-based antineoplastic drugs. Furthermore, GST Pi 1 (GSTP1) polymorphism is associated with peripheral neuropathy. In the present study, it was determined whether GSTP1 can predict adverse events associated with platinum-based antitumor agent-induced peripheral neuropathy among Japanese patients. The subjects included 122 patients, among whom 105 patients had colorectal, 16 had gastric, and one patient had pancreatic cancer. It was indicated that wild type (AA) GSTP1 was expressed in 99 patients (81.1%), whereas heterozygous (AG) and homozygous (GG) GSTP1 polymorphisms were present in 22 (18.0%) and 1 (0.8%) patients, respectively. Among patients with colorectal cancer, the expression of homozygous GSTP1 was observed in 88 patients (83.8%), whereas that of heterozygous GSTP1 was observed in 17 patients (16.2%). Peripheral neuropathy of grade ≥3 occurred in 10 patients (9.5%) receiving mFOLFOX therapy (a biweekly cycle consisting of a 2-h infusion of 85 mg/m2 oxaliplatin and 200 mg/m2 leucovorin followed by a bolus administration of 400 mg/m2 5-fluorouracil and a continuous 48-h infusion of 2,400 mg/m2 5-fluorouracil) for colorectal cancer, which included 6 patients with the AA allele (6.8%) and 4 patients with the AG allele (23.5%). The number of peripheral neuropathy cases of grade ≥3 was increased among patients with the AG allele, compared with patients with the AA allele (P=0.032). In patients with gastric cancer, the AA and AG types of GSTP1 were expressed in 11 (68.8%) and 5 (31.2%) patients, respectively. Cisplatin, administered to patients with gastric cancer, did not induce peripheral neuropathy. The aforementioned indicated that GSTP1 genetic polymorphism is associated with peripheral neuropathy induced by oxaliplatin treatment for colorectal cancer, and therefore serves as a predictive marker. Furthermore, early dose reduction or drug withdrawal should be implemented depending on the severity of peripheral neuropathy as a potential method for reducing the number of patients discontinuing the drug, due to adverse events involving peripheral neuropathy.

Budding yeast Rtt107 prevents checkpoint hyperactivation after replicative stress by limiting DNA damage

Cells respond to DNA damage by activating cell cycle checkpoints, arresting cell division or DNA replication while damage is repaired. In Saccharomyces cerevisiae, activation of the checkpoint kinase Rad53 leads to cell cycle arrest, with Rad53 deactivation required for proper resumption of the cell cycle. Rtt107 is a S. cerevisiae protein that acts as a scaffold in the response to DNA damage, and rtt107Δ mutants exhibit prolonged activation of Rad53 when subjected to replication stress. This phenotype has been attributed to checkpoint dampening, wherein an Rtt107-Slx4-Dpb11 interaction limits formation of a Rad9-Dpb11 complex that promotes Rad53 activation. However, we found that the rtt107Δ mutant contains higher levels of DNA damage during replication stress, presenting an alternative possible cause of Rad53 hyperactivation. We therefore sought to address the relevance of checkpoint dampening to the Rad53 hyperactivation phenotype of the rtt107Δ mutant by using a rad9-ST462,474AA allele that specifically disrupts Rad9-Dpb11 interaction. Incorporation of the rad9-ST462,474AA allele slightly suppressed the rtt107Δ mutant’s DNA damage sensitivity phenotypes, while having little effect on Rad53 hyperactivation. This indicated that in the context of acute replication stress, Rad53 hyperactivation in the rtt107Δ mutant did not primarily result from Rad9-Dpb11 interaction. A H2A-S129A mutation, which generally reduces Rad9-mediated Rad53 activation, led to more robust suppression of rtt107Δ mutant phenotypes. Suppression of rtt107Δ mutant DNA damage sensitivity by the H2A-S129A or the rad9-ST462,474AA alleles required intact DNA damage tolerance pathways, indicating a reliance of the rtt107Δ mutant on tolerance pathways for reasons other than misregulation of Rad53 activity. Collectively, this work proposed a revised model of Rad53 hyperactivation after acute replicative stress in the rtt107Δ mutant, in which this phenotype was primarily a consequence of excess DNA damage.