Association Of Specific Genotypes Research Articles

Amoebiasis: Advances in Diagnosis, Treatment, Immunology Features and the Interaction with the Intestinal Ecosystem.

This review of human amoebiasis is based on the most current knowledge of pathogenesis, diagnosis, treatment, and Entamoeba/microbiota interactions. The most relevant findings during this last decade about the Entamoeba parasite and the disease are related to the possibility of culturing trophozoites of different isolates from infected individuals that allowed the characterization of the multiple pathogenic mechanisms of the parasite and the understanding of the host-parasite relationship in the human. Second, the considerable advances in molecular biology and genetics help us to analyze the genome of Entamoeba, their genetic diversity, and the association of specific genotypes with the different amoebic forms of human amoebiasis. Based on this knowledge, culture and/or molecular diagnostic strategies are now available to determine the Entamoeba species and genotype responsible for invasive intestinal or extraintestinal amoebiasis cases. Likewise, the extensive knowledge of the immune response in amoebiasis with the appearance of new technologies made it possible to design diagnostic tools now available worldwide. Finally, the understanding of the interaction between the Entamoeba species and the intestinal microbiota aids the understanding of the ecology of this parasite in the human environment. These relevant findings will be discussed in this review.

Rotaviruses in Wild Ungulates from Germany, 2019–2022

Rotavirus A (RVA) is an important cause of diarrhea in humans and animals. However, RVA in wild animals has only scarcely been investigated so far. Here, the presence of RVA in wild ungulates hunted between 2019 and 2022 in Brandenburg, Germany, was investigated using real-time RT-PCR and sequencing of RT-PCR products. By analyzing intestinal contents, RVA-RNA was detected in 1.0% (2/197) of wild boar (Sus scrofa), 1.3% (2/152) of roe deer (Capreolus capreolus), and 2.1% (2/95) of fallow deer (Dama dama) but not in 28 red deer (Cervus elaphus) samples. Genotyping identified G3P[13] strains in wild boar, which were closely related to previously described pig and wild boar strains. Genotype G10P[15] strains, closely related to strains from roe deer, sheep, or cattle, were found in roe deer. The strains of fallow deer represented genotype G3P[3], clustering in a group containing different strains from several hosts. The results indicated a low prevalence of RVA in wild ungulates in Germany. Associations of specific genotypes with certain ungulate species seem to exist but should be confirmed by analyses of more samples in the future.

A genome-wide association study identifies single nucleotide polymorphisms associated with time-to-metastasis in colorectal cancer

BackgroundDifferentiating between cancer patients who will experience metastasis within a short time and who will be long-term survivors without metastasis is a critical aim in healthcare. The microsatellite instability (MSI)-high tumor phenotype is such a differentiator in colorectal cancer, as patients with these tumors are unlikely to experience metastasis. Our aim in this study was to determine if germline genetic variations could further differentiate colorectal cancer patients based on the long-term risk and timing of metastasis.MethodsThe patient cohort consisted of 379 stage I-III Caucasian colorectal cancer patients with microsatellite stable or MSI-low tumors. We performed univariable analysis on 810,622 common single nucleotide polymorphisms (SNPs) under different genetic models. Depending on the long-term metastasis-free survival probability estimates, we applied a mixture cure model, Cox proportional hazards regression model, or log-rank test. For SNPs reaching Bonferroni-corrected significance (p < 6.2 × 10− 8) having valid genetic models, multivariable analysis adjusting for significant baseline characteristics was conducted.ResultsAfter adjusting for significant baseline characteristics, specific genotypes of ten polymorphisms were significantly associated with time-to-metastasis. These polymorphisms are three intergenic SNPs, rs5749032 (p = 1.28 × 10− 10), rs2327990 (p = 9.59 × 10− 10), rs1145724 (p = 3 × 10− 8), and seven SNPs within the non-coding sequences of three genes: FHIT (p = 2.59 × 10− 9), EPHB1 (p = 8.23 × 10− 9), and MIR7515 (p = 4.87 × 10− 8).ConclusionsOur results suggest novel associations of specific genotypes of SNPs with early metastasis in Caucasian colorectal cancer patients. These associations, once replicated in other patient cohorts, could assist in the development of personalized treatment strategies for colorectal cancer patients.

Multiple single nucleotide polymorphism analysis and association of specific genotypes in FHIT, SAMD4A, and ANKRD17 in Indian patients with oral cancer.

Oral cancer has a high incidence primarily because of tobacco chewing habits. However, a small proportion of habitués develop oral cancer, implying a role for genomic variants in its susceptibility. Thirteen single nucleotide polymorphisms (SNPs) in an Indian cohort comprising patients with oral cancer (n = 500) and healthy controls (n = 500) were genotyped using allelic discrimination real-time polymerase chain reaction (PCR). Prevalence of SNPs rs11130760, rs1957358, rs2306058, rs4883543, rs12637722, rs1457115, rs2353292, rs709821, rs2194861, rs4789378, rs3827538, rs2667552, and rs2886093 was determined in the Indian cohort. A significant association of rs11130760 GG (odds ratio [OR] 1.41; 95% confidence interval [CI] 1.08-1.84) and rs1957358 TT (OR 1.44; 95% CI 1.10-1.90) indicated increased risk; whereas rs1957358 TC (OR 0.67; 95% CI 0.53-0.87) and rs2306058 CT (OR 0.72; 95% CI 0.56-0.93) reflected decreased risk. The SNP rs11130760 wild-type (WT) allele G indicated an increased risk for oral cancer (OR 1.38; 95% CI 1.09-1.73), whereas SNP allele T indicated a decreased risk (OR 0.73; 95% CI 0.58-0.92) for oral cancer. Our study identified SNPs with susceptibility to oral cancer in high-risk populations.

Association between COX-2 gene polymorphisms and risk of hepatocellular carcinoma development: a meta-analysis

ObjectiveTo investigate the association between cyclo-oxygenase-2 (COX-2) polymorphism and the risk of hepatocellular carcinoma (HCC) development.DesignSystematic review and meta-analysis of COX-2 polymorphism and risk of HCC development among people with...

Molecular analysis of the integrons of metallo-β-lactamase-producing Pseudomonas aeruginosa isolates collected by nationwide surveillance programs across Japan.

BackgroundWe investigate the evolving molecular epidemiology of metallo-β-lactamase (MBL)-producing Pseudomonas aeruginosa isolates collected in a 100 institution, nationwide surveillance study in Japan from 2004 to 2006.ResultsMBL-producers were detected in 23/996 isolates (2.3%) in 2004 and 21/992 (2.1%) in 2006. Antimicrobial resistance (specifically, carbapenem resistance) rates between two periods did not differ significantly. MBL-producers were more prevalent in urinary tract isolates. blaIMP-1 group was the most predominant (38 isolates, 80%), followed by 3 blaIMP-7, 2 blaIMP-11 group, and 1 blaVIM-1. All MBL genes were identified in 16 different class 1 integrons, most of which were novel to INTEGRALL database. A total of 17 isolates of sequence type (ST) 235, a recognized worldwide drug-resistant lineage, were distributed in 5 geographic regions across Japan. ST235 isolates included a sublineage associated with In113-like integron. ST357 was identified in 14 isolates, 9 of which harboring a sole blaIMP-1 gene cassette (In994) were recovered from Chugoku region in 2004. ST357 isolates with blaIMP-11 group or ST235 with blaIMP-7 emerged in 2006. We also report for the first time the presence of novel fosI gene cassette in strains other than Mycobacterium spp.ConclusionsOur data give an important “snapshot” of the molecular characteristics and dynamics of MBL-producing lineages in P. aeruginosa in Japan. The significant association of specific genotypes and integrons implies that dissemination and transmission of the preexisting resistant lineage, rather than horizontal gene transfer in situ, might largely explain their endemicity.

Association of neuropeptide Y gene rs16147 polymorphism with metabolic syndrome in patients with documented coronary artery disease

Background and aims: There have been few epidemiological studies that have investigated genetic susceptibility to cardiovascular risk associated with the prevalence of metabolic syndrome (MetS). Neuropeptide Y (NPY) is a strong candidate gene for coronary artery disease (CAD). Therefore, the aim of this study was to investigate the association between the NPY gene rs16147 polymorphism and the presence of MetS in a well defined group of Iranian subjects with angiographically-defined CAD.Methods: A cross-sectional study design was used in which a total of 364 patients were recruited; 143 patients with MetS and 221 without MetS were genotyped using the ARMS-PCR technique. Logistic regression analyses were performed to determine the odds ratios (ORs) for the association of specific genotypes with the presence of MetS and related phenotypes.Results: The frequency of the variant G allele of the NPY gene was significantly higher in CAD patients without MetS (p = 0.032). Compared to the AA genotype of the NPY gene, individuals carrying the GG genotype had a reduced risk of MetS (OR = 0.51, 95% CI = 0.27–0.95, p = 0.034).Conclusion: The rs16147 polymorphism may be associated with presence of MetS among subjects with documented CAD. Carriage of NPY A allele in patients with CAD is associated with a higher prevalence of MetS.

Association of Cyclooxygenase 2 Single-Nucleotide Polymorphisms and Hepatocellular Carcinoma in Taiwan

Hepatocellular carcinoma (HCC) is a worldwide neoplasm for which early diagnosis is difficult and the prognosis is usually poor. Overexpression of cyclooxygenase 2 (COX-2) has been suggested to be associated with hepatocarcinogenesis. Although several COX-2 inhibitors have been used in hepatoma therapy, the genetic background between COX-2 and HCC remains largely unknown. In this study, the association of genotypic polymorphisms in COX-2 with HCC was investigated. 298 patients with HCC and 298 healthy controls recruited from the China Medical Hospital in Taiwan were genotyped by a PCR-RFLP method. We have investigated six polymorphic variants of COX-2, including A-1195G, G- 765C, T+8473C, and variants in introns 1, 5 and 6, and analyzed the association of specific genotype(s) with susceptibility to HCC. The results showed that, for each of the six genotypes, no differences un distribution between the HCC and control groups were found. There was neither obvious joint effect of COX-2 G-765C/intron 6 haplotype nor its genotypes with smoking or alcohol consumption on HCC risk. Environmental factors, other than smoking and alcohol drinking, may affect the post-natal expression of COX-2 in the etiology of HCC, which is an outcome of complex genetic and environmental interactions. Moreover , our immunohistochemistrical results indicated that the COX-2 protein was significantly over-expressed in well-differentiated HCC, but not significantly increased in expression in poorly-differentiated HCC. We suggest that COX-2 may be a determinant of the differentiation grade of HCC.

Rapid Genotyping of Cytomegalovirus in Dried Blood Spots by Multiplex Real-Time PCR Assays Targeting the Envelope Glycoprotein gB and gH Genes

Genotyping of cytomegalovirus (CMV) is useful to examine potential differences in the pathogenicity of strains and to demonstrate coinfection with multiple strains involved in CMV disease in adults and congenitally infected newborns. Studies on genotyping of CMV in dried blood spots (DBS) are rare and have been hampered by the small amount of dried blood available. In this study, two multiplex real-time PCR assays for rapid gB and gH genotyping of CMV in DBS were developed. Validation of the assays with 39 CMV-positive plasma samples of transplant recipients and 21 urine specimens of congenitally infected newborns was successful in genotyping 100% of the samples, with gB1 and gB3 being the most prevalent genotypes. Multiple gB and gH genotypes were detected in 36% and 33% of the plasma samples, respectively. One urine sample from a newborn with symptomatic congenital CMV was positive for gB1 and gB2. DBS of congenitally infected newborns (n = 41) were tested using 9 μl of dried blood, and genotypes were detected in 81% (gB) and 73% (gH) of the samples, with gB3 being the most prevalent genotype. No clear association of specific genotypes with clinical outcome was observed. In conclusion, the CMV gB and gH PCR assays were found to be rapid, sensitive for detecting mixed infections, and suitable for direct usage on DBS. These assays are efficient tools for genotyping of CMV in DBS of congenitally infected newborns.

Association of Specific Genotypes in Metastatic Suppressor HTPAP with Tumor Metastasis and Clinical Prognosis in Hepatocellular Carcinoma

The phosphatidic acid phosphatase HTPAP has been defined as a metastatic suppressor of hepatocellular carcinoma (HCC), but little is known about its function or potential applications as a prognostic marker. In this study, we analyzed patterns of HTPAP genetic variation and gene expression in 864 patients who underwent HCC resection, assessing these patterns for correlations to tumor metastasis potential. Focusing on two tagSNPs that were selected (+357G/C and +1838A/G), we found that only the +357G/C genotype was significantly associated with HTPAP mRNA and protein expression levels and the probability of metastasis. In an independent cohort of 665 HCC patients, we determined that the +357G/C genotype was associated with shorter time to recurrence and overall survival. Together, these results indicated that the HTPAP tagSNP +357 GG+GC genotypes may influence HCC metastatic potential and clinical prognosis by down-regulating HTPAP expression. Extending these results, a global expression profiling analysis identified 41 genes including the pro-inflammatory genes IL-8 and TLR2 that were significantly overexpressed in the +357 GG+GC group, as possible coregulated markers with HTPAP. Together, our findings identify an HTPAP genotype and associated gene expression pattern that favors metastasis progression and that could be used to predict tumor metastasis and prognosis in HCC patients.

The Association of Cox-2 Genotypes with Pterygium Formation in Taiwan

The relationship between the cyclooxygenase 2 (Cox-2) gene and pterygium formation is not well understood. In this study, the association and interaction between genotypic polymorphisms in Cox-2 gene and pterygium formation were investigated. 113 patients with pterygium and 400 healthy controls (without pterygium) enrolled from the Chang-Hwa hospital in central Taiwan were genotyped by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Six polymorphic variants of Cox-2 were selected from the NCBI website and investigated, including G-1195A, G- 765C, T+8473C, intron 1, intron 5, and intron 6, and the association of specific genotypes with susceptibility to pterygium was analyzed. The data showed that, none of the Cox-2 G-1195A, G-765C, T+8473C, intron 1, intron 5, and intron 6 were found to have difference in the distribution between the pterygium and the control groups (P＞0.05). These findings suggest that, Cox-2 may have only post-transcriptional or post-translational regulatory effects on pterygium formation, not at the genetic level.

A Grand Challenge for Genetics of Aging: Adding Healthy Years to Our Lives

A Grand Challenge for Genetics of Aging: Adding Healthy Years to Our Lives

Lung cancer susceptibility and genetic polymorphism of DNA repair gene XRCC4 in Taiwan

Non-homologous end-joining (NHEJ) system is a major route in repairing double strand breaks (DSBs), and is important in maintaining the genome stability. The gene XRCC4 is a central role of the NHEJ system, and it is critical in carcinogenesis. In order to reveal the association between XRCC4 and lung cancer, we recruited 164 lung cancer patients and 649 healthy controls from central Taiwan, investigated seven novel polymorphic variants of XRCC4, includes C-1622T (rs7727691), G-1394T (rs6869366), G-652T (rs2075685), C-571T (rs2075686), intron3 DIP (rs28360071), S247A (rs3734091) and intron7 DIP (rs28360317), and analyzed the association of specific genotype with lung cancer susceptibility. The results showed that the XRCC4 G-1394T is significant in Taiwanese lung cancer and the GT genotype of G-1394T is an obvious risk factor of lung cancer susceptibility (P=0.0049), and the G allele is a risky factor (P=0.0087). As for XRCC4 C-1622T (rs7727691), G-652T (rs2075685), C-571T (rs2075686), intron3 DIP (rs28360071), S247A (rs3734091) and intron7 DIP (rs28360317) polymorphism sites, there was no difference in the distribution between the lung cancer and control groups. The analyzing results of joint effect for smoking habit and XRCC4 G-1394T polymorphism was that people with GT genotype and smoking habit present the highest risk of lung cancer than other groups (OR=2.31, 95% CI=1.43-3.72). The G allele of the XRCC4 G-1394T may be responsible for lung carcinogenesis and maybe useful in early detection and prevention of lung cancer.

Cell Culture Modeling of Genotype-Directed Sensitivity to Selective Kinase Inhibitors: Targeting the Anaplastic Lymphoma Kinase (ALK)

Selective kinase inhibitors have emerged as an important class of cancer therapeutics. The clinical success of drugs such as imatinib, erlotinib, and lapatinib, together with findings demonstrating the important relationship between specific tumor genotypes and clinical response to these agents, also has brought to the forefront the concept of "personalized cancer medicine." The potential broader significance of this relationship has been further highlighted in preclinical studies using tumor-derived cell lines as a model system that can faithfully recapitulate the association of specific genotypes with drug sensitivity, suggesting the utility of cancer cell lines to identify novel candidate biomarkers for predicting clinically responsive patient subsets for newly developed anticancer agents. The case of the anaplastic lymphoma kinase (ALK) nicely exemplifies this, and cell line profiling has revealed that ALK mutations present in a subset of anaplastic large cell lymphomas (ALCLs), non-small cell lung cancers (NSCLCs), and neuroblastomas appear to sensitize cancer cells to treatment with selective ALK kinase inhibitors. Such findings suggest that genotype-based stratification of cancer patients for treatment with selective kinase inhibitors, even across multiple diseases of distinct tissue origin, may be essential for maximizing their clinical benefit.

Toll-like receptor 4 gene polymorphisms and myocardial infarction: no association in a Caucasian population

The toll-like receptor 4 (TLR4) is predominantly known for its role as an important mediator of immune reactions and has been implicated in the initiation, progression, and plaque destabilization stages of atherosclerosis. We investigated whether genotypes and haplotypes of the 896A/G (Asp299Gly; rs4986790) and 1196C/T (Thr399Ile; rs4986791) single nucleotide polymorphisms of the gene encoding the TLR4 were associated with myocardial infarction (MI) in a large Caucasian sample. The case group included 3657 patients with MI and the control group comprised 1211 individuals with angiographically normal coronary arteries and without signs or symptoms of MI. Genotypes were determined with the use of TaqMan assays. Genotype distributions of the 896A/G and 1196C/T polymorphisms were not significantly different between the control and patient groups (P> or =0.30). The frequencies of haplotypes defined by the 896A/G and 1196C/T polymorphisms were similar between the control group and the patient group (P> or =0.16). In addition, the distributions of haplotype-defined genotypes (diplotypes) were not significantly different between the control group and the patient group (P> or =0.12). Separate analyses in women and men did not reveal sex-related associations of specific genotypes or haplotypes of the polymorphisms with MI (P> or =0.11). The results indicate that the 896A/G and 1196C/T polymorphisms of the TLR4 gene or haplotypes based on these polymorphisms are not associated with MI.

No Replication of Association Between Estrogen Receptor α Gene Polymorphisms and Susceptibility to Myocardial Infarction in a Large Sample of Patients of European Descent

Background— The effects of estrogen on blood vessels are partly due to changes in vascular cell gene expression and protein synthesis that are mediated by estrogen receptors. In previous association studies, the −397T/C (rs2234693) and −351A/G (rs9340799) single nucleotide polymorphisms in the estrogen receptor α gene ( ESR1 ) have been implicated in the risk of coronary atherosclerosis and myocardial infarction. To test these findings, we examined the relationship of the polymorphisms to myocardial infarction in a large sample of white patients and control individuals of predominantly European descent. Methods and Results— The case group included 3657 patients with myocardial infarction, and the control group comprised 1211 individuals with angiographically normal coronary arteries and without signs or symptoms of myocardial infarction. TaqMan assays were used for the determination of genotypes. Genotype distributions of the −397T/C and −351A/G polymorphisms were not significantly different between the control and patient groups ( P ≥0.85). The frequencies of haplotypes defined by the −397T/C and −351A/G polymorphisms were similar in the control group and the patient group ( P =0.42). In addition, the distributions of haplotype-defined genotypes (diplotypes) were not significantly different between the control group and the patient group ( P =0.81). Separate analyses in women and men did not reveal sex-related associations of specific genotypes or haplotypes of the polymorphisms with myocardial infarction ( P ≥0.25). Conclusions— The results indicate that the −397T/C and −351A/G polymorphisms of ESR1 or haplotypes based on these polymorphisms are not associated with myocardial infarction in a white population.

Association of specific genotype and haplotype of p53 gene with cervical cancer in India

Background: The predictive value of codon 72 arginine homozygosity at the p53 gene for human papilloma virus associated cervical cancer risk remains inconclusive. It has also been proposed that the...

Impact of genotypic variation of Borrelia burgdorferi sensu stricto on kinetics of dissemination and severity of disease in C3H/HeJ mice.

Various genotypes of Borrelia burgdorferi sensu stricto have been previously identified among a large collection of isolates cultured from patients with Lyme disease in the United States. Furthermore, association of specific genotypes with hematogenous dissemination early in the disease course has been observed. The present study assessed kinetics of spirochete dissemination and disease severity in C3H/HeJ mice infected with two different genotypes of B. burgdorferi. Spirochete load in plasma and ear and other tissue samples of infected mice was measured by quantitative PCR, and these data were compared to those obtained by culture and histopathologic analysis. In mice infected with isolate BL206 (a type 1 strain), the peak number of spirochetes was observed in plasma between day 4 and 7, in heart and ear tissue on day 14, and in joints on day 28 postinoculation. There was a correlation between the peak number of spirochetes in plasma on day 4 or 7 and that in ear biopsy and joint specimens on day 14. By contrast, spirochete burdens in plasma of mice infected with isolate B356 (a type 3 strain) were 16- and 5-fold lower than those of BL206-infected mice on days 7 and 14 of infection, respectively. Similarly, approximately 6- and 13-fold fewer spirochetes were detected in the heart tissues of B356-infected mice compared to BL206-infected mice. Histopathologically, severe arthritis and aortitis were noted only in mice infected with isolate BL206. Spirochete dissemination and disease severity vary significantly in mice infected with distinct genotypes of B. burgdorferi, suggesting that genotypic differences in the infecting spirochetes play a key role in the pathogenesis and development of clinical disease.

The polymorphism of the immunoglobulin heavy chain switch region gene in IgA nephropathy, Henoch-Schönlein nephritis and idiopathic nephrotic syndrome.

It is well known genetic predisposition may play an important role in the pathogenesis of renal diseases. Recently, there has been some controversy about the possible role of the polymorphism of the immunoglobulin heavy chain switch region gene. We have studied this gene by SstI restriction fragment length polymorphisms using DNA from 41 children with IgA nephropathy, 44 with Henoch-Schönlein nephritis and 60 with idiopathic nephrotic syndrome. There was no association of specific genotype with these diseases, in contrast to previous reports. These results are probably due to the differing genetic background of Japanese and Caucasoid patients as far as the switch region is concerned; no switch region genotype constitutes a genetic risk factor for the Japanese in these diseases.