Crucial Role In Susceptibility Research Articles

Breast cancer: Risk factors and prevention strategies

Among the cancer diseases, breast cancer is becoming fast growing leading cause of oncologic mortality among women. It is hoped that, evaluation of different dimensions of breast cancer and its associated factors such as environmental and genetic factors, will increase the efforts of prevention. Current studies suggest that mutations in some genes play an crucial role in susceptibility of breast cancer. Thus, researchers aimed to isolate such breast cancer susceptible genes. Some epidemiologic studied also suggested that, moderate to vigorous exercise for 3-4 hours per week can lower the risk for breast cancer for 30%-40% in women than those of the sedentary women. Obese or overweight women have 50%-250% greater risk for breast cancer after menopause. Alcohol use also increases the risk of both postmenopausal and premenopausal breast cancer. Thus, these trends of sedentary lifestyle, decreasing physical activity and increasing obesity may lead to an increase in the incidence of breast cancer. Thus, adoption of healthy food habits, increasing physical activity and changes in sedentary lifestyle may have a great impact on the prevalence of this disease in future. The treatment strategies for breast cancer are broad-ranging depending on tumor’s biology; stages of the disease; tolerance, and acceptance of the patient. There is various treatment approaches of breast cancer such as radiology, surgery, and systematic therapy (chemotherapy, endocrine therapy and biological therapy) etc. In this article required information about risk factors and current breast cancer prevention strategies are collected through literature review.

Ingestion of Faecalibaculum rodentium causes depression-like phenotypes in resilient Ephx2 knock-out mice: A role of brain–gut–microbiota axis via the subdiaphragmatic vagus nerve

BackgroundThe brain–gut–microbiota axis plays a crucial role in the bidirectional interactions between the brain and the gut. Soluble epoxide hydrolase (coded by the Ephx2 gene) plays an important role in inflammation, which has been implicated in stress-related depression. Ephx2 knock-out (KO) mice exposed to chronic social defeat stress (CSDS) did not show depression-like behaviors, indicating stress resilience. Here we examined whether the brain–gut–microbiota axis influences the resilience in Ephx2 KO mice. MethodsEffects of fecal microbiota transplantation (FMT) from CSDS-susceptible (or control) mice in wild-type (WT) mice and Ephx2 KO mice treated with an antibiotic cocktail (ABX) were investigated. Behavioral, biochemical tests and 16S ribosome RNA analysis were performed. ResultsFMT from CSDS-susceptible mice produced anhedonia-like behavior in ABX-treated WT and Ephx2 KO mice. The 16S ribosome RNA analysis showed that Faecalibaculum rodentium (F. rodentium) may be responsible for the observed anhedonia-like behavior following FMT from CSDS-susceptible mice. Ingestion of F. rodentium for 14 days produced depression- and anhedonia-like behaviors, higher blood levels of interleukin-6, and reduced expression of synaptic proteins in the prefrontal cortex of ABX-treated Ephx2 KO mice. Furthermore, subdiaphragmatic vagotomy blocked the development of these behavioral abnormalities after ingestion of F. rodentium. LimitationsDetailed mechanisms are unclear. ConclusionsThese findings suggest that F. rodentium might contribute to the conversion of resilient Ephx2 KO mice into KO mice with depression-like phenotypes. The brain–gut–microbiota axis via the subdiaphragmatic vagus nerve plays a crucial role in susceptibility and resilience to stress.

Single nucleotide polymorphisms associated with gastric cancer in Iranian patients

Gastric cancer is one of the leading worldwide cancers formed in the lining of the stomach, and is the most prevalent cancer in northern Iran. Recent interventions for the early diagnosis of gastric cancer are based on genetic susceptibility parameters and the interactions between genes and the environment. Accordingly, this narrative review was designed to summarize the genetic markers involved in Iranian patients with gastric cancer, classified by cellular function. There was a significant relationship between single nucleotide polymorphisms (SNPs) in rs1051208 C allele (RAF1), rs531564 (pri-miR-124-1), rs1053023 (STAT3), rs8193 C allele (CD44), rs3130932G allele (OCT4), rs283821943, rs2032586 (ABCB1), codons 72,248 (p53), -137 G/C (IL-18), Pro12Ala (PPARγ), rs1053023 (STAT3), rs4647603 (caspase 3), -712C>T (caspase 9), -1263 A> (caspase 9) and gastric cancer. Increased risk was observed in C677T (MTHFR). Finally, decreased risk of gastric cancer was explored in -938 C>A (bcl2). Asp299Gly (TLR-4), rs1028181-513T/C (IL-19) Pro12Ala (PPARγ) may play a crucial role in susceptibility of Helicobacter pylori and gastric pathogenesis. According to the findings, the genetic polymorphisms in the immune-associated genes were related to the gastric cancer among the Iranian patients. Therefore, further large-scale functional investigations are needed to draw definite conclusions.

Single Nucleotide Polymorphisms of PTPN22 Gene in Iranian Patients with Ulcerative Colitis

Objectives: Protein tyrosine phosphatase non-receptor type 22 gene (PTPN22) single-nucleotide polymorphisms (SNP) have been associated with a number of different autoimmune diseases. This study aimed to investigate the association of five polymorphisms of PTPN22 gene with susceptibility to ulcerative colitis (UC) in Iran.Materials and methods: A total of 67 patients diagnosed with UC (35 female and 32 male all under 18 years) and 93 healthy subjects were selected. The samples were genotyped for the, rs12760457, rs2476601, rs1310182, rs1217414, and rs33996649 in PTPN22 gene using real-time polymerase chain reaction (PCR) allelic discrimination TaqMan genotyping assays.Results: The frequencies of the rs1310182 A and G alleles, and also the AA and GG genotypes were significantly different between the patient and the control groups (p < 0.05). The carriage of G allele of rs1310182 was significantly associated with increased risk of UC (OR (95% CI) = 1.17 (0.70–1.98), p < 0.001). Moreover, the genotype GG of SNP rs1310182 was significantly associated with UC (OR (95% CI) = 2.32 (1.13–4.76), p < 0.01). No association was found between other PTPN22 gene SNPs among UC patients.Conclusion: PTPN22 gene polymorphism in rs1310182 could play a crucial role in susceptibility to UC.

Association of DFNA5, SYK, and NELL1 variants along with HPV infection in oral cancer among the prolonged tobacco-chewers.

Southeast Asia, especially India, is well known for the highest use of smokeless tobacco. These products are known to induce oral squamous cell carcinoma. However, not all long-term tobacco-chewers develop oral squamous cell carcinoma. In addition, germline variants play a crucial role in susceptibility, prognosis, development, and progression of the disease. These prompted us to study the genetic susceptibility to oral squamous cell carcinoma among the long-term tobacco-chewers. Here, we presented a retrospective study on prolonged tobacco-chewers of Northeast India to identify the potential protective or risk-associated germline variants in tobacco-related oral squamous cell carcinoma along with HPV infection. Targeted re-sequencing (n = 60) of 170 genetic regions from 75 genes was carried out in Ion-PGM™ and validation (n = 116) of the observed variants was done using Sequenom iPLEX MassARRAY™ platform followed by polymerase chain reaction-based HPV genotyping and p16-immunohistochemistry study. Subsequently, estimation of population structure, different statistical and in silico approaches were undertaken. We identified one nonsense-mediated mRNA decay transcript variant in the DFNA5 region (rs2237306), associated with Benzo(a)pyrene, as a protective factor (odds ratio = 0.33; p = 0.009) and four harmful (odds ratio > 2.5; p < 0.05) intronic variants, rs182361, rs290974, and rs169724 in SYK and rs1670661 in NELL1 region, involved in genetic susceptibility to tobacco- and HPV-mediated oral oncogenesis. Among the oral squamous cell carcinoma patients, 12.6% (11/87) were HPV positive, out of which 45.5% (5/11) were HPV16-infected, 27.3% (3/11) were HPV18-infected, and 27.3% (3/11) had an infection of both subtypes. Multifactor dimensionality reduction analysis showed that the interactions among HPV and NELL1 variant rs1670661 with age and gender augmented the risk of both non-tobacco- and tobacco-related oral squamous cell carcinoma, respectively. These suggest that HPV infection may be one of the important risk factors for oral squamous cell carcinoma in this population. Finally, we newly report a DFNA5 variant probably conferring protection via nonsense-mediated mRNA decay pathway against tobacco-related oral squamous cell carcinoma. Thus, the analytical approach used here can be useful in predicting the population-specific significant variants associated with oral squamous cell carcinoma in any heterogeneous population.

CAMP-dependent activation of protein kinase A attenuates respiratory syncytial virus-induced human airway epithelial barrier disruption.

Airway epithelium forms a barrier to the outside world and has a crucial role in susceptibility to viral infections. Cyclic adenosine monophosphate (cAMP) is an important second messenger acting via two intracellular signaling molecules: protein kinase A (PKA) and the guanidine nucleotide exchange factor, Epac. We sought to investigate effects of increased cAMP level on the disruption of model airway epithelial barrier caused by RSV infection and the molecular mechanisms underlying cAMP actions. Human bronchial epithelial cells were infected with RSV-A2 and treated with either cAMP releasing agent, forskolin, or cAMP analogs. Structure and functions of the Apical Junctional Complex (AJC) were evaluated by measuring transepithelial electrical resistance and permeability to FITC-dextran, and determining localization of AJC proteins by confocal microscopy. Increased intracellular cAMP level significantly attenuated RSV-induced disassembly of AJC. These barrier-protective effects of cAMP were due to the activation of PKA signaling and did not involve Epac activity. Increased cAMP level reduced RSV-induced reorganization of the actin cytoskeleton, including apical accumulation of an essential actin-binding protein, cortactin, and inhibited expression of the RSV F protein. These barrier-protective and antiviral-function of cAMP signaling were evident even when cAMP level was increased after the onset of RSV infection. Taken together, our study demonstrates that cAMP/PKA signaling attenuated RSV-induced disruption of structure and functions of the model airway epithelial barrier by mechanisms involving the stabilization of epithelial junctions and inhibition of viral biogenesis. Improving our understanding of the mechanisms involved in RSV-induced epithelial dysfunction and viral pathogenesis will help to develop novel anti-viral therapeutic approaches.

Association of the Genetic Polymorphisms RRM1 -756T>C and -269C>A With Cervical Neoplasia.

Cervical neoplasia is one of the most prevalent malignant neoplasms worldwide. Ribonucleotide reductase 1 (RRM1) is thought to play an essential role in modulating the development and progression of cervical neoplasia. Two novel genetic polymorphisms, RRM1 -756T>C and -269 C>A, are significantly correlated with RRM1 expression. Some epidemiological studies have demonstrated that genetic variants play a crucial role in susceptibility to cervical cancer. The present study aimed to identify the genetic polymorphisms RRM1 -756T>C and -269 C>A in patients with cervical neoplasia and healthy controls. In total, 493 subjects, comprising 324 healthy controls and 169 patients with cervical neoplasia, were enrolled for this study. The allelic discrimination of the RRM1 -756T>C (rs11030918) and -269C>A (rs12806698) polymorphisms was assessed using the ABI StepOne™ real-time polymerase chain reaction system and analyzed using Software Design Specification (SDS), Version 3.0, software with TaqMan assays. The risk of cervical cancer was examined, revealing adjusted odds ratios and 95% confidence intervals of 1.25 [0.51, 3.08] and 1.09 [0.43, 2.78] for individuals with CC alleles of RRM1 -756T>C and for individuals with AA alleles of RRM1 -269C>A genetic polymorphisms, respectively, compared to individuals with wild-type RRM1 genetic polymorphisms. No significant genetic interaction effect was observed in susceptibility to cervical neoplasia, and no association was found between genetic polymorphisms and clinical statuses of invasive cervical cancer. The genetic polymorphisms RRM1 -756T>C and -269C>A may not be a factor for susceptibility to cervical neoplasia.

Infant exposure to Chinese famine increased the risk of hypertension in adulthood: results from the China Health and Retirement Longitudinal Study.

BackgroundEarly-life developmental adaptations in response to severe malnutrition may play a crucial role in susceptibility to hypertension. This study aimed to explore the associations between exposure to the Chinese famine (1959–1961) at fetal, infant and preschool stages during fetal life or childhood and the risk of hypertension in adulthood.MethodsWe used the data of 1,966 adults born between 1956 and 1964 in selected families from the China Health and Retirement Longitudinal Study (CHARLS) national survey.ResultsPrevalence of hypertension among adults in non-exposed, fetal-exposed, infant-exposed, and preschool-exposed cohorts was 18.9, 20.7, 28.7, and 23.4 %, respectively. In severely affected famine areas, only infant-exposed cohort had a significant increased risk of hypertension compared with non-exposed cohort (OR 2.12; 95 % CI 1.19, 3.79; P = 0.011), and the significance remained after adjusted gender, smoking, and drinking (OR 2.11; 95 % CI 1.18, 3.77; P = 0.012). After stratification by BMI and economic status, the risk of hypertension was higher for subjects with BMI ≥ 24 kg/m2(OR 2.09; 95 % CI 1.09, 4.01; P = 0.026) or high economic status(OR 2.26; 95 % CI 1.19, 4.31; P = 0.013) than those with BMI < 24 kg/m2(OR 1.65; 95 % CI 0.71, 3.83; P = 0.246) or low economic status (OR 2.18; 95 % CI 1.14, 4.18; P = 0.019) in infant-exposed cohort of severely affected famine areas. However, there was no consistent association observed in less severely affected area or other exposed cohorts in severely affected areas.ConclusionsInfanthood exposed to famine might increase the risk of hypertension in adulthood, and a postnatal ‘rich’ nutrient environment further increased the risk.

Chemokines and chemokine receptors in susceptibility to HIV-1 infection and progression to AIDS.

A multitude of host genetic factors plays a crucial role in susceptibility to HIV-1 infection and progression to AIDS, which is highly variable among individuals and populations. This review focuses on the chemokine-receptor and chemokine genes, which were extensively studied because of their role as HIV co-receptor or co-receptor competitor and influences the susceptibility to HIV-1 infection and progression to AIDS in HIV-1 infected individuals.

Chemokines and Chemokine Receptors in Susceptibility to HIV-1 Infection and Progression to AIDS

A multitude of host genetic factors plays a crucial role in susceptibility to HIV-1 infection and progression to AIDS, which is highly variable among individuals and populations. This review focuses on the chemokine-receptor and chemokine genes, which were extensively studied because of their role as HIV co-receptor or co-receptor competitor and influences the susceptibility to HIV-1 infection and progression to AIDS in HIV-1 infected individuals.

Susceptibility to winter vomiting disease: a sweet matter

Norovirus, the cause of winter vomiting disease, has emerged in recent years to be a major cause of sporadic and epidemic gastroenteritis worldwide. The virus has been estimated to cause >200,000 deaths each year in developing countries. Although the virus is highly contagious, volunteer and field studies have shown that a subset of individuals appears resistant to infections. A single nucleotide mutation (G428A) in the fucosyltransferase gene (FUT2) on chromosome 19 provides strong protection from infection in 20% of the white population. Histo-blood group ABO(H) antigens with terminal fucose are believed to function as receptors for human norovirus in the gastrointestinal tract, but also negatively charged potential receptors have been identified. Norovirus infection is a unique example where a single nucleotide mutation in a fucosyltransferase gene plays a crucial role in susceptibility to one of the most common viral diseases. This review discusses the role of host genetics and carbohydrate structures in susceptibility to winter vomiting disease.

Cost-effective HLA typing with tagging SNPs predicts celiac disease risk haplotypes in the Finnish, Hungarian, and Italian populations

Human leukocyte antigen (HLA) genes, located on chromosome 6p21.3, have a crucial role in susceptibility to various autoimmune and inflammatory diseases, such as celiac disease and type 1 diabetes. Certain HLA heterodimers, namely DQ2 (encoded by the DQA1*05 and DQB1*02 alleles) and DQ8 (DQA1*03 and DQB1*0302), are necessary for the development of celiac disease. Traditional genotyping of HLA genes is laborious, time-consuming, and expensive. A novel HLA-genotyping method, using six HLA-tagging single-nucleotide polymorphisms (SNPs) and suitable for high-throughput approaches, was described recently. Our aim was to validate this method in the Finnish, Hungarian, and Italian populations. The six previously reported HLA-tagging SNPs were genotyped in patients with celiac disease and in healthy individuals from Finland, Hungary, and two distinct regions of Italy. The potential of this method was evaluated in analyzing how well the tag SNP results correlate with the HLA genotypes previously determined using traditional HLA-typing methods. Using the tagging SNP method, it is possible to determine the celiac disease risk haplotypes accurately in Finnish, Hungarian, and Italian populations, with specificity and sensitivity ranging from 95% to 100%. In addition, it predicts homozygosity and heterozygosity for a risk haplotype, allowing studies on genotypic risk effects. The method is transferable between populations and therefore suited for large-scale research studies and screening of celiac disease among high-risk individuals or at the population level.

A functional polymorphism in the IL1B gene promoter, IL1B -31C&gt;T, is not associated with cerebral malaria in Thailand

BackgroundIL-1β and IL-1RA levels are higher in the serum of cerebral malaria patients than in patients with mild malaria. Recently, the level of IL1B expression was reported to be influenced by a polymorphism in the promoter of IL1, IL1B -31C>T.MethodsTo examine whether polymorphisms in IL1B and IL1RA influence the susceptibility to cerebral malaria, IL1B -31C>T, IL1B 3953C>T, and IL1RA variable number of tandem repeat (VNTR) were analysed in 312 Thai patients with malaria (109 cerebral malaria and 203 mild malaria patients).ResultsIn this population, IL1B -31C>T and IL1RA VNTRwere detected, while IL1B 3953C>T (i.e., IL1B 3953T) was not observed in the polymorphism screening for 32 patients. Further analyses for IL1B -31C>T and IL1RA VNTR in 110 cerebral malaria and 206 mild malaria patients showed no significant association of these polymorphisms with cerebral malaria.ConclusionThe present results suggest that IL1B -31C>T and IL1RA VNTR polymorphisms do not play a crucial role in susceptibility or resistance to cerebral malaria.