Carrying Susceptibility Genes Research Articles

Functional Alterations in Patients with Bipolar Disorder and Their Unaffected First-Degree Relatives: Insight from Genetic, Epidemiological, and Neuroimaging Data.

Bipolar disorder (BD) profoundly affects cognitive and psychosocial functioning, leading to a significant illness burden on patients and their families. Genetic factors are predominant in the onset of bipolar disorder and functional impairments. This disorder exhibits a strong family aggregation, with heritability estimates reaching up to 80%. Individuals with BD often experience impaired functioning, especially in significant areas such as physical performance, sleep, cognition, interpersonal interactions, socioeconomic status, family and marital relationships, work and school performance, well-being, and life expectancy. However, patients with different subtypes exhibit significant heterogeneity in social functioning, cognition, and creativity levels. There are notable differences in psychosocial and cognitive function in their unaffected first-degree relatives (UFR) who do not suffer but may carry susceptibility genes compared to healthy control (HC) without a family history. The observations indicate common genetic structures between BD patients and their UFR, which results in varying degrees of functional abnormalities. Therefore, this article mainly provides evidence on cognition, creativity, and psychosocial functioning in patients with BD and their UFR to provide a more comprehensive understanding of this critical topic in the field of BD. By integrating various findings, including clinical data and neuroimaging studies, our article aims to provide insights and valuable information for a deeper exploration of the pathogenesis of BD and the development of more targeted therapeutic strategies in the future.

A Review on Positron Emission Tomography in Treatment of Alzheimer Disease

Positron Emission Tomography (PET) is a noninvasive imaging technique and it allows the visualization of molecular processor and the early disease was detected and it is also used to measure the metabolic activity of the cells of the body tissues. It is a combination of nuclear medicine and combined biochemical elements. Alzheimer's disease (AD) is a neurodegenerative disorder, which causes memory loss and other functional disorders. Amyloid is an abnormal protein that is produced by your bone marrow and settled in any tissue or any organ. In this, we go to see, its advantage, disadvantage, and its applications for diagnosis of Alzheimer disease & amyloid fibrils in the human body. The study of PET proves the demonstration of the abnormalities maybe, cause in the prodromal stages of AD and cause damage, which carrying susceptibility genes. PET which radiotracers and neuropathological specifications are crucial to determine amyloid and to assess treatment response in clinical tests. The majority of these test examinations in AD patients have focused on AD imaging technic, and several ‘non-amyloid' substances are radiopharmaceuticals used for evaluating neurodegeneration, neuroinflammation, and excitations given by neurotransmission across the spectrum of AD, potentially examine to improve the therapeutic perspectives for Alzheimer disease (AD).

Housing laboratory mice deficient for Nod2 and Atg16l1 in a natural environment uncovers genetic and environmental contributions to immune variation

Abstract The relative contributions of genetic and environmental factors to variation in immune responses are still poorly understood. Here, we performed a deep phenotypic analysis of immunological parameters of laboratory mice released into an outdoor enclosure, carrying susceptibility genes (Nod2 and Atg16l1) implicated in the development of inflammatory bowel diseases. Variations of immune cell populations were largely driven by environment, whereas cytokine production in response to stimulation was affected more by genetic mutations. Multi-omic models identified transcriptional signatures associated with differences in T cell populations. Subnetworks associated with responses against Clostridium perfringens, Candida albicans and Bacteroides vulgatus were also coupled with rewilding. Hence, exposing laboratory mice carrying different genetic mutations to a natural environment uncovered important contributors to immune variation.

Rewilding Nod2 and Atg16l1 Mutant Mice Uncovers Genetic and Environmental Contributions to Microbial Responses and Immune Cell Composition

The relative contributions of genetic and environmental factors to variation in immune responses are poorly understood. Here, we performed a phenotypic analysis of immunological parameters in laboratory mice carrying susceptibility genes implicated in inflammatory bowel disease (IBD) (Nod2 and Atg16l1) upon exposure to environmental microbes. Mice were released into an outdoor enclosure (rewilded) and then profiled for immune responses in the blood and lymph nodes. Variations of immune cell populations were largely driven by the environment, whereas cytokine production elicited by microbial antigens was more affected by the genetic mutations. We identified transcriptional signatures in thelymph nodes associated with differences in Tcell populations. Subnetworks associated with responses against Clostridium perfringens, Candida albicans, and Bacteroides vulgatus were also coupled with rewilding. Therefore, exposing laboratory mice with genetic mutations to a natural environment uncovers different contributions to variations in microbial responses and immune cell composition.

Особенности взаимодействия генов TSN1-SnTOXA и SNN1-SnTOX1 в патосистеме Triticum aestivum - Stagonospora nodorum

The virulence of the causal agent of Septoria nodorum blotch of wheat pathogenic fungus Stagonospora nodorum Berk. is caused by the presence of necrotrophic effectors (SnTox). Isolates infect wheat varieties that carry susceptibility genes (Snn) corresponding to toxins in the genome. SnTox-Snn interactions are mirror images of classical gene-for-gene interactions and lead to the development of disease. In the present work, we have studied SnTox-Tsn1 and SnTox1-Snn1 interactions resulting in development of necrosis and chlorosis in wheat plant tissues with the formation of extensive lesions. It is assumed that the multiplicity of SnTox-Snn reactions can be carried out through the regulation of transcription of plant susceptibility genes. The aim of the work was to study the transcriptional activity of the Tsn1 and Snn1 susceptibility genes in wheat varieties with varying degrees of resistance to S. nodorum. Alleles of the Tsn1 and Snn1 susceptibility genes were identified by PCR in 12 varieties of winter and spring wheat. Seedling resistance was determined for all samples by the lawns method. Then five varieties were selected for further study. The resistance of the Omskaya 35 variety, which carries a single dominant Snn1 allele, was determined by the suppression of transcription of the Snn1 gene by almost 2 times. The resistance of the Yubileynaya 100 variety, which carries two dominant alleles Tsn1/Snn1, was determined by suppression of transcription of the Tsn1 gene by 8 times. The resistance of the Esaul and Yermak varieties, as well as the susceptibility of the Zhnitsa variety, were determined not only by the transcriptional activity of the Tsn1 gene, but possibly by other factors. A statistically significant positive correlation of 0.97 was found between the transcription level of the Tsn1 gene and the resistance of the variety.

High Prevalence of Hereditary Cancer Syndromes and Outcomes in Adults with Early-Onset Pancreatic Cancer.

Introduction: We aimed to determine the prevalence and landscape of germline mutations among patients with young-onset pancreatic ductal adenocarcinoma (PDAC) as well as their influence in prognosis.Methods: Patients from two cohorts were studied, the high-risk cohort (HRC), which included 584 PDAC patients who received genetic counseling at The University of Texas MD Anderson Cancer Center, and a general cohort (GC) with 233 metastatic PDAC patients. We defined germline DNA sequencing on 13 known pancreatic cancer susceptibility genes. The prevalence and landscape of mutations were determined, and clinical characteristics including survival were analyzed.Results: A total of 409 patients underwent genetic testing (277 from HRC and 132 from GC). As expected, the HRC had higher prevalence of germline mutations compared with the GC: 17.3% versus 6.81%. The most common mutations in both cohorts were in BRCA1/2 and mismatch-repair (MMR) genes. Patients younger than 60 years old had significantly higher prevalence of germline mutations in both the HRC [odds ratios (OR), 1.93 ± 1.03-3.70, P = 0.039] and GC (4.78 ± 1.10-32.95, P = 0.036). Furthermore, PDAC patients with germline mutations in the GC had better overall survival than patients without mutations (HR, 0.44; 95% CI of HR, 0.25-0.76, P = 0.030).Discussion: Germline mutations are highly prevalent in patients with PDAC of early onset and can be predictive of better outcomes. Considering emerging screening strategies for relatives carrying susceptibility genes as well as impact on therapy choices, genetic counseling and testing should be encouraged in PDAC patients, particularly those of young onset. Cancer Prev Res; 11(11); 679-86. ©2018 AACR.

VIRAL DIABETES: VIRUS DIABETOGENICITY AND HOST SUSCEPTIBILITY

Diabetes mellitus (DM) is on the rise worldwide, and is associated with improvement in socioeconomic conditions, increasing wealth, high caloric and fat intake, and reduced physical activity. Accumulating evidence also suggests a causal/triggering link with environmental factors, such as toxins and viruses. A variety of viral infections have been associated with the development of diabetes. There might be no ‘diabetes virus’, but there might be a variety of ‘diabetogenic viruses’ that contribute to diabetes in people who are particularly susceptible due to genetic or physiologic conditions. Increasing evidence is showing that human enteroviruses (EVs) are prominent among possible causal candidates for type 1 diabetes mellitus (T1D). However, evidence for diabetogenicity of viruses is still missing. For a pathogen, causality should fulfill the etiologic criteria known as ‘modified Koch’s postulates’. Recently, we presented evidence that mutations of Tyk2 gene are responsible for diabetes susceptibility of mice infected with the diabetogenic D strain of encephalomyocarditis virus (EMC-D). Observations have been extended to identify the human polymorphism of TYK2 gene associated with increased risk for virus-induced diabetes in humans. An update is given on the possible diabetogenic role of EVs with reference to experimental work in animals and to human studies (viral serology, pancreas histopathology, virus detection in blood and in tissues of diabetic patients). For the identification of a diabetogenic virus, the development of a sensitive experimental model is imperative. In vivo assay systems should include an animal model appropriately simulating a susceptible human and carrying susceptibility genes or factors. This work summarizes current knowledge on virus-induced diabetes together with evidence from experimental models, susceptibility genes in mice, candidate diabetogenic viruses and susceptibility genes in humans. Perspectives on the identification of diabetogenic viruses - which may possibly lead to innovative strategies for the cure or prevention of diabetes – are also presented.

Polymorphisms in the CTNND2 Gene and 11q24.1 Genomic Region Are Associated with Pathological Myopia in a Chinese Population

Pathological myopia is a refractive error that can result in legal blindness and is prevalent in China. A number of genomic loci have been associated with pathological myopia, but only a few have been validated. This study further evaluated the association of polymorphisms in the CTNND2 gene and the 11q24.1 genomic region with pathological myopia. Both regions had previously been implicated in carrying susceptibility genes for this eye disorder. Genotypic and association analyses were performed on 24 single-nucleotide polymorphisms (SNPs) in the CTNND2 and 11q21.1 genomic regions of 321 subjects with pathological myopia and 310 control subjects with normal vision using matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Allele and genotype frequency analyses found that the distribution of variants of the SNP rs1479617 located in the CTNND2 gene significantly differed between the pathological myopia and control groups. Haplotype linkage analysis identified 2 genomic blocks in 11q24.1 that were independently associated with pathological myopia. Specific polymorphisms in the CTNND2 gene and 11q24.1 genomic region were found to be significantly associated with pathological myopia in this Chinese population, further supporting the idea that these genomic regions carry susceptibility loci for this disease.

Mitochondrial DNA origins of the Latvian clefting population

Latvia has one of the highest prevalence of isolated cleft lip with or without cleft palate (CL/P) in Europe. To clarify the genetic origins of the Latvian cleft population and establish a method for genetic mapping, mitochondrial DNA variation was studied in a population affected with clefting. One-hundred and seven subjects and 351 samples from unrelated healthy volunteers representing four anthropologically, archaeologically and ethno-linguistically different regions of Latvia were selected. The case group showed a higher frequency of haplogroups U4 (p = 0.02) and U5 (p = 0.0003) than in non-U haplogroups. We hypothesize that U4 and U5 mtDNA haplotype carriers may also carry susceptibility genes for clefts. Future studies will take into consideration these definitions based on mtDNA haplotypes when analyzing genetic variations and their possible contribution to CL/P susceptibility.

Exploration of the postponing mechanism that delays carcinoma onset

The average age at onset of malignancies arising from epithelial tissues is between 40 and 70 years old even in familial cancers. Although it is believed that the accumulation of multiple genetic alterations is needed for cancer onset, we hypothesize--based on the diversity of ages at onset for most types of epithelial cancer--that there is a postponing mechanism inside the human body that significantly delays the process of carcinogenesis. The key molecules controlling the cancer onset, here called "postponers", are hypothesized to be functioning in the individuals carrying susceptibility genes. As a consequence, cancers occur in middle age or even old age, with several decades of cancer-free lifetime for the patient. Genome-wide association studies and genomic expression profiling are suggested to identify candidate postponers. Hypothetic gene expression patterns for identifying candidate postponers are illustrated. Animal models will be helpful to test whether the absence or presence of the postponer molecules can alter the onset age of spontaneous tumors. If this hypothesis is true, by amplification of the postponing mechanism we might be able to significantly delay the onset of tumors, so that individuals carrying cancer susceptibility traits could gain an additional significant period of cancer-free life. Moreover, destructive prophylactic surgeries, e.g., for women who have BRCA1/2 gene mutations, might be avoided.

Incomplete penetrance of susceptibility genes for MHC-determined immunoglobulin deficiencies in monozygotic twins discordant for type 1 diabetes

Incomplete intrinsic penetrance is the failure of some genetically susceptible individuals (e.g., monozygotic twins of those who have a trait) to exhibit that trait. For the first time, we examine penetrance of susceptibility genes for multiple MHC gene-determined traits in the same subjects. Serum levels of IgA, IgD, IgG3, but not IgG4, in 50 pairs of monozygotic twins discordant for type 1 diabetes (T1D) correlated more closely in the twins than in random paired controls. The frequencies of subjects deficient in IgA (6%), IgD (33%) and IgG4 (12%), but not in IgG3, were higher in the twins than in controls. We postulate that this was because the MHC haplotypes (and possible non-MHC genes) that predispose to T1D also carry susceptibility genes for certain immunoglobulin deficiencies. Immunoglobulin deficiencies were not associated with T1D. Pairwise concordance for the deficiencies in the twins was 50% for IgA, 57% for IgD and 50% for IgG4. There were no significant associations among the specific immunoglobulin deficiencies except that all IgA-deficient subjects had IgD deficiency. Thus, intrinsic penetrance is a random process independently affecting different MHC susceptibility genes. Because multiple different external triggers would be required to explain the results, differential environmental determinants appear unlikely.

Neuroimaging and early diagnosis of Alzheimer disease: a look to the future.

Alzheimer disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia in the elderly. Current consensus statements have emphasized the need for early recognition and the fact that a diagnosis of AD can be made with high accuracy by using clinical, neuropsychologic, and imaging assessments. Magnetic resonance (MR) or computed tomographic (CT) imaging is recommended for the routine evaluation of AD. Coronal MR images can be useful to document or quantify atrophy of the hippocampus and entorhinal cortex, both of which occur early in the disease process. Both volumetric and subtraction MR techniques can be used to quantify and monitor dementia progression and rates of regional atrophy. MR measures are also increasingly being used to monitor treatment effects in clinical trials of cognitive enhancers and antidementia agents. Positron emission tomography (PET) and single photon emission CT offer value in the differential diagnosis of AD from other cortical and subcortical dementias and may also offer prognostic value. In addition, PET studies have demonstrated that subtle abnormalities may be apparent in the prodromal stages of AD and in subjects who carry susceptibility genes. PET ligands are in late-stage development for demonstration of amyloid plaques, and human studies have already begun. Functional MR-based memory challenge tests are in development as well.

Screening for cancer in high-risk families.

To review screening for cancer in high risk families.Screening for hereditary cancer involves three steps: it is first necessary to identify families at high risk by examining the number and sites of cancer in a family. Special attention is given to cancers appearing at an early age, to unusual sites, and multiple primary cancers. Second, a molecular diagnostic test is performed in order to identify family members who carry a mutant copy of the suspected gene. DNA-based diagnostic testing is now available for hereditary breast-ovarian cancer, for hereditary nonpolyposis colon cancer, for Gardner syndrome (familial polyposis coli), for neurofibromatosis, multiple endocrine neoplasia, and for Von-Hippel Lindau disease. Third, individuals found to carry susceptibility genes are offered screening for the early detection of tumours. Some screening methods are in conventional use (e.g., colonoscopy and mammography); others are reserved for the investigation of familial cancers (e.g., pentagastrin challenge test).A comprehensive clinic for hereditary cancer must consider all three phases of the screening program and will provide expert genetic counselling to family members involved in the process.

Association studies of a polymorphism in the Wilms' tumor 1 locus in Norwegian patients with testicular cancer.

One strategy for identifying genes involved in genetic predisposition to testicular germ-cell tumors (TC) is to perform association studies with polymorphic loci at or closely linked to candidate genes. Genes involved in normal fetal genital development, such as the Wilms' tumor 1 gene (WT1) located at 11p13, are among such candidates. The present study compares a TC (n = 442) and a control (n = 384) population for the allele frequencies of 2 polymorphic loci located at chromosome band 11p13. One of the polymorphisms (WT) was located within and the other (D11S325) in close proximity to the WT1 gene. No differences in allele frequencies between cancer patients and controls were found. However, the frequency of the Al allele of the WT polymorphism was significantly increased in one of the cancer subgroups most likely to carry susceptibility genes (patients with bilateral cancer) compared to controls. Furthermore, the frequency of the Al allele was increased in patients with metastatic disease. Such differences in allele frequencies were not observed for the D11S325 locus. The findings might indicate an involvement of the WT1 gene both in susceptibility to TC and in progression of the disease.