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Results for “Genetic causality”

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PubMed2003

Proposed pathogenetic cascade of inclusion-body myositis: importance of amyloid-beta, misfolded proteins, predisposing genes, and aging.

PURPOSE OF REVIEW: Sporadic inclusion-body myositis, the most common muscle disease of older persons, is of unknown cause, and there is no successful treatment. Interest in sporadic inclusion-body myositis has been enhanced by the recent identification within the sporadic inclusion-body myositis muscle fibers of several abnormally accumulated proteins, which provides novel and important clues to the pathogenesis of sporadic inclusion-body myositis. RECENT FINDINGS: This article summarizes the most recent findings leading to better understanding of the players in the pathogenetic cascade. It is suggested that lymphocytic inflammatory component is probably secondary, and it may contribute only slightly to muscle fiber damage in sporadic inclusion-body myositis. However, it is proposed that the identified abnormal accumulation, aggregation, and misfolding of proteins, combined with and perhaps provoked by an aging intracellular milieu, more essentially lead to the vacuolar degeneration and atrophy of the muscle fibers that are specific to sporadic inclusion-body myositis. Abnormal accumulations of the amyloid-beta precursor protein and of its proteolytic fragment, amyloid-beta, associated with the aging cellular muscle fiber environment, appear to be key pathogenic events. SUMMARY: In conceptualizing a treatment for sporadic inclusion-body myositis, the accumulations of amyloid-beta42 and other unfolded proteins are now phenomena to be reckoned with. One would like to stop intracellular increase of the unfolded/misfolded proteins by reducing their formation and/or increasing their disposal. In addition, the identification of factors that would decrease intra-muscle fiber expressions of beta- and gamma-secretases might lead to decreased production of putatively myotoxic oligomeric amyloid-beta42. Better understanding of the mechanisms and consequences of genes that predispose to sporadic inclusion-body myositis, and of human muscle fiber aging, could also provide new avenues toward the therapy of sporadic inclusion-body myositis. How to therapeutically capitalize on the new findings is now the challenge.

Age Factors↗
PubMed2004

Paternal phenotype is associated with microalbuminuria in young adults with Type 1 diabetes mellitus of short duration.

AIMS: Susceptibility to diabetic nephropathy has not yet been causally linked to any genetic factors. We investigated in nuclear families whether parental ambulatory blood pressure, lipids and urine albumin excretion were early markers of risk of microalbuminuria in young adults with Type 1 diabetes. SUBJECTS AND METHODS: A subset of 98 young adults from the Oxford Regional Prospective Study were followed from diagnosis until aged >or= 16 years and duration of diabetes >or= 5 years (probands). Of these subjects, 24 developed microalbuminuria (males >or= 3.5 mg/mmol; females >or= 4 mg/mmol) and were designated cases, whereas 74 were controls. Family medical history, 24-h ambulatory blood pressure, urine albumin to creatinine ratio (ACR), non-fasting lipid profile and apolipoproteins (A1 and B) were measured in mothers and fathers. RESULTS: The prevalence of a parental hypertension (taking anti-hypertensive medication or daytime blood pressure > 140/90 mmHg), was similar in cases and controls (29% vs. 35%; chi2 test, P = 0.3). The systolic blood pressure night to day ratio and also ACR were higher in the fathers of cases when compared with the fathers of controls [systolic 0.88 (0.08), n = 14 vs. 0.85 (0.12), n = 53, P = 0.041]; [ACR median (IQ range) 0.6 mg/mmol (0.2-16.9) vs. 0.47 mg/mmol (0.3-3.7), P = 0.049]. Paternal night-time systolic blood pressure, night to day systolic blood pressure ratio and ACR were correlated with an index of susceptibility to albuminuria (r = 0.25, P = 0.042, n = 69 and r = 0.28, P = 0.022, n = 0.67 and r = 0.24, P = 0.029, n = 0.85, respectively). CONCLUSIONS: Higher paternal ACR and night to day ratio of ambulatory blood pressure, but not parental hypertension or maternal factors, are associated with microalbuminuria in young adults with Type 1 diabetes.

Adolescent↗
PubMed1993

Genes and environment in the inheritance of morbidity and mortality.

During the past 30 years, the Danish Adoption Registry has been used in the analysis of the effect of genes and family environment on the development of mental disorders. During the last 15 years, the registry has also been used for similar analyses of somatic disorders, including obesity and premature death from somatic disorders. This article discusses the potential problems generally related to inference on morbidity from mortality data and particularly when using mortality data in adoption studies. We conclude that further insight into the question of nature, nurture or both requires extending the studies to include morbidity data as well as mortality data. We suggest that expanding the study by including biological and adoptive siblings and by using recently developed statistical methods will considerably strengthen the adoption study of morbidity and mortality.

Adoption↗
PubMed2002

Balancing life-style and genomics research for disease prevention.

Genetic and environmental factors, including diet and life-style, both contribute to cardiovascular disease, cancers, and other major causes of mortality, but various lines of evidence indicate that environmental factors are most important. Overly enthusiastic expectations regarding the benefits of genetic research for disease prevention have the potential to distort research priorities and spending for health. However, integration of new genetic information into epidemiologic studies can help clarify causal relations between both life-style and genetic factors and risks of disease. Thus, a balanced approach should provide the best data to make informed choices about the most effective means to prevent disease.

Disease↗
PubMed1989

Expression of human recombinant plasminogen activators enhances invasion and experimental metastasis of H-ras-transformed NIH 3T3 cells.

The gene transfer technique was used to examine the role of plasminogen activator (PA) in the invasive and metastatic behavior of tumorigenic cells. H-ras-transformed NIH 3T3 clonal cells producing a very low level of PA were generated and further transfected with an expression plasmid containing a cDNA sequence encoding either the urokinase-type or the tissue-type human PA. Compared with the parental transformed cells, clonal cells expressing high levels of both types of recombinant PA invaded more rapidly through a basement membrane reconstituted in vitro. Furthermore, cells expressing high levels of recombinant urokinase-type PA also caused a higher incidence of pulmonary metastatic lesions after intravenous injection into nude mice. Both activities were reduced by the serine proteinase inhibitor EACA; invasion was also suppressed by antibodies blocking the activity of human PAs and by the synthetic collagenase inhibitor SC-44463. These findings provide direct genetic evidence for a causal role of PA in invasive and metastatic activities.

Animals↗
PubMed2001

Attributable risk of common and rare determinants of subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Smoking, hypertension, alcohol consumption, autosomal dominant polycystic kidney disease (ADPKD), and positive family history for subarachnoid hemorrhage (SAH) are well-known risk factors for SAH. For effective prevention, knowledge about the contribution of these risk factors to the overall occurrence of SAH in the general population is pivotal. We therefore investigated the population attributable risks of the risk factors for SAH. METHODS: We retrieved the relative risk and prevalence of established risk factors for SAH from the literature and calculated the population attributable risks of these risk factors. RESULTS: Drinking alcohol 100 to 299 g/wk accounted for 11% of the cases of SAH, drinking alcohol >/=300 g/wk accounted for 21%, and smoking accounted for 20%. An additional 17% of the cases could be attributed to hypertension, 11% to a positive family history for SAH, and 0.3% to ADPKD. CONCLUSIONS: Screening and preventive treatment of patients with familial preponderance of SAH alone will cause a modest reduction of the incidence of SAH in the general population. Further reduction can be achieved by reducing the prevalence of the modifiable risk factors alcohol consumption, smoking, and hypertension.

Alcohol-Induced Disorders, Nervous System↗
PubMed1998

Role of the p16 tumor suppressor gene in cancer.

Since its discovery as a CDKI (cyclin-dependent kinase inhibitor) in 1993, the tumor suppressor p16 (INK4A/MTS-1/CDKN2A) has gained widespread importance in cancer. The frequent mutations and deletions of p16 in human cancer cell lines first suggested an important role for p16 in carcinogenesis. This genetic evidence for a causal role was significantly strengthened by the observation that p16 was frequently inactivated in familial melanoma kindreds. Since then, a high frequency of p16 gene alterations were observed in many primary tumors. In human neoplasms, p16 is silenced in at least three ways: homozygous deletion, methylation of the promoter, and point mutation. The first two mechanisms comprise the majority of inactivation events in most primary tumors. Additionally, the loss of p16 may be an early event in cancer progression, because deletion of at least one copy is quite high in some premalignant lesions. p16 is a major target in carcinogenesis, rivaled in frequency only by the p53 tumor-suppressor gene. Its mechanism of action as a CDKI has been elegantly elucidated and involves binding to and inactivating the cyclin D-cyclin-dependent kinase 4 (or 6) complex, and thus renders the retinoblastoma protein inactive. This effect blocks the transcription of important cell-cycle regulatory proteins and results in cell-cycle arrest. Although p16 may be involved in cell senescence, the physiologic role of p16 is still unclear. Future work will focus on studies of the upstream events that lead to p16 expression and its mechanism of regulation, and perhaps lead to better therapeutic strategies that can improve the clinical course of many lethal cancers.

Animals↗
PubMed1991

The nasal septum in relation to the development of the nasomaxillary complex: a study in identical twins.

The influence of the nasal septum and respiration, evaluated by the total nasal resistance (TR) on the development of the nasomaxillary complex, was studied in 42 identical twins. An understanding of this influence is important for a determination of whether surgery involving the nose should be performed in children. Comparison within and between twins with different septal deformities indicated that the cartilaginous nasal septum influences the development of the nose and the anteroposterior dimensions of the maxilla. Anterior septal deformities resulted in underdeveloped cartilaginous noses and a shorter anteroposterior dimension for the maxilla. No relation was found with regard to posterior septal deformities, which may be considered as part of the development of the midface. Vertical dimensions of the face were related to TR. Increased values of TR were significantly related to a shorter maxillary height. This may not express a causal relationship but rather genetically determined shorter facial dimensions.

Adolescent↗
PubMed2001

[Muscle weakness or rigidity due to hereditary ion channel diseases].

Three men, aged 36, 16 and 66 years, had suffered for several years from muscular weakness; after a low serum potassium level had been established, supplementary examination revealed hypokalaemic periodic paralysis. A woman aged 25 had suffered since youth from muscular stiffness on sudden movements; she suffered from hereditary myotonia of the recessive type (Becker's disease). Both rare skeletal muscle ion channel diseases are characterized by the fact that the variable clinical expression complicates making the diagnosis. Since the causal mutations are known, genetic analysis is an essential step in confirming the diagnosis. Additional EMG procedures may be of diagnostic value, even in cases that cannot be clarified genetically.

Adolescent↗
PubMed1995

Genetic testing for cancer predisposition: behavioral science issues.

The discovery of major cancer susceptibility genes is likely to create strong pressures for clinical testing from biotechnology companies, insurance carriers, the medical community, and the public. However, before genetic testing for cancer predisposition is made widely available, we must identify the optimum strategies to enhance informed decision making, minimize adverse psychologic consequences, and promote adherence to recommended surveillance. This report provides an overview of behavioral research in these areas and, on the basis of this literature, presents suggestions for developing effective and ethical genetic testing protocols.

Causality↗
PubMed2006

Colletotrichum sublineolum genetic instability assessed by mutants resistant to chlorate.

The fungus Colletotrichum sublineolum, causal agent of sorghum anthracnose, presents high variability, genetic instability and host specialization. The aims of the present work were to investigate the mechanisms involved in the genetic instability in this species. Mutants resistant to chlorate and unable to use nitrate (Nit mutants), were obtained spontaneously, isolated and characterized for complementation pattern, reversion frequency and RAPD profile. The results showed that chlorate-resistant mutants could be divided into six phenotypic classes that probably represented mutations in the structural nitrate reductase locus (nit1), in the structural nitrite reductase locus (nit6 and niiA of Neurospora and Aspergillus, respectively), in the specific regulator locus (nit3), in the main regulator locus (nit2), in loci that codified the cofactor containing molybdenum necessary for nitrate reductase activity (NitM), and one or more genes responsible for nitrate intake (crn). In addition, the genetic control of this metabolism in C. sublineolum seems to be similar to other fungi species such as Aspergillus, Neurospora and Fusarium. The high reversion frequency (10(-4) to 10(-5)) presented by nit1 mutants suggests that the instability in evaluated strains could be a result of transposable elements activity. The RAPD analysis enabled confirmation that the Nit mutants have a similar genetic background to original strain, and that polymorphism exists among wild-type strains, nit1 mutants and revertants of C. sublineolum. These are important aspects for the later direction of molecular analysis, where these mutants will be used as a tool to isolate the active transposable elements in the C. sublineolum genome.

Chlorates↗