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Results for “Genetic causality”

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At least 541 records · Page 30Linked to original sources
PubMed1999

Socioeconomic status and health: what we know and what we don't.

In the past 15 years, we have seen a marked increase in research on socioeconomic status (SES) and health. Research in the first part of this era examined the nature of the relationship of SES and health, revealing a graded association; SES is important to health not only for those in poverty, but at all levels of SES. On average, the more advantaged individuals are, the better their health. In this paper we examine the data regarding the SES-health gradient, addressing causal direction, generalizability across populations and diseases, and associations with health for different indicators of SES. In the most recent era, researchers are increasingly exploring the mechanisms by which SES exerts an influence on health. There are multiple pathways by which SES determines health; a comprehensive analysis must include macroeconomic contexts and social factors as well as more immediate social environments, individual psychological and behavioral factors, and biological predispositions and processes.

Causality↗
PubMed2001

Are male reproductive disorders a common entity? The testicular dysgenesis syndrome.

Growing evidence from clinical and epidemiological studies points to a synchronized increase in the incidence of male reproductive problems, such as genital abnormalities, testicular cancer, reduced semen quality, and subfertility. Together these male reproductive problems may reflect the existence of one common entity, a testicular dysgenesis syndrome (TDS). Experimental and epidemiological studies suggest that TDS is a result of disruption of embryonal programming and gonadal development during fetal life. The recent rise in the prevalence of TDS may be causally linked to endocrine disrupters affecting genetically susceptible individuals. We recommend that future epidemiological studies on trends in male reproduction do not focus on one symptom only, but take all aspects of TDS into account. The potential impact of adverse environmental factors and the role of genetic polymorphisms involved in gonadal development requires further research.

Adult↗
PubMed2004

A novel pathological role of p53 in kidney development revealed by gene-environment interactions.

Gene-environment interactions are implicated in congenital human disorders. Accordingly, there is a pressing need to develop animal models of human disease, which are the product of defined gene-environment interactions. Previously, our laboratory demonstrated that gestational salt stress of bradykinin B(2) receptor (B(2)R)-null mice induces renal dysgenesis and early death of the offspring. In contrast, salt-stressed B(2)R +/+ or +/- littermates have normal development. The present study investigates the mechanisms underlying the susceptibility of B(2)R-null mice to renal dysgenesis. Proteomic and conventional Western blot screens identified E-cadherin among the differentially repressed proteins in B(2)R-/- kidneys, whereas the checkpoint kinase Chk1 and its substrate P-Ser(20) p53 were induced. We tested the hypothesis that p53 mediates repression of E-cadherin gene expression and is causally linked to the renal dysgenesis. Genetic crosses between B(2)R -/- and p53+/- mice revealed that germline reduction of p53 gene dosage rescues B(2)R-/- mice from renal dysgenesis and restores kidney E-cadherin gene expression. Furthermore, gamma-irradiation induces repression of E-cadherin gene expression in p53+/+ but not -/- cells. In transient transfection assays, p53 repressed human E-cadherin promoter-driven reporter activity, whereas a mutant p53, which cannot bind DNA, did not. Functional promoter analysis indicated the presence of a p53-responsive element in exon 1, which partially mediates p53-induced repression. Chromatin immunoprecipitation assays revealed that p53 inhibits histone acetylation of the E-cadherin promoter. Treatment with a histone deacetylase inhibitor reversed both p53-mediated promoter repression and deacetylation. In conclusion, this study demonstrates that gene-environment interactions cooperate to induce congenital defects through p53 activation.

Animals↗
PubMedDate not supplied

Voice and resonance disorders in genetic syndromes: a meta-analysis.

It is well known that many genetic syndromes are associated with communication disorders and especially with disorders of voice and resonance. This paper reports the results of a meta-analysis with the aim of documenting the occurrence of voice and resonance disorders in genetic syndromes. The analysis studied the occurrence of voice and resonance disorders in general, the occurrence in different etiological subtypes of syndromes and the association with other disorders, in particular clefting, a cognitive impairment and hearing problems. The database for the analysis was a list by Sphrintzen of 299 different syndromes all of which have been reported to entail communication disorders. Major findings are that disorders of voice and resonance in genetic syndromes are only rarely isolated problems, that causal mechanisms are not a major factor in determining the presence of voice and resonance disorders and, foremost, that voice and resonance disorders in genetic syndromes constitute an underresearched area.

Cognition Disorders↗
PubMed2001

Structural abnormalities of great arterial walls in congenital heart disease: light and electron microscopic analyses.

BACKGROUND: Great arteries in congenital heart disease (CHD) may dilate, become aneurysmal, or rupture. Little is known about medial abnormalities in these arterial walls. Accordingly, we studied 18 types of CHD in patients from neonates to older adults. METHODS AND RESULTS: Intraoperative biopsies from ascending aorta, paracoarctation aorta, truncus arteriosus, and pulmonary trunk in 86 patients were supplemented by 16 necropsy specimens. The 102 patients were 3 weeks to 81 years old (average, 32+/-6 years). Biopsies were examined by light (LM) and electron (EM) microscopy; necropsy specimens by LM. Positive aortic controls were from 15 Marfan patients. Negative aortic controls were from 11 coronary artery disease patients and 1 transplant donor. Nine biopsies from acquired trileaflet aortic stenosis were compared with biopsies from bicuspid aortic stenosis. Negative pulmonary trunk controls were from 7 coronary artery disease patients. A grading system consisted of negative controls and grades 1, 2, and 3 (positive controls) based on LM and EM examination of medial constituents. CONCLUSIONS: Medial abnormalities in ascending aorta, paracoarctation aorta, truncus arteriosus, and pulmonary trunk were prevalent in patients with a variety of forms of CHD encompassing a wide age range. Aortic abnormalities may predispose to dilatation, aneurysm, and rupture. Pulmonary trunk abnormalities may predispose to dilatation and aneurysm; hypertensive aneurysms may rupture. Pivotal questions are whether these abnormalities are inherent or acquired, whether CHD plays a causal or facilitating role, and whether genetic determinants are operative.

Adolescent↗
PubMed1996

Hypothalamic lesions induce obesity and sex-dependent glomerular damage and increases in blood pressure in rats.

Placement of two symmetrical lesions in the ventromedial hypothalamus of the rat causes massive overeating and obesity. We have studied male (n=8) and female (n=5) Munich-Wistar rats 7 months after induction of obesity and compared them with age-matched controls. Body weight and kidney weight were greater in control males versus females (396 +/- 7 and 1.5 +/- 0.1 g versus 229 +/- 4 and 1.0 +/- 0.1 g, respectively; both P <.001). Both obese males and females were heavier than lean counterparts (592 +/- 30 and 361 +/- 19 g, both P <.001), whereas kidney weight was similar between obese and control rats of each sex (obese males, 1.5 +/- 0.1 g; obese females, 1.1 +/- 0.1 g). Blood pressure was higher in obese versus control males; there was no differences between other groups. Single-nephron glomerular filtration rate was similar in control females and males and obese females but depressed in obese males. Glomerular blood pressure was normal in all groups. Urinary protein excretion and the percentage of sclerosed glomeruli were similar in control females and males and obese females but elevated in obese males. Plasma triglyceride levels were elevated in obesity, particularly in males. We conclude that hypothalamic lesioning induces overeating and obesity and selectively in the male causes hypertension and glomerular damage as well as declines in renal function. This injury is not hemodynamically mediated (glomerular blood pressure is normal) but may be related to the elevation in plasma triglyceride levels, which has previously been causally linked to glomerular damage in genetically obese rats.

Animals↗
PubMed1999

Elevated frequency of diabetes mellitus in hospitalized manic-depressive patients.

OBJECTIVE: Disturbance in glucose homeostasis in psychiatric populations has been suggested since the early part of this century. Increased comorbidity of diabetes mellitus in persons with major mood disorders has also been suggested. The goal of this study was to determine whether subjects diagnosed with bipolar disorder have an elevated rate of comorbid diabetes mellitus. METHOD: Three hundred forty-five hospitalized patients, aged 20-74 years, who met the DSM-III-R criteria for bipolar disorder, manic or mixed subtype, were evaluated for a comorbid diagnosis of diabetes mellitus. The frequency of diabetes mellitus in the study group was determined and compared with the expected frequency, calculated as a weighted average based on sex and age from national norms. Variables characterizing the course and severity of the affective disorder in the group of diabetic bipolar subjects and a group of nondiabetic age-matched bipolar subjects were compared. RESULTS: The prevalence of diabetes mellitus among these bipolar patients was 9.9%, significantly greater than expected from national norms (3.4%). The patients with comorbid diabetes mellitus had significantly more lifetime psychiatric hospitalizations than the nondiabetic subjects, but age at first hospitalization and duration of psychiatric disorder were similar in the two groups. CONCLUSIONS: The frequency of diabetes mellitus in hospitalized patients diagnosed with bipolar disorder is higher than in the general population. Manic-depressive patients with diabetes mellitus have a more severe course of illness, as indicated by a greater number of psychiatric hospitalizations. Possible reasons for this increased comorbidity include a genetic relationship between the disorders, a causal relationship in which hypercortisolemia induces diabetes or diabetic vascular lesions contribute to mania, an overlapping functional disturbance affecting similar regions of the brain, or the effect of psychotropic medications.

Adult↗
PubMed2026

Genome-wide association study of asthma with high treatment burden and/or worse outcomes defined using electronic healthcare data in UK Biobank.

BACKGROUND: In &#x223c;10% of asthma patients, symptoms remain uncontrolled despite maximal treatment, representing an unmet clinical need. The causal variants, genes and pathways underlying genetic risk factors have not been fully elucidated, and it is unclear whether there are unique genetic risk factors for this asthma subtype. METHODS: We used electronic healthcare records linked to UK Biobank to identify asthma patients with high treatment burden and/or worse outcomes. We performed a genome-wide association study (GWAS) with this case population and healthy controls. We sought replication for associated (p&#x2264;5&#xd7;10-6) signals in four independent studies (12&#x2009;152 cases and 32&#x2009;316 controls). Replicated signals were fine-mapped and linked to genes and pathways. RESULTS: In total, 7681 participants met our case definition and showed enrichment for adult-onset asthma, female gender and higher body mass index compared to asthma individuals not meeting case criteria. GWAS with 7681 cases and 38&#x2009;405 controls revealed 21 reproducible association signals that had previously been associated with asthma, but had a larger effect size in our study. Variant-to-gene mapping highlighted 85 candidate genes, five of which were considered high confidence (BACH2, D2HGDH, IL1RL1, RPS26, SMAD3). CONCLUSION: We present the first use of electronic healthcare records in UK Biobank to identify a subtype of asthma enriched for patients with high treatment burden and/or worse outcomes. Our findings support the role of known asthma genes, highlighting genetic risk variants with stronger effect in these groups of patients. The prioritised genes provide potential therapeutic opportunities for this difficult-to-treat patient population.

Journal Article↗
PubMed1998

Premorbid adjustment and personality in people with schizophrenia.

BACKGROUND: Schizoid personality and poor social adjustment have been thought of as common antecedents of schizophrenia but the existing literature is inconclusive. We have carried out a large cohort study with improved methodology. METHOD: The premorbid personality and adjustment of 50,054 Swedish men were assessed on entry into the army at the age of 18. Individuals who developed schizophrenia or another psychosis after 15-year follow-up were identified. Odds ratios for variables independently associated with the later development of schizophrenia were calculated, adjusting for potential confounders. RESULTS: Four variables reflecting early problems with interpersonal relationships were strongly associated with later schizophrenia and, to a lesser extent, non-schizophrenic psychoses, but also occurred commonly in the cohort as a whole. These associations with schizophrenia persisted after early-onset cases were excluded, though their predictive value was low (3.0%, 95% CI 1.5-4.5). CONCLUSIONS: Some aspects of premorbid personality and adjustment may act as risk factors for schizophrenia. The results appear to be most consistent with a multi-factorial aetiology for schizophrenia and offer tentative support for a psychological disturbance mediating genetic and environmental effects on the causal pathway to the illness.

Adolescent↗
PubMed2002

Chronic fatigue and anxiety/depression: a twin study.

BACKGROUND: Up to three-quarters of patients with fatigue syndromes have comorbid mood or anxiety disorders, suggesting that chronic fatigue is a forme fruste of anxiety or depressive states. AIMS: To establish whether the association of chronic fatigue with psychological distress is causal or due to a common genetic or environmental factor. METHOD: 69 monozygotic (MZ) and 31 dizygotic (DZ) female twin pairs, with only one co-twin reporting at least 6 months of fatigue, completed questions on fatigue, the General Health Questionnaire (GHQ) and a structured psychiatric interview. We examined the effects of three progressively more stringent definitions of chronic fatigue on four GHQ sub-scales. RESULTS: Fatigued MZ and DZ twins by all definitions were significantly more depressed, anxious, somatically preoccupied and socially dysfunctional than their non-fatigued co-twins. Intrapair differences were similar in DZ and MZ twins, but non-significant differences were observed for the somatic symptoms and anxiety/insomnia sub-scales. CONCLUSIONS: In this sample, chronic fatigue and psychological distress are strongly associated without evidence for genetic covariation, implying that the association is environmental, or due to overlapping definitions. Any genetic covariation missed is likely to involve anxiety rather than depression.

Adult↗
PubMed2005

Alzheimer disease and cancer.

Cross-sectional studies raise the possibility of protective relationships between, or a common mechanism underlying, the development of dementia of the Alzheimer type (DAT) and cancer. Using a prospective longitudinal design, the authors found that the risk of developing cancer is less among participants with DAT vs nondemented participants (p < 0.001) and that the risk of developing DAT may be less for participants with a history of cancer (p = 0.060).

Age Factors↗
PubMed1985

Male pseudohermaphroditism due to 3 beta-hydroxysteroid dehydrogenase-isomerase deficiency associated with atrial septal defect.

Male pseudohermaphroditism in a 6 month old boy, due to congenital 3 beta-hydroxysteroid dehydrogenase deficiency, associated with atrial septal defect, is reported. At 2 weeks he required therapy for severe dehydration and projectile vomiting. The parents were first cousins and one female sibling had died suddenly at 2 months. The patient presented with melanoderma, perineal hypospadias with testicles in a bifid scrotum and atrial septal defect (ostium secundum). Complete cytogenetic studies showed a 46,XY karyotype. Serum sodium ranged from 129 to 140 mEq/l and serum potassium from 5.1 to 4.6 mEq/l. Basal plasma hormonal studies showed normal androstenedione (delta 4A), decreased cortisol (F), slightly elevated ACTH, 17-hydroxy-progesterone (17-OH-P) and testosterone (T), and highly increased dehydroepiandrosterone-sulphate (DHEA-S) levels. ACTH stimulation increased and DXM suppression decreased the plasma levels of DHEA-S, 17-OH-P and T but not that of F; hCG stimulation during cortisone therapy did not change the levels of DHEA-S and T. Corticosteroid therapy normalized electrolyte levels and reduced melanoderma and hormonal hypersecretion. Moderately elevated plasma levels of 17-OH-P and T suggest a partial testicular 3 beta-HSD deficiency. The multifactorial inheritance and the relatively high prevalence of atrial septal defect vs the rarity of adrenal enzymatic defect suggest a causal association even if a common genetic factor cannot be excluded.

3-Hydroxysteroid Dehydrogenases↗
PubMed1998

Age-dependent modifications of gene expression in human fibroblasts.

Normal human fibroblasts exhibit a limited proliferative potential in culture. When populations are serially subcultured, they grow well initially, but ultimately reach a stage when they are no longer able to proliferate in response to mitogenic stimuli. This state is designated "replicative senescence". In addition to failure to proliferate, numerous morphological and physiological changes characterize the senescent phenotype. Both stochastic and genetic mechanisms have been postulated as causal effectors of the aging process. However, the pathway leading to cellular senescence is likely to be complex with numerous changes. In this article we provide an overview of cell and molecular changes that occur during cell aging, with special emphasis on signal transduction pathways and cell cycle proteins that are likely to play key roles in determining the limited replicative life span and the changes that occur.

Animals↗
PubMed2006

Autoimmune liver disease and the Canadian First Nations Aboriginal Communities of British Columbia's Pacific Northwest.

Primary biliary cirrhosis (PBC) is a well-known but uncommon chronic liver disease that is presumed to be of autoimmune etiology. Recently, investigations in British Columbia (BC), a province of Canada situated along the Pacific North-West of North America, have suggested that PBC is not a rare disease amongst BC's Aboriginal (i.e. First Nations) communities. Geographically, BC is adjacent to South East Alaska, an American state that has also reported an increased prevalence of PBC amongst its Aboriginal communities. In this article, the medical evidence supporting a hypothesis of increased risk of PBC amongst BC's First Nations communities is reviewed. Evidence suggesting that autoimmune hepatitis is also more likely amongst BC's First Nations communities is also presented.

Autoimmune Diseases↗
PubMed1992

Familial occurrence of fixed drug eruptions.

Fixed drug eruptions following the use of pyrazolone derivatives occurred in 4 members of the same family: a 12-year-old girl, her grandmother, and two of her great aunts. Although the pathophysiologic events leading to this type of reaction are unknown, these cases of familial occurrence suggest that genetic predisposition might be an important causal factor.

Child↗
PubMed2004

Helping patients cope with chronic alopecia areata.

Helping a patient cope with a frustrating and unpredictable disease like alopecia areata can be a difficult task for many dermatology nurses. Five dermatology nurses who practice in the United States and Canada say that one important resource that should not be overlooked during the course of treatment of alopecia areata is the patient support group. Another major resource is the referral of patients to the National Alopecia Areata Foundation, which coordinates the patient support groups.

Adaptation, Psychological↗
PubMed2004

[Iron storage disease].

Iron overload causes impaired function of tissues and organs due to the increased iron storage in them. Hereditary hemochromatosis is the most frequent hereditary metabolic disorder, with lethal outcome without treatment. The genetic disorder is a mutation on the short arm of the 6. chromosome, which resulted a cysteine-tyrosine substitution on the 282. amino acid position (C282Y). This mutation is less frequent in the non-Caucasian population, in opposition to the other reported mutation (H63D). The risk of the development of the disease is the highest in people who are C282Y homozygotes or C282Y/H63D compound heterozygotes. The prevalence of hemochromatosis is 1.5-5.9 per thousand. Liver disease/cirrhosis, diabetes mellitus and hyperpigmentation are the classic signs of the disease. Primer hepatocellular cancer occurs in 30% of patients with liver cirrhosis, that it is the most common cause of death among them. The diagnosis is based on the detection of iron overload (transferrin saturation, serum ferritin level, iron concentration of the liver tissue) and on the genetic examinations. Early diagnosis makes the causal therapy possible, which is the removal of the iron excess by phlebotomy. Furthermore, the early detection of iron overload allows of prevention of the development of the disease. Based in these facts population screening seems to be necessary and cost-effective, but further studies are required to determine the exact screening strategy.

Aspartic Acid↗