850 resultados para Genetic risk factors
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Hypokinesia, rigidity, tremor, and postural instability are the cardinal symptoms of Parkinson s disease (PD). Since these symptoms are not specific to PD the diagnosis may be uncertain in early PD. Etiology and pathogenesis of PD remain unclear. There is no neuroprotective therapy. Genetic findings are expected to reveal metabolic routes in PD pathogenesis and thereby eventually lead to therapeutic innovations. In this thesis, we first aimed to study the usefulness and accuracy of 123I-b-CIT SPECT in the diagnosis of PD in a consecutive clinic-based material including various movement disorders. We subsequently a genetic project to identify genetic risk factors for sporadic PD using a candidate gene approach in a case-control setting including 147 sporadic PD patients and 137 spouse controls. Dopamine transporter imaging by 123I-b-CIT SPECT could distinguish PD from essential tremor, drug-induced parkinsonism, dystonia and psychogenic parkinsonism. However, b-CIT uptake in Parkinson plus syndromes (PSP and multiple system atrophy) and dementia with Lewy bodies was not significantly different from PD. 123I-b-CIT SPECT could not reliably differentiate PD from vascular parkinsonism. 123I-b-CIT SPECT was 100% sensitive and specific in the diagnosis of PD in patients younger than 55 years but less specific in older patients, due to differential distribution of the above conditions in the younger and older age groups. 123I-b-CIT SPECT correlated with symptoms and detected bilateral nigrostriatal defect in patients whose PD was still in unilateral stage. Thus, in addition to as a differential diagnostic aid, 123I-b-CIT SPECT may be used to detect PD early, even pre-symptomatically in at-risk individuals. 123I-b-CIT SPECT was used to aid in the collection of patients to the genetic studies. In the genetic part of this thesis we found an association between PD and a polymorphic CAG-repeat in POLG1 gene encoding the catalytic subunit of mitochondrial polymerase gamma. The CAG-repeat encodes a polyglutamine tract (polyQ), the two most common lengths of which are 10Q (86-90%) and 11Q. In our Finnish material, the rarer non-10Q or non-11Q length variants (6Q-9Q, 12Q-14Q, 4R+9Q) were more frequent in patients than in spouse controls (10% vs. 3.5 %, p=0.003), or population controls (p=0.001). Therefore, we performed a replication study in 652 North American PD patients and 292 controls. Non-10/11Q alleles were more common in the US PD patients compared to the controls but the difference did not reach statistical significance (p=0.07). This larger data suggested our original definition of variant length allele might need reconsideration. Most previous studies on phenotypic effects of POLG1 polyQ have defined 10Q as the only normal allele. Non-10Q alleles were significantly more common in patients compared to the controls (17.3% vs. 12.3 %, p= 0.005). This association between non-10Q length variants and PD remained significant when compared to a larger set of 1541 literature controls (p=0.00005). In conclusion, POLG1 polyQ alleles other than 10Q may predispose to PD. We did not find association between PD and parkin or DJ-1, genes underlying autosomal recessive parkinsonism. The functional Val158Met polymorphism, which affects the catalytic effect of COMT enzyme, and another coding polymorphism in COMT were not associated with PD in our patient material. The APOE e2/3/4 polymorphism modifies risk for Alzheimer s disease and prognosis of for example brain trauma. APOE promoter and enhancer polymorphisms 219G/T and +113G/C, and APOE e3 haplotypes, have also been shown to modify the risk of Alzheimer s disease but not reported in PD. No association was found between PD and APOE e2/3/4 polymorphism, the promoter or enhancer polymorphisms, or the e3 haplotypes.
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Autoimmune diseases are more common in dogs than in humans and are already threatening the future of some highly predisposed dog breeds. Susceptibility to autoimmune diseases is controlled by environmental and genetic factors, especially the major histocompatibility complex (MHC) gene region. Dogs show a similar physiology, disease presentation and clinical response as humans, making them an excellent disease model for autoimmune diseases common to both species. The genetic background of canine autoimmune disorders is largely unknown, but recent annotation of the dog genome and subsequent development of new genomic tools offer a unique opportunity to map novel autoimmune genes in various breeds. Many autoimmune disorders show breed-specific enrichment, supporting a strong genetic background. Furthermore, the presence of hundreds of breeds as genetic isolates facilitates gene mapping in complex autoimmune disorders. Identification of novel predisposing genes establishes breeds as models and may reveal novel candidate genes for the corresponding human disorders. Genetic studies will eventually shed light on common biological functions and interactions between genes and the environment. This study aimed to identify genetic risk factors in various autoimmune disorders, including systemic lupus erythematosus (SLE)-related diseases, comprising immune-mediated rheumatic disease (IMRD) and steroid-responsive meningitis arteritis (SMRA) as well as Addison s disease (AD) in Nova Scotia Duck Tolling Retrievers (NSDTRs) and chronic superficial keratitis (CSK) in German Shepherd dogs (GSDs). We used two different approaches to identify genetic risk factors. Firstly, a candidate gene approach was applied to test the potential association of MHC class II, also known as a dog leukocyte antigen (DLA) in canine species. Secondly, a genome-wide association study (GWAS) was performed to identify novel risk loci for SLE-related disease and AD in NSDTRs. We identified DLA risk haplotypes for an IMRD subphenotype of SLE-related disease, AD and CSK, but not in SMRA, and show that the MHC class II gene region is a major genetic risk factor in canine autoimmune diseases. An elevated risk was found for IMRD in dogs that carried the DLA-DRB1*00601/DQA1*005011/DQB1*02001 haplotype (OR = 2.0, 99% CI = 1.03-3.95, p = 0.01) and for ANA-positive IMRD dogs (OR = 2.3, 99% CI = 1.07-5.04, p-value 0.007). We also found that DLA-DRB1*01502/DQA*00601/DQB1*02301 haplotype was significantly associated with AD in NSDTRs (OR = 2.1, CI = 1.0-4.4, P = 0.044) and the DLA-DRB1*01501/DQA1*00601/DQB1*00301 haplotype with the CSK in GSDs (OR=2.67, CI=1.17-6.44, p= 0.02). In addition, we found that homozygosity for the risk haplotype increases the risk for each disease phenotype and that an overall homozygosity for the DLA region predisposes to CSK and AD. Our results have enabled the development of genetic tests to improve breeding practices by avoiding the production of puppies homozygous for risk haplotypes. We also performed the first successful GWAS for a complex disease in dogs. With less than 100 cases and 100 controls, we identified five risk loci for SLE-related disease and AD and found strong candidate genes involved in a novel T-cell activation pathway. We show that an inbred dog population has fewer risk factors, but each of them has a stronger genetic risk. Ongoing studies aim to identify the causative mutations and bring new knowledge to help diagnostics, treatment and understanding of the aetiology of SLE-related diseases.
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AIM: To evaluate the association with diabetic kidney disease of single nucleotide polymorphisms (SNPs) that may contribute to mitochondrial dysfunction.
METHODS: The mitochondrial genome and 1039 nuclear genes that are integral to mitochondrial function were investigated using a case (n=823 individuals with diabetic kidney disease) vs. control (n=903 individuals with diabetes and no renal disease) approach. All people included in the analysis were of white European origin and were diagnosed with Type 1 diabetes before the age of 31 years. Replication was conducted in 5093 people with similar phenotypes to those of the discovery collection. Association analyses were performed using the plink genetic analysis toolset, with adjustment for relevant covariates.
RESULTS: A total of 25 SNPs were evaluated in the mitochondrial genome, but none were significantly associated with diabetic kidney disease or end-stage renal disease. A total of 38 SNPs in nuclear genes influencing mitochondrial function were nominally associated with diabetic kidney disease and 16 SNPS were associated with end-stage renal disease, secondary to diabetic kidney disease, with meta-analyses confirming the same direction of effect. Three independent signals (seven SNPs) were common to the replication data for both phenotypes with Type 1 diabetes and persistent proteinuria or end-stage renal disease.
CONCLUSIONS: Our results suggest that SNPs in nuclear genes that influence mitochondrial function are significantly associated with diabetic kidney disease in a white European population
Resumo:
Despite extensive research, the etiology of adult glioma remains largely unknown. We sought to further explore the role of immune and genetic factors in glioma etiology using data from the Harris County Brain Tumor Study and the first U.S. genome-wide association study of glioma. First, using a case-control study design, we examined the association between adult glioma risk and surrogates of the timing and frequency of common early childhood infections, birth order and sibship size, respectively. We found that each one-unit increase in birth order was associated with a 12% decreased risk of glioma development in adulthood (OR=0.88, 95% CI=0.81-0.96); however, sibship size was not associated with adult glioma risk (OR=0.96, 95% CI=0.91-1.02). Second, we used a multi-strategic approach to explore the relationships between glioma risk, history of asthma/allergies, and 23 functional SNPs in 11 inflammation genes. We found three inflammation gene SNPs to be significantly associated with glioma risk (COX2/PTGS2 rs20417 [OR=1.41]; IL10 rs1800896 [OR=1.57]; and IL13 rs20541 [OR=0.39]). Joint effects analysis of the risk-conferring alleles of these three SNPs revealed a trend of increasing risk with increasing number of adverse alleles among those without asthma/allergies (p<0.0001). Finally, we conducted a case-only study to explore pairwise SNP-SNP interactions in immune-related pathways among a population of 1304 non-Hispanic white glioma cases. After correction for multiple comparisons, we found 279 significant SNP-SNP interactions among polymorphisms of immune-related genes, many of which have not been previously examined. Our results, cumulatively, suggest an important role for immune and genetic factors in glioma etiology and provide several new hypotheses for future studies.^
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Following posterior fossa surgery for resection of childhood medulloblastoma and primitive neuroectodermal tumor (M/PNET), cerebellar mutism (CM) may develop. This is a condition of absent or diminished speech in a conscious patient with no evidence of oral apraxia, which can be accompanied by other symptoms of the posterior fossa syndrome complex, which includes ataxia and hypotonia. Little is known about the etiology. Therefore, we conducted a SNP, gene, and pathway-level analysis to assess the role of host genetic variation on the risk of CM in M/PNET subjects following treatment. Cases (n= 20) and controls (n= 53) were recruited from the Childhood Cancer Epidemiology and Prevention Center, in Houston, TX. DNA samples were genotyped using the Illumina Human 1M Quad SNP chip. Ten pathways were identified from logistic regression used to identify the marginal effect of each SNP on CM risk. The minP test was conducted to identify associations between SNPs categorized to genes and CM risk. Pathways were assessed to determine if there was a significant enrichment of genes in the pathway compared to all other pathways. There were 78 genes that reached the threshold of min P ≤0.05 in 948 genes. The Neurotoxicity pathway was the most significant pathway after adjusting for multiple comparisons (q=0.040 and q=0.005, using Fisher's exact test and a test of proportions, respectively). Most genes within the Neurotoxicity pathway that reached a threshold of minP ≤0.05 were known to have an apoptosis function, possibly inducing neuronal apoptosis in the dentatothalamocortical pathway, and may be important in CM etiology in this population. This is the first study to assess the potential role of genetic risk factors on CM. As an exploratory study, these results should be replicated in a larger sample. ^
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Age related macular degeneration (AMD) is the leading cause of blindness in individuals older than 65 years of age. It is a multifactorial disorder and identification of risk factors enables individuals to make lifestyle choices that may reduce the risk of disease. Collaboration between geneticists, ophthalmologists, and optometrists suggests that genetic risk factors play a more significant role in AMD than previously thought. The most important genes are associated with immune system modulation and the complement system, e.g., complement factor H (CFH), factor B (CFB), factor C3, and serpin peptidase inhibitor (SERPING1). Genes associated with membrane transport, e.g., ATP-binding cassette protein (ABCR) and voltage-dependent calcium channel gamma 3 (CACNG3), the vascular system, e.g., fibroblast growth factor 2 (FGF2), fibulin-5, lysyl oxidase-like gene (LOXL1) and selectin-P (SELP), and with lipid metabolism, e.g., apolipoprotein E (APOE) and hepatic lipase (LIPC) have also been implicated. In addition, several other genes exhibit some statistical association with AMD, e.g., age-related maculopathy susceptibility protein 2 (ARMS2) and DNA excision repair protein gene (ERCC6) but more research is needed to establish their significance. Modifiable risk factors for AMD should be discussed with patients whose lifestyle and/or family history place them in an increased risk category. Furthermore, calculation of AMD risk using current models should be recommended as a tool for patient education. It is likely that AMD management in future will be increasingly influenced by assessment of genetic risk as such screening methods become more widely available. © 2013 Spanish General Council of Optometry.
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Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity.
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Purpose: Several occupational carcinogens are metabolized by polymorphic enzymes. The distribution of the polymorphic enzymes N-acetyltransferase 2 (NAT2; substrates: aromatic amines), glutathione S-transferase M1 (GSTM1; substrates: e.g., reactive metabolites of polycyclic aromatic hydrocarbons), and glutathione S-transferase T1 (GSTT1; substrates: small molecules with 1-2 carbon atoms) were investigated. Material and Methods: At the urological department in Lutherstadt Wittenberg, 136 patients with a histologically proven transitional cell cancer of the urinary bladder were investigated for all occupations performed for more than 6 months. Several occupational and non-occupational risk factors were asked. The genotypes of NAT2, GSTM1, and GSTT1 were determined from leucocyte DNA by PCR. Results: Compared to the general population in Middle Europe, the percentage of GSTT1 negative persons (22.1 %) was ordinary; the percentage of slow acetylators (59.6%) was in the upper normal range, while the percentage of GSTM1 negative persons (58.8%) was elevated in the entire group. Shifts in the distribution of the genotypes were observed in subgroups who had been exposed to asbestos (6/6 GSTM1 negative, 5/6 slow acetylators), rubber manufacturing (8/10 GSTM1 negative), and chlorinated solvents (9/15 GSTM1 negative). Conclusions: The overrepresentation of GSTM1 negative bladder cancer patients also in this industrialized area and more pronounced in several occupationally exposed subgroups points to an impact of the GSTM1 negative genotype in bladder carcinogenesis. [Article in German]
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Background: Delirium is defined as an acute disorder of attention and cognition. Delirium is common in hospitalized elderly patient and is associated with increased morbidity, length of stay and patient care costs. Although Delirium can develop at any time during hospitalization, it typically presents early in the post-operative period (Post-Operative Delirium, POD) in the surgery context. The molecular mechanism and possible genetics basis of POD onset are not known, as well as all the risk factors are not completely defined. Our hypothesis is that genetic risk factor involving the inflammatory response could have possible effects on the immunoneuroendocrine system. Moreover, our previous data (inflamm-aging) suggest that aging is associated with an increase of inflammatory status, favouring age-related diseases such as neurodegenerative diseases, frailty, depression among other. Some pro-inflammatory or anti-inflammatory cytokines, seem to play a crucial role in increasing the inflammatory status and in the communication and regulation of immunoneuroendocrine system. Objective: this study evaluated the incidence of POD in elderly patients undergoing general surgery, clinical/physical and psychological risk factors of POD insurgency and investigated inflammatory and genetic risk factors. Moreover, this study evaluated the consequence of POD in terms of institutionalization, development of permanent cognitive dysfunction or dementia and mortality Methods: patients aged over 65 admitted for surgery at the Urgency Unit of S.Orsola-Malpighi Hospital were eligible for this case–control study. Risk factors significantly associated with POD in univariate analysis were entered into multivariate analysis to establish those independently associated with POD. Preoperative plasma level of 9 inflammatory markers were measured in 42 control subjects and 43 subjects who developed POD. Functional polymorphisms of IL-1 α , IL-2, IL-6, IL-8, IL-10 and TNF-alpha cytokine genes were determined in 176 control subjects and 27 POD subjects. Results: A total of 351 patients were enrolled in the study. The incidence of POD was 13•2 %. Independent variables associated with POD were: age, co-morbidity, preoperative cognitive impairment, glucose abnormalities. Median length of hospital stay was 21 days for patients with POD versus 8 days for control patients (P < 0•001). The hospital mortality rate was 19 and 8•4 % respectively (P = 0•021) and mortality rate after 1 year was also higher in POD (P= 0.0001). The baseline of IL-6 concentration was higher in POD patients than patients without POD, whereas IL-2 was lower in POD patients compared to patients without POD. In a multivariate analysis only IL-6 remained associated with POD. Moreover IL-6, IL-8 and IL-2 are associated with co-morbidity, intra-hospital mortality, compromised functional status and emergency admission. No significant differences in genotype distribution were found between POD subjects and controls for any SNP analyzed in this study. Conclusion: In this study we found older age, comorbidity, cognitive impairment, glucose abnormalities and baseline of IL-6 as independent risk factors for the development of POD. IL-6 could be proposed as marker of a trait that is associated with an increased risk of delirium; i.e. raised premorbid IL-6 level predict for the development of delirium.
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A large number of risk factors have been associated with Alzheimer’s disease (AD). This article discusses the validity of the major risk factors that have been identified including age, genetics, exposure to aluminium, head injury, malnutrition and diet, mitochondrial dysfunction, vascular disease, immune system dysfunction, and infection. Rare forms of early-onset familial AD (FAD) are strongly linked to the presence of specific gene mutations, viz. mutations in amyloid precursor protein (APP) and presenilin (PSEN1/2) genes. By contrast, late-onset sporadic AD (SAD) is a multifactorial disorder in which age-related changes, genetic risk factors, such as allelic variation in apolipoprotein E (Apo E) gene, vascular disease, head injury and risk factors associated with diet, the immune system, mitochondrial function, and infection may all be involved. Life-style changes that may reduce the effect of these risk factors and therefore, the risk of AD are discussed.
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A large number of possible risk factors have been associated with Alzheimer'sdisease (AD).This chapter discusses the validity of the major risk factors that have been identifiedincluding age, genetics, exposure to aluminum, head injury, malnutrition and diet,mitochondrial dysfunction, vascular disease, immune system dysfunction, and infectionand proposes a hypothesis to explain how these various risk factors may cause ADpathology.Rare forms of early-onset familial AD (FAD) are strongly linked to the presence ofspecific gene mutations, viz. mutations in amyloid precursor protein (APP) andpresenilin (PSEN1/2) genes. By contrast, late-onset sporadic AD (SAD) is amultifactorial disorder in which age-related changes, genetic risk factors, such as allelicvariation in apolipoprotein E (Apo E) gene, vascular disease, head injury and risk factorsassociated with diet, immune system, mitochondrial function, and infection may all beinvolved.These risk factors interact to increase the rate of normal aging (=allostatic load')which over a lifetime results in degeneration of neurons and blood vessels and as aconsequence, the formation of abnormally aggregated =reactive' proteins such as ß-amyloid (Aß) and tau leading to the development of senile plaques (SP) andneurofibrillary tangles (NFT) respectively. Life-style changes that may reduce theallostatic load and therefore, the risk of dementia are discussed.
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According to the models conceptualizing work stress, increased risk of health problems arise when high job demands co-occur with low job control (the demand-control model) or the efforts invested by the employee are disproportionately high compared to the rewards received (effort-reward imbalance model). This study examined the association between work stress and early atherosclerosis with particular attention to the role of pre-employment risk factors and genetic background in this association. The subjects were young healthy adults aged 24-39 who were participating in the 21-year follow-up of the ongoing prospective "Cardiovascular Risk in Young Finns" study in 2001-2002. Work stress was evaluated with questionnaires on demand-control model and on effort-reward model. Atherosclerosis was assessed with ultrasound of carotid artery intima-media thickness (IMT). In addition, risk for enhanced atherosclerotic process was assessed by measuring with heart rate variability and heart rate. Pre-employment risk factors, measured at age 12 to 18, included such as body mass index, blood lipids, family history of coronary heart disease, and parental socioeconomic position. Variants of the neuregulin-1 were determined using genomic DNA. The results showed that higher work stress was associated with higher IMT in men. This association was not attenuated by traditional risk factors of atherosclerosis and coronary heart disease or by pre-employment risk factors measured in adolescence. Neuregulin-1 gene moderated the association between work stress and IMT in men. A significant association between work stress and IMT was found only for the T/T genotype of the neuregulin-1 gene but not for other genotypes. Among women an association was found between higher work stress and lower heart rate variability, suggesting higher risk for developing atherosclerosis. These associations could not be explained by demographic characteristics or coronary risk factors. The present findings provide evidence for an association between work stress and atherosclerosis in relatively young population. This association seems to be modified by genetic influences but it does not appear to be confounded by pre-employment adolescent risk factors.
