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1.
Mult Scler J Exp Transl Clin ; 6(2): 2055217320928101, 2020.
Article in English | MEDLINE | ID: mdl-32728476

ABSTRACT

BACKGROUND: Breastfeeding as an infant appears protective against later development of some autoimmune diseases, but research into its influence on multiple sclerosis (MS) risk has yielded inconclusive results. OBJECTIVE: We investigated the possible impact of breastfeeding on MS risk. METHODS: We used two population-based case-control studies comprising 3670 cases and 6737 matched controls. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for association between MS and exposure to prolonged breastfeeding (4 months or longer) versus reduced breastfeeding (less than 4 months). A meta-analysis of case-control studies that assessed the impact of breastfeeding on MS risk among women and men was conducted. RESULTS: Prolonged breastfeeding was associated with reduced MS risk among men (OR 0.7, 95% CI 0.5-0.9) but not among women (OR 0.9, 95% CI 0.8-1.1). Among men, a synergistic effect was observed between HLA-DRB1*15:01 carrier status and reduced breastfeeding. CONCLUSIONS: Findings from the current study add to accumulating evidence that breastfeeding may be a modifiable protective factor for reducing the risk of MS in offspring. When possible, mothers should be supported to breastfeed their infants; however, the mechanism of a sex-specific biologic effect of breastfeeding on MS risk is unclear.

2.
J Neurol Sci ; 375: 371-375, 2017 Apr 15.
Article in English | MEDLINE | ID: mdl-28320170

ABSTRACT

BACKGROUND: Multiple sclerosis (MS) and allergies are both considered to be related to imbalanced Th1 and Th2 immune responses. Previous studies evaluating the relationship between MS and allergies provide conflicting results. OBJECTIVE: To assess allergies and asthma as risk factors for MS and as predictors of MS relapses in a pediatric cohort. METHODS: The environment and genetic risk factors for pediatric MS study is a national case-control project with 16 participating US sites. An environmental questionnaire is used that includes history of allergies in the first five years of life. Case-control data are entered in the pediatric MS Network database and cases at 12 of the 16 sites enter relapse data prospectively. Annualized relapse rate was calculated for patients with follow-up and adjusted for age at disease onset, gender, race, ethnicity, and use of disease-modifying therapy (DMT). RESULTS: We included 271 cases (mean age at disease onset of 15.7years and 62% female) and 418 controls. Relapse data were available for 193 cases. There was no difference in prevalence of allergies or asthma between cases and controls. Patients with food allergies had fewer relapses compared to patients without food allergies (0.14 vs 0.48, p=0.01). CONCLUSIONS: While allergies and asthma are not associated with pediatric MS, cases with food allergies have fewer relapses compared to those without food allergies.


Subject(s)
Disease Susceptibility , Hypersensitivity/epidemiology , Multiple Sclerosis/epidemiology , Adolescent , Asthma/epidemiology , Case-Control Studies , Cohort Studies , Female , Humans , Male , Risk Factors
3.
Genes Immun ; 17(6): 358-62, 2016 09.
Article in English | MEDLINE | ID: mdl-27467283

ABSTRACT

Systemic lupus erythematous (SLE) is a chronic autoimmune disease associated with genetic and environmental risk factors. However, the extent to which genetic risk is causally associated with disease activity is unknown. We utilized longitudinal-targeted maximum likelihood estimation to estimate the causal association between a genetic risk score (GRS) comprising 41 established SLE variants and clinically important disease activity as measured by the validated Systemic Lupus Activity Questionnaire (SLAQ) in a multiethnic cohort of 942 individuals with SLE. We did not find evidence of a clinically important SLAQ score difference (>4.0) for individuals with a high GRS compared with those with a low GRS across nine time points after controlling for sex, ancestry, renal status, dialysis, disease duration, treatment, depression, smoking and education, as well as time-dependent confounding of missing visits. Individual single-nucleotide polymorphism (SNP) analyses revealed that 12 of the 41 variants were significantly associated with clinically relevant changes in SLAQ scores across time points eight and nine after controlling for multiple testing. Results based on sophisticated causal modeling of longitudinal data in a large patient cohort suggest that individual SLE risk variants may influence disease activity over time. Our findings also emphasize a role for other biological or environmental factors.


Subject(s)
Genetic Predisposition to Disease , Lupus Erythematosus, Systemic/genetics , Cohort Studies , Female , Humans , Likelihood Functions , Longitudinal Studies , Lupus Erythematosus, Systemic/ethnology , Male , Middle Aged , Polymorphism, Single Nucleotide , Risk Factors , Surveys and Questionnaires
4.
J Neurol Neurosurg Psychiatry ; 87(5): 454-60, 2016 May.
Article in English | MEDLINE | ID: mdl-26940586

ABSTRACT

OBJECTIVE: Previous studies on consumption of caffeine and risk of multiple sclerosis (MS) have yielded inconclusive results. We aimed to investigate whether consumption of coffee is associated with risk of MS. METHODS: Using two population-representative case-control studies (a Swedish study comprising 1620 cases and 2788 controls, and a US study comprising 1159 cases and 1172 controls), participants with different habits of coffee consumption based on retrospective data collection were compared regarding risk of MS, by calculating ORs with 95% CIs. Logistic regression models were adjusted for a broad range of potential confounding factors. RESULTS: Compared with those who reported no coffee consumption, the risk of MS was substantially reduced among those who reported a high consumption of coffee exceeding 900 mL daily (OR 0.70 (95% CI 0.49 to 0.99) in the Swedish study, and OR 0.69 (95% CI 0.50 to 0.96) in the US study). Lower odds of MS with increasing consumption of coffee were observed, regardless of whether coffee consumption at disease onset or 5 or 10 years prior to disease onset was considered. CONCLUSIONS: In accordance with studies in animal models of MS, high consumption of coffee may decrease the risk of developing MS. Caffeine, one component of coffee, has neuroprotective properties, and has been shown to suppress the production of proinflammatory cytokines, which may be mechanisms underlying the observed association. However, further investigations are needed to determine whether exposure to caffeine underlies the observed association and, if so, to evaluate its mechanisms of action.


Subject(s)
Coffee , Drinking , Multiple Sclerosis/epidemiology , Adult , Case-Control Studies , Female , Humans , Male , Protective Factors , Retrospective Studies , Sweden/epidemiology , United States/epidemiology , Young Adult
5.
Rev. bras. plantas med ; 17(2): 215-223, Apr-Jun/2015. graf
Article in English | LILACS | ID: lil-746130

ABSTRACT

RESUMO: The effects of anesthesia with the essential oil of Ocimum gratissimum (EOO) in parameters of stress after handling were investigated in silver catfish (Rhamdia quelen). EOO was obtained from the aerial parts by hydrodistillation. Juveniles were anesthetized with 70 or 300 mg L-1 EOO and submitted to air exposure for 1 minute. The fishes were sampled immediately or transferred to anesthetic-free aquaria until sampling. In the first experiment, juveniles had their blood collected at 0, 1, 4, and 8 h after handling to assay plasma cortisol and blood glucose levels. The unanesthetized animals were restrained manually for blood collection. In the second experiment, water samples of the recovery aquaria were collected to evaluate net ion fluxes at 0 - 4 h and 4 - 8 h. Water and ethanol controls were also performed under the same conditions. The results showed that the cortisol levels did not differ among the treatments. Hyperglycemia was verified in fish exposed to 70 and 300 mg L-1 EOO at 1 h and 4 h after handling. After 8 h, cortisol and glucose concentrations were lower or similar than those from immediately after handling for all treatments. EOO anesthesia prevented Na+ efflux observed in the control groups in both flux periods. There were net Cl- and K+ effluxes at 0 - 4 h and influxes at 4 - 8 h after handling in most treatments, and these fluxes did not differ among the treatments. The results suggest that EOO did not impair stress recovery and did not act as an additional handling stressor in silver catfish.


RESUMO: Os efeitos da anestesia com o óleo essencial de Ocimum gratissimum (EOO) em parâmetros de estresse após manuseio foram investigados em jundiás (Rhamdia quelen). EOO foi obtido a partir das partes aéreas por hidrodestilação. Os juvenis foram anestesiados com 70 ou 300 mg L-1 de EOO e expostos ao ar por 1 minuto. Os peixes foram amostrados imediatamente ou transferidos para aquários sem anestésico até amostragem. No primeiro experimento, os juvenis tiveram seu sangue coletado em 0, 1, 4, e 8 h após manuseio para avaliar os níveis de cortisol e glicemia. Os animais não anestesiados foram contidos manualmente para coleta sanguínea. No segundo experimento, amostras de água foram coletadas do aquário de recuperação dos animais para avaliação do fluxo iônico entre 0 - 4 h e 4 - 8 h. Grupos controles em água e etanol também foram realizados sobre as mesmas condições. Os resultados demonstraram que os níveis de cortisol não diferiram entre os tratamentos. Hiperglicemia foi detectada em peixes expostos a 70 e 300 mg L-1 de EOO em 1 h e 4 h após o manuseio. Após 8 h, os teores de cortisol e glicose foram menores ou similares aqueles imediatamente após o manuseio para todos os tratamentos. A anestesia com EOO preveniu o efluxo de Na+ observado para os grupos controle em ambos os períodos avaliados. Ocorreram efluxos de Cl- and K+ entre 0 - 4 h e influxos entre 4 - 8 h após o manuseio para a maioria dos tratamentos, e estes eventos não diferiram entre os tratamentos. Os resultados sugerem que o EOO não prejudica a recuperação do animal frente ao evento estressor ou atua como estressor adicional ao manuseio em jundiás.


Subject(s)
Oils, Volatile/pharmacology , Fishes , Anesthesia , Hydrocortisone/administration & dosage , Ocimum basilicum/anatomy & histology , Glucose/analysis
6.
Brain Res Bull ; 112: 7-13, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25617713

ABSTRACT

Monoamines levels in central nervous system have been associated with exercise performance and fatigue. The present study investigated whether intrinsic exercise capacity is associated with differential activity of monoamines in the caudate-putamen (CPu) and accumbens (ACC) nucleus. Male Wistar rats were subjected to a progressive testing protocol. Based on the maximal time of exercise in the progressive testing protocol (TEPmax), the animals were divided into low-performance (LP), high-performance (HP), and standard-performance (SP) groups. After classification, eight animals in each group were chosen randomly and evaluated in two experimental situations: rest (n=8) or moderate exercise (ME) at 60% of maximal velocity (n=8). The CPu and ACC were dissected for analyses of monoamine levels. At rest, HP rats exhibited higher 3,4-dihydroxyphenylacetic acid (DOPAC)/dopamine (DA) ratio and lower serotonin (5-HT) concentration compared other groups, and lower 5-hydroxyindoleacetic (5-HIAA) compared with the LP rats. The ME resulted in increased DOPAC/DA ratio in the CPu of all experimental groups. In both the CPu and ACC, ME increased 5-HIAA levels in SP and HP rats and 5-HIAA/5-HT ratio only in HP rats. Thus, our findings demonstrate that rats with natural intrinsic differences in performance to exercise exhibit alterations in dopaminergic and serotonergic systems at rest and after ME exercise until fatigue.


Subject(s)
Biogenic Monoamines/metabolism , Caudate Nucleus/metabolism , Physical Fitness/physiology , Putamen/metabolism , 3,4-Dihydroxyphenylacetic Acid/metabolism , Animals , Dopamine/metabolism , Fatigue , Hydroxyindoleacetic Acid/metabolism , Male , Random Allocation , Rats, Wistar , Rest , Serotonin/metabolism
7.
Genes Immun ; 15(7): 466-76, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25030428

ABSTRACT

There is a strong and complex genetic component to multiple sclerosis (MS). In addition to variation in the major histocompatibility complex (MHC) region on chromosome 6p21.3, 110 non-MHC susceptibility variants have been identified in Northern Europeans, thus far. The majority of the MS-associated genes are immune related; however, similar to most other complex genetic diseases, the causal variants and biological processes underlying pathogenesis remain largely unknown. We created a comprehensive catalog of putative functional variants that reside within linkage disequilibrium regions of the MS-associated genic variants to guide future studies. Bioinformatics analyses were also conducted using publicly available resources to identify plausible pathological processes relevant to MS and functional hypotheses for established MS-associated variants.


Subject(s)
Genetic Loci , Multiple Sclerosis/genetics , Polymorphism, Single Nucleotide , Case-Control Studies , Genetic Predisposition to Disease , Genome , Humans , Linkage Disequilibrium
8.
Braz J Med Biol Res ; 47(6): 499-504, 2014 Jun.
Article in English | MEDLINE | ID: mdl-25009838

ABSTRACT

Fish vaccination has been increasingly exploited as a tool to control pathogen infection. The production of immunoglobulin following vaccination might be affected by several factors such as management procedures, water temperature, and the presence of xenobiotics. In the present study, we aimed to investigate the kinetics of immunoglobulin production in silver catfish (Rhamdia quelen) inoculated with inactivated Aeromonas hydrophila and kept at two different water temperatures (17.4±0.46 or 21.3±0.36C). The effect of a second antigen inoculation and exposure of fish to sublethal concentrations of the herbicides atrazine and glyphosate at 10% of the lethal concentration (LC50-96h) on specific serum antibodies were also investigated. Antibodies to A. hydrophila were detected as early as 7 days post-inoculation and increased steadily up to 35 days. The kinetics of antibody production were similar in fish kept at 17.4±0.46 and 21.3±0.36C, and reinoculation of antigen at 21 days after priming failed to increase specific antibody levels. Intriguingly, we found that, in fish exposed to atrazine and glyphosate, the secretion of specific antibodies was higher than in non-exposed inoculated fish. These findings are important for the design of vaccines and vaccination strategies in Neotropical fish species. However, because atrazine and glyphosate are widespread contaminants of soil and water, their immune-stimulating effect could be harmful, in that fish living in herbicide-contaminated water might have increased concentrations of nonspecific antibodies that could mediate tissue injury.


Subject(s)
Catfishes/immunology , Gram-Negative Bacterial Infections/prevention & control , Herbicides/pharmacology , Immunoglobulins/biosynthesis , Vaccination , Aeromonas hydrophila/immunology , Animals , Antibodies/blood , Atrazine/pharmacology , Blood Proteins/isolation & purification , Catfishes/microbiology , Glycine/analogs & derivatives , Glycine/pharmacology , Gram-Negative Bacterial Infections/immunology , Immunoglobulins/drug effects , Injections, Intraperitoneal , Vaccines, Inactivated , Glyphosate
9.
Genes Immun ; 15(4): 210-7, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24598797

ABSTRACT

Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease affecting multiple organ systems and characterized by autoantibody formation to nuclear components. Although genetic variation within the major histocompatibility complex (MHC) is associated with SLE, its role in the development of clinical manifestations and autoantibody production is not well defined. We conducted a meta-analysis of four independent European SLE case collections for associations between SLE sub-phenotypes and MHC single-nucleotide polymorphism genotypes, human leukocyte antigen (HLA) alleles and variant HLA amino acids. Of the 11 American College of Rheumatology criteria and 7 autoantibody sub-phenotypes examined, anti-Ro/SSA and anti-La/SSB antibody subsets exhibited the highest number and most statistically significant associations. HLA-DRB1*03:01 was significantly associated with both sub-phenotypes. We found evidence of associations independent of MHC class II variants in the anti-Ro subset alone. Conditional analyses showed that anti-Ro and anti-La subsets are independently associated with HLA-DRB1*0301, and that the HLA-DRB1*03:01 association with SLE is largely but not completely driven by the association of this allele with these sub-phenotypes. Our results provide strong evidence for a multilevel risk model for HLA-DRB1*03:01 in SLE, where the association with anti-Ro and anti-La antibody-positive SLE is much stronger than SLE without these autoantibodies.


Subject(s)
Autoantibodies , HLA-DRB1 Chains , Lupus Erythematosus, Systemic/genetics , Models, Genetic , Autoantibodies/genetics , Autoantibodies/immunology , Europe , Female , HLA-DRB1 Chains/genetics , HLA-DRB1 Chains/immunology , Humans , Lupus Erythematosus, Systemic/immunology , Male
11.
Genes Immun ; 12(8): 667-71, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21614020

ABSTRACT

The major histocompatibility complex (MHC) class II transactivator gene (CIITA) encodes an important transcription factor required for human leukocyte antigens (HLA) class II MHC-restricted antigen presentation. MHC genes, including the HLA class II DRB1*03:01 allele, are strongly associated with systemic lupus erythematosus (SLE). Recently the rs4774 CIITA missense variant (+1632G/C) was reported to be associated with susceptibility to multiple sclerosis. In the current study, we investigated CIITA, DRB1*03:01 and risk of SLE using a multi-stage analysis. In stage 1, 9 CIITA variants were tested in 658 cases and 1363 controls (N=2021). In stage 2, rs4774 was tested in 684 cases and 2938 controls (N=3622). We also performed a meta-analysis of the pooled 1342 cases and 4301 controls (N=5643). In stage 1, rs4774(*)C was associated with SLE (odds ratio (OR)=1.24, 95% confidence interval (95% CI)=1.07-1.44, P=4.2 × 10(-3)). Similar results were observed in stage 2 (OR=1.16, 95% CI=1.02-1.33, P=8.5 × 10(-3)) and the meta-analysis of the combined data set (OR=1.20, 95% CI=1.09-1.33, P(meta)=2.5 × 10(-4)). In all three analyses, the strongest evidence for association between rs4774(*)C and SLE was present in individuals who carried at least one copy of DRB1*03:01 (P(meta)=1.9 × 10(-3)). Results support a role for CIITA in SLE, which appears to be stronger in the presence of DRB1*03:01.


Subject(s)
Genetic Predisposition to Disease , Lupus Erythematosus, Systemic/genetics , Mutation, Missense , Nuclear Proteins/genetics , Trans-Activators/genetics , Adult , Aged , Aged, 80 and over , Alleles , Female , HLA-DRB1 Chains/genetics , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Risk , Young Adult
12.
J Mater Sci Mater Med ; 22(5): 1357-64, 2011 May.
Article in English | MEDLINE | ID: mdl-21437637

ABSTRACT

The high incidence of wounds by second intention and the high costs associated with their treatment give rise to the need for the development of wound dressings that protect not only the wounds themselves but that are also able to promote cell proliferation and skin regeneration. Moreover, it is also very important that no damage to the new regenerated tissue is generated while removing the dressing. In this work, a novel wound dressing, which would be able to favor tissue repair and be removed at an appropriate scheduled moment by means of an external stimulus without promoting extensive damage to the new tissue, was produced and tested. Polyurethane membranes were modified by grafting polymers based on poly(n-isopropylacrylamide) (P-N-IPAAm). P-N-IPAAm undergoes a phase transition at approximately 32°C, which changes its behavior from hydrophilic (below 32°C) to hydrophobic. It was hypothesized that, by reducing the temperature near the wound dressing to values lower than 32°C, the detachment of the dressing would become more effective. The wound dressings containing P-N-IPAAm grafts were tested in vivo by covering excisional wounds produced in mice. The produced dressings were placed in direct contact with the lesions for 3 days. Results showed that the hypothermia due to anesthesia required to remove the dressings from mice lowered the local temperature to 28°C and favored the detachment of the wound dressings containing P-N-IPAAm grafts. Histological analyses showed that lesions covered by dressings presented less intense inflammatory events and denser connective tissue than did the wounds without dressings. The wounds covered by polyurethane membranes with P-N-IPAAm grafts showed signs of more intense re-epithelization and angiogenesis than did the lesions covered by polyurethane without grafts.


Subject(s)
Acrylamides/chemistry , Bandages , Biocompatible Materials/pharmacology , Polymers/chemistry , Wound Healing/physiology , Acrylic Resins , Animals , Biocompatible Materials/chemistry , Mice , Temperature , Wounds and Injuries/pathology
13.
Genes Immun ; 12(3): 235-8, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21248776

ABSTRACT

The major histocompatibility complex (MHC) class II transactivator gene (CIITA) encodes an important transcription factor regulating genes required for human leukocyte antigen (HLA) class II MHC-restricted antigen presentation. MHC genes, particularly HLA class II, are strongly associated with risk of developing rheumatoid arthritis (RA). Given the strong biological relationship between CIITA and HLA class II genes, a comprehensive investigation of CIITA variation in RA was conducted. This study tested 31 CIITA single-nucleotide polymorphisms in 2542 RA cases and 3690 controls (N=6232). All individuals were of European ancestry, as determined by ancestry informative genetic markers. No evidence for association between CIITA variation and RA was observed after a correction for multiple testing was applied. This is the largest study to fully characterize common genetic variation in CIITA, including an assessment of haplotypes. Results exclude even a modest role for common CIITA polymorphisms in susceptibility to RA.


Subject(s)
Arthritis, Rheumatoid/genetics , Nuclear Proteins/genetics , Trans-Activators/genetics , Adult , Aged , Aged, 80 and over , Alleles , Case-Control Studies , Female , Genetic Predisposition to Disease/genetics , Genotype , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Promoter Regions, Genetic/genetics , Young Adult
14.
Genes Immun ; 11(8): 660-4, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20574445

ABSTRACT

Several single-nucleotide polymorphism (SNP) genome-wide association studies (GWASs) have been completed in multiple sclerosis (MS). Follow-up studies of the variants with the most promising rankings, especially when supplemented by informed candidate gene selection, have proven to be extremely successful. In this study we report the results of a multi-stage replication analysis of the putatively associated SNPs identified in the Wellcome Trust Case Control Consortium non-synonymous SNP (nsSNP) screen. In total, the replication sample consisted of 3444 patients and 2595 controls. A combined analysis of the nsSNP screen and replication data provides evidence implicating a novel additional locus, rs3748816 in membrane metalloendopeptidase-like 1 (MMEL1; odds ratio=1.16, P=3.54 × 10⁻6) in MS susceptibility.


Subject(s)
ATP Citrate (pro-S)-Lyase/genetics , Kallikreins/genetics , Multiple Sclerosis/genetics , Neprilysin/genetics , Nerve Tissue Proteins/genetics , Polymorphism, Single Nucleotide , Adult , Case-Control Studies , Cell Cycle Proteins , Chromosome Mapping , Cytoskeletal Proteins , Genetic Predisposition to Disease , Genome-Wide Association Study , Genotype , Humans , Linkage Disequilibrium
15.
Genes Immun ; 11(6): 504-8, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20220768

ABSTRACT

CLEC16A, a putative immunoreceptor, was recently established as a susceptibility locus for type I diabetes and multiple sclerosis. Subsequently, associations between CLEC16A and rheumatoid arthritis (RA), Addison's disease and Crohn's disease have been reported. A large comprehensive and independent investigation of CLEC16A variation in RA was pursued. This study tested 251 CLEC16A single-nucleotide polymorphisms in 2542 RA cases (85% anti-cyclic citrullinated peptide (anti-CCP) positive) and 2210 controls (N=4752). All individuals were of European ancestry, as determined by ancestry informative genetic markers. No evidence for significant association between CLEC16A variation and RA was observed. This is the first study to fully characterize common genetic variation in CLEC16A including assessment of haplotypes and gender-specific effects. The previously reported association between RA and rs6498169 was not replicated. Results show that CLEC16A does not have a prominent function in susceptibility to anti-CCP-positive RA.


Subject(s)
Arthritis, Rheumatoid/genetics , Autoantibodies/biosynthesis , Genetic Association Studies/methods , Genetic Predisposition to Disease/genetics , Lectins, C-Type/genetics , Monosaccharide Transport Proteins/genetics , Peptides, Cyclic/genetics , Adult , Aged , Aged, 80 and over , Arthritis, Rheumatoid/blood , Autoantibodies/blood , Cohort Studies , Female , Humans , Lectins, C-Type/blood , Male , Middle Aged , Monosaccharide Transport Proteins/blood , Peptides, Cyclic/blood , Peptides, Cyclic/immunology , Polymorphism, Single Nucleotide/genetics , Young Adult
16.
Genes Immun ; 11(3): 209-18, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20054343

ABSTRACT

Human leukocyte antigen (HLA) class II DRB1 and DQB1 represent the major type I diabetes (T1D) genetic susceptibility loci; however, other genes in the HLA region are also involved in T1D risk. We analyzed 1411 pedigrees (2865 affected individuals) from the type I diabetes genetics consortium genotyped for HLA classical loci and for 12 single-nucleotide polymorphisms (SNPs) in the class III region previously shown to be associated with T1D in a subset of 886 pedigrees. Using the transmission disequilibrium test, we compared the proportion of SNP alleles transmitted from within the high-risk DR3 and DR4 haplotypes to affected offspring. Markers rs4151659 (mapping to CFB) and rs7762619 (mapping 5' of LTA) were the most strongly associated with T1D on DR3 (P=1.2 x 10(-9) and P=2 x 10(-12), respectively) and DR4 (P=4 x 10(-15) and P=8 x 10(-8), respectively) haplotypes. They remained significantly associated after stratifying individuals in analyses for B*1801, A*0101-B*0801, DPB1*0301, DPB1*0202, DPB1*0401 or DPB1*0402. Rs7762619 and rs4151659 are in strong linkage disequilibrium (LD) (r(2)=0.82) with each other, but a joint analysis showed that the association for each SNP was not solely because of LD. Our data support a role for more than one locus in the class III region contributing to risk of T1D.


Subject(s)
Diabetes Mellitus, Type 1/genetics , HLA Antigens/genetics , Haplotypes , Polymorphism, Single Nucleotide , Family Health , Female , Gene Frequency , Genetic Predisposition to Disease , Genetic Variation , Humans , Linkage Disequilibrium , Male , Pedigree , Risk Factors
17.
Genes Immun ; 11(3): 199-208, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20090771

ABSTRACT

Investigating genetic interactions (epistasis) has proven difficult despite the recent advances of both laboratory methods and statistical developments. With no 'best' statistical approach available, combining several analytical methods may be optimal for detecting epistatic interactions. Using a multi-stage analysis that incorporated supervised machine learning and methods of association testing, we investigated epistatic interactions with a well-established genetic factor (PTPN22 1858T) in a complex autoimmune disease (rheumatoid arthritis (RA)). Our analysis consisted of four principal stages: Stage I (data reduction)-identifying candidate chromosomal regions in 292 affected sibling pairs, by predicting PTPN22 concordance using multipoint identity-by-descent probabilities and a supervised machine learning algorithm (Random Forests); Stage II (extension analysis)-testing detailed genetic data within candidate chromosomal regions for epistasis with PTPN22 1858T in 677 cases and 750 controls using logistic regression; Stage III (replication analysis)-confirmation of epistatic interactions in 947 cases and 1756 controls; Stage IV (combined analysis)-a pooled analysis including all 1624 RA cases and 2506 control subjects for final estimates of effect size. A total of seven replicating epistatic interactions were identified. SNP variants within CDH13, MYO3A, CEP72 and near WFDC1 showed significant evidence for interaction with PTPN22, affecting susceptibility to RA.


Subject(s)
Arthritis, Rheumatoid/genetics , Artificial Intelligence , Logistic Models , Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics , Epistasis, Genetic , Genetic Predisposition to Disease , Genome-Wide Association Study , Genotype , Humans , Polymorphism, Single Nucleotide , Risk Assessment , Risk Factors , Siblings
18.
Diabetes Obes Metab ; 11 Suppl 1: 74-83, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19143818

ABSTRACT

AIM: Type 1 diabetes (T1D) is a complex trait for which variation in the classical human leucocyte antigen (HLA) loci within the Major Histocompatibility Complex (MHC) significantly influences disease risk. To date, HLA class II DR-DQ genes confer the strongest known genetic effect in T1D. HLA loci may also influence T1D through additional inherited or non-inherited effects. Evidence for the role of increased maternal-offspring HLA compatibility, and both parent-of-origin (POO) and non-inherited maternal HLA (NIMA) effects in autoimmune disease has been previously established. The current study tested hypotheses that classical HLA loci influence T1D through these mechanisms, in addition to genetic transmission of particular risk alleles. METHODS: The Type 1 Diabetes Genetics Consortium (T1DGC) cohort was of European descent and consisted of 2271 affected sib-pair families (total n = 11 023 individuals). Class I genes HLA-A, Cw and B, and class II genes HLA-DRB1, DQA1, DQB1, DPA1 and DPB1 were studied. The pedigree disequilibrium test was used to examine transmission of HLA alleles to individuals with T1D. Conditional logistic regression was used to model compatibility relationships between mother-offspring and father-offspring for all HLA loci. POO and NIMA effects were investigated by comparing frequencies of maternal and paternal transmitted and non-transmitted HLA alleles for each locus. Analyses were also stratified by gender of T1D-affected offspring. RESULTS: Strong associations were observed for all classical HLA loci except for DPA1, as expected. Compatibility differences between mother-offspring and father-offspring were not observed for any HLA loci. Furthermore, POO and NIMA HLA effects influencing T1D were not present. CONCLUSIONS: Maternal-offspring HLA compatibility, POO and NIMA effects for eight classical HLA loci were investigated. Results suggest that these HLA-related effects are unlikely to play a major role in the development of T1D.


Subject(s)
Diabetes Mellitus, Type 1/genetics , Genes, MHC Class II/genetics , Genetic Predisposition to Disease/genetics , Fathers , Female , Gene Frequency/genetics , Genotype , HLA-DQ Antigens/genetics , HLA-DQ beta-Chains , HLA-DR Antigens/genetics , HLA-DRB1 Chains , Humans , Linkage Disequilibrium/genetics , Male , Mothers , Pedigree
19.
Genes Immun ; 9(6): 493-500, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18580885

ABSTRACT

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system with a strong genetic component. Variation in the major histocompatibility complex on chromosome 6p21, specifically the HLA-DRB1*15 haplotype, is the strongest genetic factor for MS, yet it is estimated to account for only a portion of risk for the disease. Previous evidence has implicated the nitric oxide synthase gene (NOS2A) encoding inducible NOS on chromosome 17q11 as a potential MS susceptibility gene. To determine whether variation in the NOS2A gene contributes to MS risk, we investigated a total of 50 polymorphisms within or flanking the locus for evidence of association using a comprehensive analytical strategy. A total of 6265 members from 1858 well-characterized MS families were utilized. No evidence for overtransmission of any individual single-nucleotide polymorphism allele or haplotype to the MS-affected individuals was observed. Furthermore, different transmission rates were not observed in either DRB1*15-positive or DRB1*15-negative family subgroups, or when extreme clinical outcomes characterizing disease progression were examined. The very largest study of NOS2A variation in MS, to date, excludes even a modest role for this locus in susceptibility.


Subject(s)
Genetic Predisposition to Disease , Multiple Sclerosis/genetics , Nitric Oxide Synthase Type II/genetics , Case-Control Studies , HLA-DR Antigens/genetics , HLA-DRB1 Chains , Multiple Sclerosis/immunology , Polymorphism, Genetic , Polymorphism, Single Nucleotide
20.
Arq. bras. med. vet. zootec ; 60(3): 755-761, jun. 2008. graf
Article in English | LILACS | ID: lil-487925

ABSTRACT

The stress in dorado fingerlings (Salminus brasiliensis) caused by transportation at densities of 5, 10, and 15g/l after 4, 8, and 12h was evaluated by the concentration of tissue cortisol measured by ELISA. The conditions of transportation were simulated on an orbital table shaker with horizontal movements, inside 15 litres plastic bags filled with 4 litres of water and pure oxygen. Cortisol concentrations increased in all densities after 4h of transportation converging to a common concentration at the end of the tested times. Electrical conductivity of water increased with density and transportation time. The transportation caused stress on fish, but the increase on density and in times of transportation did not cause mortality to fingerlings. The transportation of S. brasiliensis fingerlings can be done without mortality or apparent injuries to animals until the maximum analyzed density of 15g/l and up to 12h.


O estresse em alevinos de dourado (Salminus brasiliensis) causado pelo transporte nas densidades 5, 10 e 15g/l após 4, 8 e 12h, foi avaliado por meio dos níveis de cortisol tecidual quantificado por ELISA. O transporte foi simulado em uma mesa agitadora com movimento orbital, em sacos plásticos de 15 litros, contendo 4 litros de água e oxigênio puro. As concentrações de cortisol aumentaram em todas as densidades após 4h de transporte e convergiram para uma mesma concentração ao final dos tempos de transporte. A condutividade elétrica da água aumentou com a densidade e com os tempos de transporte. O transporte causou estresse aos peixes, mas o aumento da densidade e do tempo de transporte não causou mortalidade nos alevinos. O transporte de alevinos de S. brasiliensis pode ser realizado até a densidade máxima avaliada de 15g/l e o tempo máximo de 12h sem que haja mortalidade ou danos aparentes aos animais.


Subject(s)
Animals , Enzyme-Linked Immunosorbent Assay , Fishes , Hydrocortisone , Stress, Physiological
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