Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 94
Filtrar
1.
Eur J Neurol ; 2020 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-32741033

RESUMO

BACKGROUND AND PURPOSE: Unexpected stressful life events may alter immune function and affect susceptibility to autoimmune diseases including multiple sclerosis (MS). Current results from epidemiological investigations examining the role of stress in MS remain inconsistent. The aim was to conduct the hitherto largest population-based case-control study on this topic. METHODS: Extensive questionnaire information collected on lifestyle environmental factors available for 2930 incident MS cases and 6170 controls were used to assess the association of 10 major life events that had occurred before disease onset with the risk of MS by unconditional logistic regressions, adjusting for potential confounders. Stratified analyses were also performed by sex and time. RESULTS: Compelling evidence was found for a link between major life events and risk of MS - most events significantly increased disease risk by 17%-30%. It was further observed that women were affected to a greater extent than men under certain stressful scenarios, and that most events that happened recently (≤5 years prior to MS onset) had significant effects on MS, indicating a critical window in disease development. CONCLUSION: Stressful life events may have an adverse effect on the risk of MS. Research into the mechanisms of this observation may give important clues to triggering pathogenetic events in MS.

3.
Genes Immun ; 18(2): 75-81, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28332559

RESUMO

The influenza A(H1N1)pdm09 vaccination campaign from 2009 to 2010 was associated with a sudden increase in the incidence of narcolepsy in several countries. Narcolepsy with cataplexy is strongly associated with the human leukocyte antigen (HLA) class II DQB1*06:02 allele, and protective associations with the DQB1*06:03 allele have been reported. Several non-HLA gene loci are also associated, such as common variants of the T-cell receptor-α (TRA), the purinergic receptor P2RY11, cathepsin H (CTSH) and TNFSF4/OX40L/CD252. In this retrospective multicenter study, we investigated if these predisposing gene loci were also involved in vaccination-associated narcolepsy. We compared HLA- along with single-nucleotide polymorphism genotypes for non-HLA regions between 42 Pandemrix-vaccinated narcolepsy cases and 1990 population-based controls. The class II gene loci associations supported previous findings. Nominal association (P-value<0.05) with TRA as well as suggestive (P-value<0.1) associations with P2RY11 and CTSH were found. These associations suggest a very strong gene-environment interaction, in which the influenza A(H1N1)pdm09 strain or Pandemrix vaccine can act as potent environmental triggers.


Assuntos
Interação Gene-Ambiente , Vacinas contra Influenza/efeitos adversos , Narcolepsia/induzido quimicamente , Narcolepsia/genética , Cadeias beta de HLA-DQ/genética , Humanos , Vírus da Influenza A Subtipo H1N1 , Estudos Retrospectivos
4.
Genes Immun ; 18(1): 48-56, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28053322

RESUMO

Rheumatoid arthritis (RA) patients can be stratified into two subgroups defined by the presence or absence of antibodies against citrullinated circular peptides (anti-CCP) with most of the genetic association found in anti-CCP positive RA. Here we addressed the role of VAV1, previously associated to multiple sclerosis (MS), in the pathogenesis of RA in experimental models and in a genetic association study. Experimental arthritis triggered by pristane or collagen type II was induced in DA rats and in the DA.BN-R25 congenic line that carries a polymorphism in Vav1. Difference in arthritis severity was observed only after immunization with pristane. In a case-control study, 34 SNPs from VAV1 locus were analyzed by Immunochip genotyping in 11475 RA patients (7573 anti-CCP positive and 3902 negative) and 15,870 controls in six cohorts of European Caucasians. A combination of the previous MS-associated haplotype and two additional SNPs was associated with anti-CCP negative RA (alleles G-G-A-A of rs682626-rs2546133-rs2617822-rs12979659, OR=1.13, P=1.27 × 10-5). The same markers also contributed to activity of RA at baseline with the strongest association in the anti-CCP negative group for the rs682626-rs12979659 G-A haplotype (ß=-0.283, P=0.0048). Our study suggests a role for VAV1 and T-cell signaling in the pathology of anti-CCP-negative RA.


Assuntos
Artrite Experimental/genética , Artrite Reumatoide/genética , Doenças Autoimunes/genética , Peptídeos Cíclicos/imunologia , Polimorfismo Genético/genética , Proteínas Proto-Oncogênicas c-vav/genética , Animais , Artrite Experimental/sangue , Artrite Experimental/imunologia , Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Doenças Autoimunes/sangue , Doenças Autoimunes/imunologia , Biomarcadores/análise , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Prognóstico , Ratos , Ratos Endogâmicos BN
5.
Genes Immun ; 16(8): 541-51, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26513234

RESUMO

The possible interrelations between human leukocyte antigen (HLA)-DQ, non-HLA single-nucleotide polymorphisms (SNPs) and islet autoantibodies were investigated at clinical onset in 1-34-year-old type 1 diabetes (T1D) patients (n=305) and controls (n=203). Among the non-HLA SNPs reported by the Type 1 Diabetes Genetics Consortium, 24% were supported in this Swedish replication set including that the increased risk of minor PTPN22 allele and high-risk HLA was modified by GAD65 autoantibodies. The association between T1D and the minor AA+AC genotype in ERBB3 gene was stronger among IA-2 autoantibody-positive patients (comparison P=0.047). The association between T1D and the common insulin (AA) genotype was stronger among insulin autoantibody (IAA)-positive patients (comparison P=0.008). In contrast, the association between T1D and unidentified 26471 gene was stronger among IAA-negative (comparison P=0.049) and IA-2 autoantibody-negative (comparison P=0.052) patients. Finally, the association between IL2RA and T1D was stronger among IAA-positive than among IAA-negative patients (comparison P=0.028). These results suggest that the increased risk of T1D by non-HLA genes is often modified by both islet autoantibodies and HLA-DQ. The interactions between non-HLA genes, islet autoantibodies and HLA-DQ should be taken into account in T1D prediction studies as well as in prevention trials aimed at inducing immunological tolerance to islet autoantigens.


Assuntos
Autoanticorpos/imunologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Antígenos HLA-DQ/genética , Ilhotas Pancreáticas/imunologia , Adolescente , Adulto , Autoanticorpos/genética , Criança , Pré-Escolar , Antígenos HLA-DQ/imunologia , Humanos , Lactente , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Receptor ErbB-3/genética , Adulto Jovem
6.
J Intern Med ; 278(3): 264-76, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25683265

RESUMO

BACKGROUND: Type 1 narcolepsy is a neurological disorder characterized by excessive daytime sleepiness and cataplexy associated with the HLA allele DQB1*06:02. Genetic predisposition along with external triggering factors may drive autoimmune responses, ultimately leading to the selective loss of hypocretin-positive neurons. OBJECTIVE: The aim of this study was to investigate potential aetiological factors in Swedish cases of postvaccination (Pandemrix) narcolepsy defined by interferon-gamma (IFNγ) production from immune cells in response to molecularly defined targets. METHODS: Cellular reactivity defined by IFNγ production was examined in blood from 38 (HLA-DQB1*06:02(+) ) Pandemrix-vaccinated narcolepsy cases and 76 (23 HLA-DQB1*06:02(+) and 53 HLA-DQB1*06:02(-) ) control subjects, matched for age, sex and exposure, using a variety of different antigens: ß-haemolytic group A streptococcal (GAS) antigens (M5, M6 and streptodornase B), influenza (the pandemic A/H1N1/California/7/09 NYMC X-179A and A/H1N1/California/7/09 NYMC X-181 vaccine antigens, previous Flu-A and -B vaccine targets, A/H1N1/Brisbane/59/2007, A/H1N1/Solomon Islands/3/2006, A/H3N2/Uruguay/716/2007, A/H3N2/Wisconsin/67/2005, A/H5N1/Vietnam/1203/2004 and B/Malaysia/2506/2004), noninfluenza viral targets (CMVpp65, EBNA-1 and EBNA-3) and auto-antigens (hypocretin peptide, Tribbles homolog 2 peptide cocktail and extract from rat hypothalamus tissue). RESULTS: IFN-γ production was significantly increased in whole blood from narcolepsy cases in response to streptococcus serotype M6 (P = 0.0065) and streptodornase B protein (P = 0.0050). T-cell recognition of M6 and streptodornase B was confirmed at the single-cell level by intracellular cytokine (IL-2, IFNγ, tumour necrosis factor-alpha and IL-17) production after stimulation with synthetic M6 or streptodornase B peptides. Significantly, higher (P = 0.02) titres of serum antistreptolysin O were observed in narcolepsy cases, compared to vaccinated controls. CONCLUSION: ß-haemolytic GAS may be involved in triggering autoimmune responses in patients who developed narcolepsy symptoms after vaccination with Pandemrix in Sweden, characterized by a Streptococcus pyogenes M-type-specific IFN-γ cellular immune response.


Assuntos
Narcolepsia/imunologia , Streptococcus agalactiae/imunologia , Estreptodornase e Estreptoquinase/imunologia , Adolescente , Adulto , Idoso , Antiestreptolisina/sangue , Criança , Feminino , Humanos , Interferon gama/biossíntese , Interferon gama/sangue , Masculino , Pessoa de Meia-Idade , Narcolepsia/epidemiologia , Fragmentos de Peptídeos/biossíntese , Fragmentos de Peptídeos/sangue , Sorotipagem , Streptococcus agalactiae/enzimologia , Suécia/epidemiologia
7.
Genes Immun ; 15(3): 162-7, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24430172

RESUMO

The human leukocyte antigen (HLA) is the main genetic determinant of multiple sclerosis (MS) risk. Within the HLA, the class II HLA-DRB1*15:01 allele exerts a disease-promoting effect, whereas the class I HLA-A*02 allele is protective. The CIITA gene is crucial for expression of class II HLA molecules and has previously been found to associate with several autoimmune diseases, including MS and type 1 diabetes. We here performed association analyses with CIITA in 2000 MS cases and up to 6900 controls as well as interaction analysis with HLA. We find that the previously investigated single-nucleotide polymorphism rs4774 is associated with MS risk in cases carrying the HLA-DRB1*15 allele (P=0.01, odds ratio (OR): 1.21, 95% confidence interval (CI): 1.04-1.40) or the HLA-A*02 allele (P=0.01, OR: 1.33, 95% CI: 1.07-1.64) and that these associations are independent of the adjacent confirmed MS susceptibility gene CLEC16A. We also confirm interaction between rs4774 and HLA-DRB1*15:01 such that individuals carrying the risk allele for rs4774 and HLA-DRB1*15:01 have a higher than expected risk for MS. In conclusion, our findings support previous data that variability in the CIITA gene affects MS risk, but also that the effect is modulated by MS-associated HLA haplotypes. These findings further underscore the biological importance of HLA for MS risk.


Assuntos
Epistasia Genética , Variação Genética , Antígenos HLA/genética , Esclerose Múltipla/genética , Proteínas Nucleares/genética , Transativadores/genética , Alelos , Estudos de Casos e Controles , Frequência do Gene , Genótipo , Antígenos HLA/imunologia , Humanos , Desequilíbrio de Ligação , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/imunologia , Razão de Chances , Polimorfismo de Nucleotídeo Único
8.
J Intern Med ; 275(6): 640-51, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24354957

RESUMO

OBJECTIVE: The main aim of this study was to identify foetal susceptibility genes on chromosome six for Ro/SSA autoantibody-mediated congenital heart block. SUBJECTS AND DESIGN: Single nucleotide polymorphism (SNP) genotyping of individuals in the Swedish Congenital Heart Block (CHB) study population was performed. Low-resolution HLA-A, -Cw and -DRB1 allele typing was carried out in 86 families comprising 339 individuals (86 Ro/SSA autoantibody-positive mothers, 71 fathers, 87 CHB index cases and 95 unaffected siblings). RESULTS: A case-control comparison between index cases and population-based out-of-study controls (n = 1710) revealed association of CHB with 15 SNPs in the 6p21.3 MHC locus at a chromosome-wide significance of P < 2.59 × 10(-6) (OR 2.21-3.12). In a family-based analysis of association of SNP markers as well as distinct MHC class I and II alleles with CHB, HLA-DRB1*04 and HLA-Cw*05 variants were significantly more frequently transmitted to affected individuals (P < 0.03 and P < 0.05, respectively), whilst HLA-DRB1*13 and HLA-Cw*06 variants were significantly less often transmitted to affected children (P < 0.04 and P < 0.03). We further observed marked association of increased paternal (but not maternal) HLA-DRB1*04 transmission to affected offspring (P < 0.02). CONCLUSIONS: HLA-DRB1*04 and HLA-Cw*05 were identified as novel foetal HLA allele variants that confer susceptibility to CHB in response to Ro/SSA autoantibody exposure, whilst DRB1*13 and Cw*06 emerged as protective alleles. Additionally, we demonstrated a paternal contribution to foetal susceptibility to CHB for the first time.


Assuntos
Antígenos HLA-C/genética , Cadeias HLA-DRB1/genética , Bloqueio Cardíaco/congênito , Adulto , Anticorpos Antinucleares , Criança , Saúde da Família , Pai , Feminino , Frequência do Gene , Genes MHC da Classe II/genética , Predisposição Genética para Doença , Bloqueio Cardíaco/epidemiologia , Bloqueio Cardíaco/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Suécia/epidemiologia
9.
Scand J Immunol ; 79(2): 137-48, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24313339

RESUMO

We determined A/H1N1-hemagglutinin (HA) antibodies in relation to HLA-DQ genotypes and islet autoantibodies at clinical diagnosis in 1141 incident 0.7-to 18-year-old type 1 diabetes patients diagnosed April 2009-December 2010. Antibodies to (35) S-methionine-labelled A/H1N1 hemagglutinin were determined in a radiobinding assay in patients diagnosed before (n = 325), during (n = 355) and after (n = 461) the October 2009-March 2010 Swedish A(H1N1)pdm09 vaccination campaign, along with HLA-DQ genotypes and autoantibodies against GAD, insulin, IA-2 and ZnT8 transporter. Before vaccination, 0.6% patients had A/H1N1-HA antibodies compared with 40% during and 27% after vaccination (P < 0.0001). In children <3 years of age, A/H1N1-HA antibodies were found only during vaccination. The frequency of A/H1N1-HA antibodies during vaccination decreased after vaccination among the 3 < 6 (P = 0.006) and 13 < 18 (P = 0.001), but not among the 6 < 13-year-olds. HLA-DQ2/8 positive children <3 years decreased from 54% (15/28) before and 68% (19/28) during, to 30% (9/30) after vaccination (P = 0.014). Regardless of age, DQ2/2; 2/X (n = 177) patients had lower frequency (P = 0.020) and levels (P = 0.042) of A/H1N1-HA antibodies compared with non-DQ2/2; 2/X (n = 964) patients. GADA frequency was 50% before, 60% during and 51% after vaccination (P = 0.009). ZnT8QA frequency increased from 30% before to 34% during and 41% after vaccination (P = 0.002). Our findings suggest that young (<3 years) along with DQ2/2; 2/X patients were low responders to Pandemrix(®) . As the proportion of DQ2/8 patients <3 years of age decreased after vaccination and the frequencies of GADA and ZnT8QA were enhanced, it cannot be excluded that the vaccine affected clinical onset of type 1 diabetes.


Assuntos
Anticorpos Antivirais/sangue , Diabetes Mellitus Tipo 1/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/imunologia , Vacinação , Adolescente , Autoanticorpos/sangue , Proteínas de Transporte de Cátions/genética , Criança , Pré-Escolar , Glutamato Descarboxilase/metabolismo , Antígenos HLA-DQ/genética , Humanos , Modelos Logísticos , Transportador 8 de Zinco
10.
Mult Scler ; 20(2): 165-73, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23999606

RESUMO

BACKGROUND: Epidemiological data suggest a role for common viruses in the pathogenesis of multiple sclerosis (MS), and recent data showed a negative association of past cytomegalovirus (CMV) infection on pediatric MS risk. OBJECTIVE: Our aim was to analyze the association of CMV infection with MS risk in an adult case-control material. A meta-analysis was performed to validate our findings. METHODS: Epidemiological Investigation in MS (EIMS) is a case-control study with incident cases and population-based controls. Anti-CMV antibody titers were measured with ELISA, and HLA-A and DRB1 genotyping was performed with SSP-PCR, in 658 MS cases, who all fulfilled the McDonald criteria for MS, and 786 controls. RESULTS: CMV seropositivity was associated with a decreased MS risk, OR = 0.73 (0.58-0.92 95% CI), p = 0.005, adjusted for index age, gender, smoking, sun exposure, EBNA1 IgG titer and HLA-A*02 and DRB1*15. When we removed all cases and controls younger than 18 years at index, the protective effect was still apparent. CONCLUSIONS: CMV is negatively associated with adult-onset MS pathology, consistent with results from a study on pediatric MS cases. It remains to be shown whether this negative association is due to a true protective effect of CMV infection on MS risk.


Assuntos
Infecções por Citomegalovirus/epidemiologia , Esclerose Múltipla/virologia , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
11.
Mult Scler ; 19(7): 863-70, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23175382

RESUMO

BACKGROUND: The mechanisms of multiple sclerosis (MS) pathogenesis are still largely unknown. The heterogeneity of disease manifestations make the prediction of prognosis and choice of appropriate treatment protocols challenging. Recently, increased cerebrospinal fluid (CSF) levels of the B-cell chemokine CXCL13 was proposed as a possible marker for a more severe disease course and conversion from clinically isolated syndrome (CIS) to relapsing-remitting MS (RRMS). OBJECTIVE: To investigate whether there are genetic susceptibility variants in MS that correlate with the levels of CXCL13 present in the CSF of MS patients. METHODS: We genotyped the human leukocyte antigens HLA-DRB1 and HLA-A, plus a panel of single nucleotide polymorphisms (SNPs) that have been associated with susceptibility to MS and then correlated the genotypes with the levels of CXCL13, as measured with ELISA in the CSF of a total of 663 patients with MS, CIS, other neurological diseases (OND) or OND with an inflammatory component (iOND). RESULTS: Presence of the HLA-DRB1*15 and the MS risk genotypes for SNPs in the RGS1, IRF5 and OLIG3/TNFAIP3 gene regions correlated significantly with increased levels of CXCL13. CONCLUSION: Our results pointed towards a genetic predisposition for increased CXCL13 levels, which in MS patients correlates with the severity of the disease course. These findings encourage further investigation and replication, in an independent patient cohort.


Assuntos
Quimiocina CXCL13/líquido cefalorraquidiano , Predisposição Genética para Doença/genética , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/genética , Biomarcadores/líquido cefalorraquidiano , Ensaio de Imunoadsorção Enzimática , Genótipo , Antígenos HLA-A/genética , Cadeias HLA-DRB1/genética , Humanos , Polimorfismo de Nucleotídeo Único , Prognóstico , Fatores de Risco , Transcriptoma
12.
Diabetes Metab Res Rev ; 29(1): 85-9, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23081842

RESUMO

BACKGROUND: There are seasonal variations and gender differences in incidence of type 1 diabetes (T1D), metabolic control and responses to immune interventions at onset of the disease. We hypothesized that there are seasonal and gender differences in residual insulin secretion already at diagnosis of T1D. METHODS: In 2005, a national study, the Better Diabetes Diagnosis, was started to classify all newly diagnosed children and adolescents with diabetes. About 95% (3824/4017) of the patients were classified as T1D, and our analyses are based on the patients with T1D. RESULTS: C-peptide was lower in younger children, 0-10 years of age (0.23 ± 0.20 nmol/L) than in older children, 11-18 years of age (0.34 ± 0.28 nmol/L) (p < 0.000 ). There was a seasonal variation in non-fasting serum C-peptide, significantly correlated to the seasonal variation of diagnosis (p < 0.01). Most children were diagnosed in January, February and March as well as in October when C-peptide was highest, whereas fewer patients were diagnosed in April and May when serum C-peptide was significantly lower (p < 0.01). The seasonal variation of C-peptide was more pronounced in boys than in girls (p < 0.000 and p < 0.01, respectively). Girls had higher C-peptide than boys (p < 0.05), especially in early puberty. CONCLUSIONS: Both seasonal and gender differences in residual beta cell function exist already at diagnosis of T1D. These observations have consequences for treatment and for randomizing patients in immune intervention clinical trials.


Assuntos
Peptídeo C/sangue , Diabetes Mellitus Tipo 1/metabolismo , Células Secretoras de Insulina/metabolismo , Estações do Ano , Caracteres Sexuais , Adolescente , Glicemia/metabolismo , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Lactente , Masculino , Estudos Prospectivos
13.
Genes Immun ; 13(8): 632-40, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23052709

RESUMO

The major histocompatibility complex class II transactivator (CIITA) gene (16p13) has been reported to associate with susceptibility to multiple sclerosis, rheumatoid arthritis and myocardial infarction, recently also to celiac disease at genome-wide level. However, attempts to replicate association have been inconclusive. Previously, we have observed linkage to the CIITA region in Scandinavian type 1 diabetes (T1D) families. Here we analyze five Swedish T1D cohorts and a combined control material from previous studies of CIITA. We investigate how the genotype distribution within the CIITA gene varies depending on age, and the association to T1D. Unexpectedly, we find a significant difference in the genotype distribution for markers in CIITA (rs11074932, P=4 × 10(-5) and rs3087456, P=0.05) with respect to age, in the collected control material. This observation is replicated in an independent cohort material of about 2000 individuals (P=0.006, P=0.007). We also detect association to T1D for both markers, rs11074932 (P=0.004) and rs3087456 (P=0.001), after adjusting for age at sampling. The association remains independent of the adjacent T1D risk gene CLEC16A. Our results indicate an age-dependent variation in CIITA allele frequencies, a finding of relevance for the contrasting outcomes of previously published association studies.


Assuntos
Diabetes Mellitus Tipo 1/genética , Grupo com Ancestrais do Continente Europeu , Predisposição Genética para Doença , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Transativadores/genética , Adolescente , Adulto , Fatores Etários , Alelos , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Frequência do Gene , Humanos , Lactente , Recém-Nascido , Lectinas Tipo C/genética , Desequilíbrio de Ligação , Masculino , Proteínas de Transporte de Monossacarídeos/genética , Suécia
14.
Eur J Neurol ; 19(7): 955-62, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22289117

RESUMO

BACKGROUND: Both insufficient exposure to sunlight and vitamin D deficiency have been associated with an increased risk for multiple sclerosis (MS). An interaction between human leukocyte antigen HLA-DRB1*15 and vitamin D in MS was recently proposed. We investigated the association between previous exposure to ultraviolet radiation (UVR), vitamin D status at inclusion in the study, and MS risk including the interaction of these factors with HLA-DRB1*15. METHODS: A population-based case-control study involving 1013 incident cases of MS and 1194 controls was performed in Sweden during 2005-2010. Subjects were classified according to their UVR exposure habits, vitamin D status, and HLA genotypes. The associations between different sun exposure habits/vitamin D levels and MS were calculated as odds ratios (OR) with 95% confidence intervals (CI) using logistic regression. Potential interaction was evaluated by calculating the attributable proportion due to interaction. RESULTS: Subjects with low UVR exposure had a significantly increased risk of MS compared with those who reported the highest exposure (OR 2.2, 95% CI 1.5-3.3). Similarly, subjects who had 25-hydroxy-vitamin D levels less than 50 nM/l had an increased risk for MS (OR 1.4, 95% CI 1.2-1.7). The association between UVR exposure and MS risk persisted after adjustment for vitamin D status. There was no interaction with HLA-DRB1*15 carriage. CONCLUSIONS: UVR and vitamin D seem to affect MS risk in adults independently of HLA-DRB1*15 status. UVR exposure may also exert a protective effect against developing MS via other pathways than those involving vitamin D.


Assuntos
Cadeias HLA-DRB1/metabolismo , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/genética , Vigilância da População , Luz Solar , Adulto , Estudos de Casos e Controles , Regulação para Baixo/genética , Feminino , Cadeias HLA-DRB1/efeitos adversos , Humanos , Masculino , Esclerose Múltipla/etiologia , Vigilância da População/métodos , Fatores de Risco , Vitamina D/análogos & derivados , Vitamina D/metabolismo , Vitamina D/fisiologia , Adulto Jovem
15.
Genes Immun ; 13(1): 14-20, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21776012

RESUMO

Epstein-Barr virus (EBV) infection, history of infectious mononucleosis (IM) and HLA-A and DRB1 have all been proposed as risk factors for multiple sclerosis (MS). Our aim was to analyse possible interactions between antibodies against Epstein-Barr virus nuclear antigen 1 (EBNA1) or EBNA1 fragments, presence of DRB1*15 and absence of A*02. The study population includes newly diagnosed cases and matched controls. Interaction on the additive scale was calculated using attributable proportion due to interaction (AP), which is the proportion of the incidence among individuals exposed to two interacting factors that is attributable to the interaction per se. IM showed association with MS, odds ratio (OR)=1.89 (1.45-2.48% confidence interval (CI)), as did raised EBNA1 IgG OR=1.74 (1.38-2.18 95%CI). All EBNA1 fragment IgGs were associated with MS risk. However, EBNA1 fragment 385-420 IgG levels were more strongly associated to MS than total EBNA1 IgG, OR=3.60 (2.75-4.72 95%CI), and also interacted with both DRB1*15 and absence of A*02, AP 0.60 (0.45-0.76 95%CI) and AP 0.39 (0.18-0.61 95%CI), respectively. The observed interaction between HLA class I and II genotype and reactivity to EBV-related epitopes suggest that the mechanism through which HLA genes influence the risk of MS may, at least in part, involve the immune control of EBV infection.


Assuntos
Antígenos HLA/genética , Herpesvirus Humano 4/imunologia , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Antígenos HLA/imunologia , Antígenos HLA-A/genética , Antígenos HLA-A/imunologia , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB1/imunologia , Humanos , Imunoglobulina G/imunologia , Mononucleose Infecciosa/genética , Mononucleose Infecciosa/imunologia , Mononucleose Infecciosa/virologia , Pessoa de Meia-Idade , Esclerose Múltipla/virologia , Fatores de Risco , Fumar/efeitos adversos , Adulto Jovem
16.
Int J Obes (Lond) ; 36(5): 718-24, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-21712811

RESUMO

OBJECTIVE: Type 1 diabetes and obesity has increased in childhood. We therefore tested the hypothesis that type 1 diabetes human leukocyte antigen DQ (HLA-DQ) risk genotypes may be associated with increased body mass index (BMI). DESIGN: The type 1 diabetes high-risk HLA-DQ A1*05:01-B1*02:01/A1*03:01-B1*03:02 genotype along with lower risk DQ genotypes were determined at the time of clinical onset by PCR and hybridization with allele-specific probes. BMI was determined after diabetes was stabilized. SUBJECTS: A total of 2403 incident type 1 diabetes children below 18 years of age were ascertained in the Swedish national Better Diabetes Diagnosis (BDD) study between May 2005 to September 2009. All children classified with type 1 diabetes, including positivity for at least one islet autoantibody, were investigated. RESULTS: Overall, type 1 diabetes HLA-DQ risk was negatively associated with BMI (P<0.0008). The proportion of the highest risk A1*05:01-B1*02:01/A1*03:01-B1)03:02 genotype decreased with increasing BMI (P<0.0004). However, lower risk type 1 diabetes DQ genotypes were associated with an increased proportion of patients who were overweight or obese (P<0.0001). Indeed, the proportion of patients with the low-risk A1*05:01-B1*02:01/A1*05:01-B1*02:01 genotype increased with increasing BMI (P<0.003). The magnitude of association on the multiplicative scale between the A1*05:01-B1*02:01/A1*05:01-B1*02:01 genotype and increased BMI was significant (P<0.006). The odds ratio in patients with this genotype of being obese was 1.80 (95% confidence interval 1.21-2.61; P<0.006). The increased proportion of overweight type 1 diabetes children with the A1*05:01-B1*02:01 haplotype was most pronounced in children diagnosed between 5 and 9 years of age. CONCLUSIONS: Susceptibility for childhood type 1 diabetes was unexpectedly found to be associated with the A1*05:01-B1*02:01/A1*05:01-B1*02:01 genotype and an increased BMI. These results support the hypothesis that overweight may contribute to the risk of type 1 diabetes in children positive for HLA-DQ A1*05:01-B1*02:01.


Assuntos
Índice de Massa Corporal , Diabetes Mellitus Tipo 1/genética , Antígenos HLA-DQ/genética , Haplótipos , Obesidade/genética , Adolescente , Fatores Etários , Criança , Pré-Escolar , Estudos de Coortes , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Obesidade/epidemiologia , Razão de Chances , Estudos Prospectivos , Suécia/epidemiologia
17.
Pediatr Diabetes ; 13(1): 45-50, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21910810

RESUMO

AIM: To report C-peptide results in newly diagnosed patients and the relation to clinical diagnosis of diabetes. METHODS: A nation-wide cohort, the Better Diabetes Diagnosis study was used to determine serum C-peptide at diagnosis in 2734 children and adolescents. Clinical data were collected at diagnosis and follow-up. C-peptide was determined in a validated and controlled time-resolved fluoroimmunoassay. RESULTS: The clinical classification of diabetes, before any information on human leukocyte antigen, islet autoantibodies, or C-peptide was received, was type 1 diabetes (T1D) in 93%, type 2 diabetes (T2D) in 1.9%, maturity onset diabetes of the young (MODY) in 0.8%, secondary diabetes (0.6%), while 3.3% could not be classified. In a random, non-fasting serum sample at diagnosis, 56% of the patients had a C-peptide value >0.2 nmol/L. Children classified as T2D had the highest mean C-peptide (1.83 + 1.23 nmol/L) followed by MODY (1.04 ± 0.71 nmol/L) and T1D (0.28 ± 0.25 nmol/L). Only 1/1037 children who had C-peptide <0.2 nmol/L at diagnosis was classified with a type of diabetes other than T1D. Predictive value of C-peptide >1.0 nmol/L for the classification of either T2D or MODY was 0.46 [confidence interval 0.37-0.58]. CONCLUSIONS: More than half of children with newly diagnosed diabetes have clinically important residual beta-cell function. As the clinical diagnosis is not always straightforward, a random C-peptide taken at diagnosis may help to classify diabetes. There is an obvious use for C-peptide determinations to evaluate beta-cell function in children with diabetes.


Assuntos
Peptídeo C/sangue , Diabetes Mellitus/sangue , Diabetes Mellitus/classificação , Diabetes Mellitus/epidemiologia , Técnicas de Diagnóstico Endócrino , Adolescente , Idade de Início , Peptídeo C/análise , Criança , Pré-Escolar , Estudos de Coortes , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Concentração Osmolar , Valor Preditivo dos Testes
18.
Tissue Antigens ; 78(4): 271-4, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21736561

RESUMO

Multiple sclerosis (MS) patients, with a second autoimmune disease after lymphocyte depletion, had elevated serum IL-21 before and after treatment which correlated to IL21 genotypes. In addition, the IL21 gene has been associated to several other autoimmune diseases. However, in a Spanish population there was no association to MS. Here, in a Swedish cohort (2090 MS cases and 1732 controls) 12 single nucleotide polymorphisms (SNPs) tagging IL21 were not associated to disease. There was no interaction with risk alleles of IL21R and HLA-DRB1*15. Lack of genetic association was confirmed in a meta-analysis with pooled data from the present study and the Spanish study. In conclusion, IL21 has not been shown to be a major risk gene for MS.


Assuntos
Cadeias HLA-DRB1/genética , Subunidade alfa de Receptor de Interleucina-21/genética , Interleucinas/genética , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único , Alelos , Estudos de Coortes , Epistasia Genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Fatores de Risco , Suécia
19.
Eur Respir J ; 38(5): 1151-7, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21565911

RESUMO

Heerfordt's syndrome (HS) consists in its complete form of uveitis, parotid or salivary gland enlargement and cranial nerve palsy. The objective of the present study was to analyse if there are also links between HLA-DRB1* alleles and HS, as it is a specific phenotype of sarcoidosis. 1,000 patients with sarcoidosis, out of whom 83 had symptoms associated with HS, were included in the study together with a group of 2,000 healthy individuals from the same population, matched for sex and age. HLA-DRB1* allelic groups were determined for all individuals, and comparisons were made between different disease subgroups and between patients and healthy controls. We found that the HLA-DRB1*04 allele was overrepresented in patients with symptoms associated with HS. 83 (8.3%) of all patients had one or more of the symptoms and 46 (55%) of them were HLA-DRB1*04 positive. 44 (55%) of the patients with ocular sarcoidosis, i.e. the most common symptom associated with HS, were HLA-DRB1*04 positive, compared with 35.9% of healthy controls (p=0.0008), and only 26.6% of the whole group of sarcoidosis patients (p<0.0001). HLA-DRB1*04 seems to protect against overall sarcoidosis but appears to be a significant risk factor for ocular sarcoidosis as well as for other manifestations associated with HS.


Assuntos
Frequência do Gene , Cadeias HLA-DRB1/genética , Sarcoidose/genética , Febre Uveoparotídea/genética , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Uveíte/genética , Febre Uveoparotídea/diagnóstico , Adulto Jovem
20.
J Clin Endocrinol Metab ; 95(11): E310-8, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20685858

RESUMO

CONTEXT: The previously reported absence of 65-kDa glutamate decarboxylase antibody (GAD65Ab)-specific antiidiotypic antibodies (anti-Id) in type 1 diabetes (T1D) patients at clinical onset could be due to an inability to mount an antibody response to GAD65Ab or a longitudinal decline in anti-Id levels. OBJECTIVE AND DESIGN: We investigated anti-Id levels in longitudinal samples obtained from T1D patients (n = 41) (clinical diagnosis - 12 months), and latent autoimmune diabetes in adults (LADA) patients (n = 32) who received alum-formulated human recombinant GAD65 (baseline - 12 months). We also determined anti-Id levels in a small cohort of Type 2 diabetes patients during their development of autoimmune T cell responses. RESULTS: At clinical onset T1D patients presented no or low anti-Id levels. However, 22/41 T1D patients showed ≥50% increase in GAD65Ab-specific anti-Id levels during follow-up; peaking at 3 (n = 1), 6 (n = 10), 9 (n = 10), or 12 (n = 1) months. Increasing anti-Id levels marked patients who experienced a temporary increase in C-peptide levels. Anti-Id levels correlated significantly with glycated hemoglobin and C-peptide levels at 6 and 9 months (P values ranged from <0.001 to <0.05). In LADA patients receiving placebo, anti-Id levels declined in seven of nine patients, whereas four of five patients receiving 20 µg alum-formulated human recombinant GAD65 showed increasing anti-Id levels. Changes in anti-Id and C-peptide levels closely correlated (P < 0.0001). The significant decline in anti-Id levels (P = 0.03) in T2D patients developing T cell autoimmune responses supports our hypothesis that declining anti-Id levels are associated with developing islet autoimmunity. CONCLUSIONS: The close association between GAD65Ab-specific anti-Id levels and ß-cell function may provide a novel marker for the progression of autoimmune diabetes.


Assuntos
Anticorpos Anti-Idiotípicos/sangue , Autoimunidade/imunologia , Peptídeo C/sangue , Diabetes Mellitus Tipo 1/sangue , Progressão da Doença , Glutamato Descarboxilase/sangue , Ilhotas Pancreáticas/imunologia , Adolescente , Análise de Variância , Anticorpos Anti-Idiotípicos/imunologia , Peptídeo C/imunologia , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/imunologia , Feminino , Glutamato Descarboxilase/imunologia , Humanos , Lactente , Masculino , Estudos Prospectivos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA