RESUMO
Selective IgA deficiency (IgAD; serum IgA<0.07 g/l) is the most common form of human primary immune deficiency, affecting approximately 1â¶600 individuals in populations of Northern European ancestry. The polygenic nature of IgAD is underscored by the recent identification of several new risk genes in a genome-wide association study. Among the characterized susceptibility loci, the association with specific HLA haplotypes represents the major genetic risk factor for IgAD. Despite the robust association, the nature and location of the causal variants in the HLA region remains unknown. To better characterize the association signal in this region, we performed a high-density SNP mapping of the HLA locus and imputed the genotypes of common HLA-B, -DRB1, and -DQB1 alleles in a combined sample of 772 IgAD patients and 1,976 matched controls from 3 independent European populations. We confirmed the complex nature of the association with the HLA locus, which is the result of multiple effects spanning the entire HLA region. The primary association signal mapped to the HLA-DQB1*02 allele in the HLA Class II region (combined Pâ=â7.69×10(-57); ORâ=â2.80) resulting from the combined independent effects of the HLA-B*0801-DRB1*0301-DQB1*02 and -DRB1*0701-DQB1*02 haplotypes, while additional secondary signals were associated with the DRB1*0102 (combined Pâ=â5.86×10(-17); ORâ=â4.28) and the DRB1*1501 (combined Pâ=â2.24×10(-35); ORâ=â0.13) alleles. Despite the strong population-specific frequencies of HLA alleles, we found a remarkable conservation of these effects regardless of the ethnic background, which supports the use of large multi-ethnic populations to characterize shared genetic association signals in the HLA region. We also provide evidence for the location of association signals within the specific extended haplotypes, which will guide future sequencing studies aimed at characterizing the precise functional variants contributing to disease pathogenesis.
Assuntos
Antígenos HLA-B/genética , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Deficiência de IgA/genética , Alelos , Estudos de Casos e Controles , Mapeamento Cromossômico , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Haplótipos , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , População Branca/genéticaRESUMO
INTRODUCTION: Immunoglobulin A (IgA) is important for mucosal health. Selective IgA deficiency (IgAD) is the most common primary immunodeficiency but its effect on oral health is unclear. The aim of this study was to investigate dental, periodontal and oral mucosal health in IgAD individuals. MATERIAL AND METHODS: In total, 32 adult IgAD subjects were compared with 63 randomly selected individuals. Participants answered questionnaires regarding general and oral health and underwent oral examination, including examination using the periodontal screening and recording (PSR) system and dental examination using the DMF system. RESULTS: The IgAD individuals had significantly more often undergone tonsillectomy (44%versus 24%, p=0.046) and adenoidectomy (31%versus 8%, p=0.003) compared with the controls. Furthermore, the IgAD subjects reported having pharyngitis, stomatitis and herpes labialis significantly more often. There was no significant difference in periodontal health (mean PSR index; 1.87 versus 1.77) or dental health (mean DMFS; 51.3 versus 53.7) between the two cohorts. A positive correlation between Helicobacter pylori infection and severity of periodontitis was found (p=0.036). CONCLUSION: IgAD predisposes to oral mucosal infections but does not influence periodontal or dental health. This is the first controlled study to include detailed clinical history and investigations, together with full oral and dental examination, in adults with IgAD.
Assuntos
Deficiência de IgA/complicações , Doenças da Boca/complicações , Doenças Periodontais/complicações , Doenças Dentárias/complicações , Adenoidectomia , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Índice CPO , Feminino , Refluxo Gastroesofágico/complicações , Gengivite/complicações , Nível de Saúde , Helicobacter/isolamento & purificação , Infecções por Helicobacter/complicações , Herpes Labial/complicações , Humanos , Deficiência de IgA/sangue , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Saúde Bucal , Índice Periodontal , Periodontite/complicações , Faringite/complicações , Estomatite/complicações , Tonsilectomia , Xerostomia/complicaçõesRESUMO
BACKGROUND: The prevalence of autoimmunity is thought to be increased among IgA deficient (IgAD) individuals. However, it is currently unclear if the two conditions coincide within families. OBJECTIVE: To evaluate the prevalence of autoimmunity among IgAD individuals and their 1 degrees relatives. MATERIAL AND METHODS: A total of 43 IgAD individuals (32 adults and 11 children) and all available 1 degrees relatives were evaluated by a physician. A family history of autoimmunity was obtained, together with physical examination and a structured questionnaire that focused on symptoms and signs suggestive of autoimmunity. RESULTS: Eight of the 32 (25%) adult IgAD, were found to have definite autoimmunity, with organ specific- and systemic autoimmune diseases equally distributed. None of the IgAD children had autoimmunity. Among the 1 degrees relatives, 27/269 (10%) had autoimmunity, compared to an estimate of 5% in the general population (p<0.05). CONCLUSION: Autoimmune diseases are highly prevalent in individuals with IgAD and more common in their 1 degrees relatives than expected, thus, suggesting a possible common genetic component.
Assuntos
Autoimunidade/genética , Predisposição Genética para Doença , Deficiência de IgA/genética , Imunoglobulina A/genética , Inquéritos e Questionários , Adolescente , Adulto , Idade de Início , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Imunoglobulina A/imunologia , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
Immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency, with suggested association with various types of autoimmunity, including Graves' disease. This study investigated the association of IgAD with elevated thyrotropin-receptor autoantibodies (TRAb). IgA was measured in TRAb-seropositive individuals from both Iceland (N = 299] and Sweden (N = 841]. In addition, TRAb levels were evaluated in 43 Icelandic and 50 Swedish IgAD individuals using Medizym TRA immunoassay, and positive samples were re-evaluated using BRAHMS TRAK human RIA. The IgAD individuals were HLA-genotyped to determine the HLA-B, DR, and DQ alleles. None of the 299 Icelandic TRAb-seropositive individuals had IgAD, whereas, a high prevalence of IgAD (14/841 (1:60)) was observed in the Swedish cohort (p = 0.027). The prevalence of TRAb-seropositivity in IgAD individuals was, however, increased in both cohorts. The HLA-DQ6 allele was associated with TRAb-seronegativity within the Icelandic IgAD cohort (p = 0.037). The prevalence of IgAD in TRAb-seropositive individuals in Sweden is 10 times higher than expected in the general population. Furthermore, TRAb seropositivity is common among IgAD individuals, both in Iceland and Sweden, suggesting a predisposition toward Graves' disease. These findings underline the significant association of IgAD with autoimmunity and its possible association with certain HLA-DQ alleles.
Assuntos
Autoanticorpos/imunologia , Estudos de Associação Genética , Doença de Graves/imunologia , Deficiência de IgA/imunologia , Receptores da Tireotropina/imunologia , Adulto , Alelos , Autoanticorpos/genética , Autoimunidade/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Doença de Graves/epidemiologia , Doença de Graves/genética , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/imunologia , Antígenos HLA-DR/genética , Antígenos HLA-DR/imunologia , Humanos , Islândia , Deficiência de IgA/genética , Imunoglobulina A/sangue , Masculino , Pessoa de Meia-Idade , Prevalência , Radioimunoensaio , Receptores da Tireotropina/genética , SuéciaRESUMO
INTRODUCTION: The prevelance of allery and asthma has increased rapidly over the last 3 decades and is now estimated that 25-30% of population in Western industrialized countries show symptoms of allergy or asthma. The aim of this study was to reveal the success of allergen immunotherapy (AIT) in Landspitali from 1977-2006. MATERIAL AND METHODS: During the study period a total number of 289 individuals underwent immunotherapy in outpatient clinic of allergy and asthma in Landspítali. A total number of 169 individuals were contacted, of whom 128 (76%) accepted to participate in the study. The evaluation was based on medical records, standardized questionnaire and skin-prick tests. RESULTS: Patients were evaluated on the average of 20 years after finishing treatment. 118 (92%) patients were desensitized to grass pollen, to birch pollen (30%), cat dander (30%) and dust mite (28%). At the time of the study 67% reported to be asymptomatic or with greatly improved allergy symptoms. Males had better response to AIT than women (p=0.04). Participants with positive family history of allergy and/or asthma in first degree relatives also reported better response to AIT (p=0.02). Furthermore, AIT to grass pollen and dust mite seemed to be more effective than AIT to cat dander and birch (p=0.04). AIT was also shown to reduce asthma. CONCLUSION: AIT for 3-5 years provides significant beneficial effect of allergy and asthma symptoms in patients who undergo such therapy. Finally, it s findings support the notion that AIT may reduce the risk of new allergic manifestations.
Assuntos
Asma/terapia , Dessensibilização Imunológica , Hipersensibilidade/terapia , Imunoterapia , Adolescente , Adulto , Asma/diagnóstico , Asma/imunologia , Criança , Pré-Escolar , Feminino , Humanos , Hipersensibilidade/diagnóstico , Hipersensibilidade/imunologia , Islândia , Lactente , Recém-Nascido , Testes Intradérmicos , Masculino , Pessoa de Meia-Idade , Ambulatório Hospitalar , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
To understand the genetic predisposition to selective immunoglobulin A deficiency (IgAD), we performed a genome-wide association study in 430 affected individuals (cases) from Sweden and Iceland and 1,090 ethnically matched controls, and we performed replication studies in two independent European cohorts. In addition to the known association of HLA with IgAD, we identified association with a nonsynonymous variant in IFIH1 (rs1990760G>A, P = 7.3 x 10(-10)) which was previously associated with type 1 diabetes and systemic lupus erythematosus. Variants in CLEC16A, another known autoimmunity locus, showed suggestive evidence for association (rs6498142C>G, P = 1.8 x 10(-7)), and 29 additional loci were identified with P < 5 x 10(-5). A survey in IgAD of 118 validated non-HLA autoimmunity loci indicated a significant enrichment for association with autoimmunity loci as compared to non-autoimmunity loci (P = 9.0 x 10(-4)) or random SNPs across the genome (P < 0.0001). These findings support the hypothesis that autoimmune mechanisms may contribute to the pathogenesis of IgAD.