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Please use this identifier to cite or link to this item: http://hdl.handle.net/10451/2275

Título: Dissecting the complex genetics of human immune deficiency
Autor: Ferreira, Ricardo Correia Botelho Chaves, 1980-
Orientador: Behrens, Timothy W.
Telhada, Maria Margarida Blasques, 1951-
Palavras-chave: Imunodeficiência
Mapeamento genético
Teses de doutoramento - 2010
Issue Date: 2010
Resumo: The emergence of an immune system was a major hallmark in the evolutionary history of mammals. It has allowed the survival and diversification of complex organisms by conferring protection against the invasion by pathogenic microorganisms. Nevertheless, a strict regulation of the immune system is critical to prevent the chronic activation of an inflammatory response or the generation of an autoimmune response that could be detrimental to host. On the other end of the spectrum, molecular defects affecting the normal function of key components of the immune system can lead to a state of immune deficiency that weakens the host capacity to fight off pathogen invasion and therefore predisposes to chronic infection. Human primary immune deficiencies (PID) comprise of a group of over 200, generally rare, disorders that often present in childhood, and are the result of a characterized genetic defect affecting the normal functioning of the immune system. While most PIDs are rare conditions, transmitted in a few families as Mendelian traits, it is now becoming clear that others can also include much more common and sporadic conditions that can affect a significant fraction of the population. Selective IgA deficiency (IgAD), defined as serum IgA < 0.05 g/l, and common variable immunodeficiency (CVID) represent the most common forms of PID, affecting approximately 1 in every 500 individuals from populations of Northern European ancestry. Both these conditions are found to cluster frequently in the same extended families, indicating that they share a strong genetic predisposition. Despite the strong evidence for a genetic predisposition, the common genetic basis of these PID is still mostly unknown. In fact, to date the only genetic locus that has been consistently replicated across different ethnic groups lies in the Major Histocompatibility Complex (MHC) region on human chromosome 6. In this study, we used several novel genetic mapping approaches to attempt to shed new light on the complex genetic architecture of these disorders. The second chapter describes a candidate gene approach that we performed to assess the putative role of genetic variants in Mut S Homolog 5 (MSH5), located in the HLA locus, in the genetic basis of human PID. Importantly, we characterized 2 rare missense mutations which significant association with CVID. The 2 missense alleles where shown to impair the binding affinity of the mutant MSH5 to its binding partner (MSH4), and individuals carrying the missense alleles showed a very significant increase in the length of Ig switch junction microhomology, which strongly supports a novel role for MSH5 in the process of Ig class-switch recombination. In chapter 3, to have a better understanding of the common genetic basis of IgAD, we also set out to perform a large genome-wide association study (GWAS) in a combined sample of 772 patients and 1976 geographically matched controls from 3 independent European populations. Here we report that genetic variants in interferon-induced with helicase C domain 1 (IFIH1) and c-type lectin 16A (CLEC16A) are robustly associated with IgAD and, therefore, constitute the first two non-HLA genes convincingly associated with a common human PID. Intriguingly, we found a strong enrichment in the association of previously validated autoimmune loci, and a particularly striking overlap with the genetic profile of type 1 diabetes, which suggests that these two conditions may share a strong genetic basis. The hypothesis for an autoimmune etiology of IgAD was further supported by the identification of high titers of anti-BAFF receptor (BAFF-R) IgG antibodies in the serum of patients. Finally, in chapter 4 to refine the association signal mapping to the HLA locus, we also used the genotyping data from the GWAS to perform a high-density fine mapping of this genomic region. We took advantage of the strong conservation observed at this locus and of recently developed analytical methodologies to impute the more common HLA alleles that were previously shown to be associated with IgAD. In addition we also used the SNP data to phase the individual genotypes and reconstruct extended haplotypes. Using both single-marker and haplotypes analysis, we characterized a primary association signal mapping to the HLA class II region, and to the HLADQB1* 02 allele in particular. We also describe the association of additional independent alleles, most notably with the HLA-DRB1*0102, -DRB1*1501 and -B*15 alleles, and provide a more detailed location of the causal alleles within the extended haplotypes. We suggest that these data may guide future resequencing efforts in the identification of the functional variants contributing to the complex association of the HLA locus. Taken together these data provide new insights into the genetic basis of common PID, and support the hypothesis of an autoimmune component to the pathogenesis of IgAD. Selective IgA Deficiency; Primary immune deficiency; genetic mapping; genome-wide association study; HLA locus; class-switch recombination.
Descrição: Tese de doutoramento, Biologia (Genética), Universidade de Lisboa, Faculdade de Ciências, 2010
URI: http://hdl.handle.net/10451/2275
Appears in Collections:FC - Teses de Doutoramento

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