Genetics of Autoimmune Diseases: A Multistep Process

Johannesson, Martina; Hultqvist, Malin; Holmdahl, Rikard

doi:10.1007/3-540-29714-6_13

Cited by 6 publications

(6 citation statements)

References 44 publications

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“…Autosomal genetic associations in human autoimmune diseases are also largely polygenic, a pattern that has also been seen in SLE‐related disease in Nova Scotia Duck Tolling Retrievers (40), hypoadrenocorticism in Portuguese Water Spaniels (41), and a multiple autoimmune disease syndrome of Italian Greyhounds (12). The genetics of autoimmune diseases in humans has been highly elusive, as elegantly stated by Johannesson and colleagues (42)–‘from disease to genes: the monogenic success and the polygenic failure’. The discovery of simple Mendelian traits with surprisingly small numbers of case and control dogs has been remarkably easy, but studies of complex traits such as autoimmunity or epilepsy will likely be as challenging in dogs as they have been in humans (12, 40, 41, 43).…”

Section: Discussionmentioning

confidence: 95%

Genetic characterization of healthy and sebaceous adenitis affected Standard Poodles from the United States and the United Kingdom

et al. 2012

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The degree of heterogeneity associated with geographic origin and sebaceous adenitis (SA) status in Standard Poodles from the United States (US) and the United Kingdom (UK) was assessed. Healthy and SA-affected Standard Poodles from the US and the UK shared a major mitochondrial DNA (mtDNA) haplotype and a single Y chromosome haplotype. However, minor mtDNA haplotypes and frequencies were somewhat different between US and UK dogs and were significantly less associated with SA than major haplotypes across both populations. The US and UK populations exhibited recent divergence from a common gene pool, based on allele frequencies of 24 highly polymorphic short tandem repeats and principle coordinates and cluster analyses of genotype frequencies. However, there was no differentiation between SA affected and unaffected dogs. Over 90% of US and UK Poodles shared a common dog leukocyte antigen (DLA) class II haplotype, but showed some differentiation in minor haplotype frequency. No difference was observed in haplotype heterozygosity between SA affected and unaffected dogs from the same country and no disease association for SA was found within the DLA region by a high density single nucleotide polymorphism (SNP) scan. Zygosity mapping in the DLA region of Poodles indicated much lower site-specific diversity than in an outbred population of street dogs from Bali, Indonesia, reflecting the degree that breed associated historical bottlenecks have reduced diversity in a polymorphic region of the genome. This study shows possible pitfalls in more extensive genome-wide association studies, such as case and control numbers, population stratification, the involvement of multiple genes, and/or the possibility that SA susceptibility is fixed or nearly fixed within the breed, which can reduce power to detect genetic associations.

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Section: Discussionmentioning

confidence: 95%

Genetic characterization of healthy and sebaceous adenitis affected Standard Poodles from the United States and the United Kingdom

et al. 2012

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“…Specifically, autoimmune diseases are thought to represent complex phenotypes arising as the result of multiple environmental factors interacting with specific complex genotypes. For instance, it is well‐appreciated that genetic factors predispose certain individuals to develop autoimmune disease [Johannesson, Hultqvist, & Holmdahl, 2006]. The most important loci is the HLA [Reveille, 2006], but other loci are also clearly involved.…”

Section: Discussionmentioning

confidence: 99%

Autism spectrum disorders are associated with an elevated autoantibody response to tissue transglutaminase‐2

Rosenspire¹,

Yoo²,

Menard³

et al. 2011

Autism Research

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We report that a significant number of autistic children have serum levels of IgA antibodies above normal to the enzyme tissue transglutaminase II (TG2), and that expression of these antibodies to TG2 is linked to the (HLA)-DR3, DQ2 and DR7, DQ2 haplotypes. TG2 is expressed in the brain, where it has been shown to be important in cell adhesion and synaptic stabilization. Thus, these children appear to constitute a subpopulation of autistic children who fall within the autism disease spectrum, and for whom autoimmunity may represent a significant etiological component of their autism.

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“…The Q mutation resulted in a weaker association of p67phox with the guanine nucleotide exchange factor Vav, resulting in 50% lower Fc receptor-activated O 2 -generation. Similar to rheumatoid arthritis, multiple genes contribute to the development of SLE, and a change in a single gene is not sufficient to cause the disease (123). Since the disease-associated allele for both lupus and rheumatoid arthritis is rare in the general population, estimates regarding the increased risk associated with carrying the disease-associated allele are not reliable.…”

Section: Human Disease Associations With Polymorphisms In Nox2 and Phmentioning

confidence: 99%

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

Diebold

Smith

Yang

et al. 2015

Antioxidants & Redox Signaling

106

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Significance: NOX2 is important for host defense, and yet is implicated in a large number of diseases in which inflammation plays a role in pathogenesis. These include acute and chronic lung inflammatory diseases, stroke, traumatic brain injury, and neurodegenerative diseases, including Alzheimer's and Parkinson's Diseases. Recent Advances: Recent drug development programs have targeted several NOX isoforms that are implicated in a variety of diseases. The focus has been primarily on NOX4 and NOX1 rather than on NOX2, due, in part, to concerns about possible immunosuppressive side effects. Nevertheless, NOX2 clearly contributes to the pathogenesis of many inflammatory diseases, and its inhibition is predicted to provide a novel therapeutic approach. Critical Issues: Possible side effects that might arise from targeting NOX2 are discussed, including the possibility that such inhibition will contribute to increased infections and/or autoimmune disorders. The state of the field with regard to existing NOX2 inhibitors and targeted development of novel inhibitors is also summarized. Future Directions: NOX2 inhibitors show particular promise for the treatment of inflammatory diseases, both acute and chronic. Theoretical side effects include pro-inflammatory and autoimmune complications and should be considered in any therapeutic program, but in our opinion, available data do not indicate that they are sufficiently likely to eliminate NOX2 as a drug target, particularly when weighed against the seriousness of many NOX2-related indications. Model studies demonstrating efficacy with minimal side effects are needed to encourage future development of NOX2 inhibitors as therapeutic agents. Antioxid. Redox Signal. 23,

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Genetics of Autoimmune Diseases: A Multistep Process

Cited by 6 publications

References 44 publications

Genetic characterization of healthy and sebaceous adenitis affected Standard Poodles from the United States and the United Kingdom

Genetic characterization of healthy and sebaceous adenitis affected Standard Poodles from the United States and the United Kingdom

Autism spectrum disorders are associated with an elevated autoantibody response to tissue transglutaminase‐2

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

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