Mapping the Systematic Lupus Erythematosus Susceptibility Genes

Nath, SK; Ja, Kelly; Harley, JB; Rh, Scofield

doi:10.1385/1-59259-805-6:011

Cited by 5 publications

(6 citation statements)

References 62 publications

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“…A multisystem autoimmune disease, systemic lupus erythematosus (SLE), also known as lupus, shows familial co-segregates with other autoimmune disorders. Inhibition of apoptosis of regulatory T-cells has been associated with autoimmunity and is thought to contribute to the lymphopenia in SLE [ 31 32 ]. Recently GTPase, IMAP family member 5 (GIMAP5s) was identified as a key player in lymphopenia and primary T-cell apoptosis, and single nucleotide polymorphisms (SNPs) in the first proximal PAS of GIMPAP5s 3′-UTR was found in most SLE patients.…”

Section: Infection and Immunological Conditionsmentioning

confidence: 99%

Alternative Polyadenylation in Human Diseases

2017

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Varying length of messenger RNA (mRNA) 3′-untranslated region is generated by alternating the usage of polyadenylation sites during pre-mRNA processing. It is prevalent through all eukaryotes and has emerged as a key mechanism for controlling gene expression. Alternative polyadenylation (APA) plays an important role for cell growth, proliferation, and differentiation. In this review, we discuss the functions of APA related with various physiological conditions including cellular metabolism, mRNA processing, and protein diversity in a variety of disease models. We also discuss the molecular mechanisms underlying APA regulation, such as variations in the concentration of mRNA processing factors and RNA-binding proteins, as well as global transcriptome changes under cellular signaling pathway.

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Section: Infection and Immunological Conditionsmentioning

confidence: 99%

Alternative Polyadenylation in Human Diseases

2017

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“…With the determination that five tag SNPs could informatively define the genetic structure of our multi-ethnic US cohort, we typed these five SNPs among our SLE simplex family cohort and performed transmission disequilibrium testing to evaluate association with SLE susceptibility. Finally, as genetic linkages among SLE cohorts often have been more striking when assessed according to specific clinical phenotype, 10 we further characterized the role of PDCD1 gene polymorphism by SLE clinical phenotypes. For these analyses, we conducted a nested case-control study within our multiethnic US cohort to evaluate the role of PDCD1 in the development of LN, APLA positivity, arthritis and double-stranded DNA (dsDNA) antibody positivity.…”

Section: Introductionmentioning

confidence: 99%

Association of PDCD1 genetic variation with risk and clinical manifestations of systemic lupus erythematosus in a multiethnic cohort

et al. 2007

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We evaluated the roles of five single-nucleotide polymorphisms (SNPs) within PDCD1, and haplotypes defined by these SNPs, for the development of systemic lupus erythematosus (SLE) and specific sub-phenotypes (nephritis, antiphospholipid antibody positive, arthritis and double-stranded DNA positive) within a multiethnic US cohort of 1036 patients. Family based analyses were performed using 844 simplex families from four ethnic groups (Caucasian, Asian, Hispanic and African American). Subjects were genotyped for five 'tag' SNPs (selected from 15) to provide complete genetic information in all main ethnic groups. We employed transmission disequilibrium testing to assess risk for SLE by allele or haplotype, and multiple logistic regression analysis of SLE cases to examine associations with specific sub-phenotypes. In family based analyses, a haplotype containing the PD1.3A allele was significantly associated with SLE susceptibility among Caucasian families (P ¼ 0.01). Among Hispanic families, two novel SNPs were associated with SLE risk (P ¼ 0.005 and 0.01). In multivariate logistic regression analyses, five haplotypes were associated with specific sub-phenotypes among the different ethnic groups. These results suggest that PDCD1 genetic variation influences the risk and expression of SLE and that these associations vary according to ethnic background.

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“…Its prevalence in the Western population is about 0.05%, 1 2 a number that differs widely in other ethnic groups. 3 Although many candidate genes have been suggested as being involved in susceptibility to SLE, 4 5 few have been replicable. 6 SLE commonly shows familial co-segregation with other autoimmune disorders: 10-20% of SLE probands have at least one first-or second-degree relative with another autoimmune disorder.…”

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confidence: 99%

“…6 SLE commonly shows familial co-segregation with other autoimmune disorders: 10-20% of SLE probands have at least one first-or second-degree relative with another autoimmune disorder. 3 Disturbances of apoptosis of regulatory T-cells, which normally facilitates maintenance of immune tolerance, has been suggested as causing autoimmunity 7 and is thought to contribute to lymphopenia in several autoimmune disorders such as autoimmune insulin-dependent diabetes, 8 Sjogren's syndrome 9 and SLE. 1 10 Recently, GIMAP5 (OMIM 608086; previously called Immunityassociated nucleotide 4-like1, IAN4L1, fig 1A) was found to cause lymphopenia and autoimmune insulin-dependent diabetes in a rat model.…”

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confidence: 99%

The human GIMAP5 gene has a common polyadenylation polymorphism increasing risk to systemic lupus erythematosus

Hellquist

Zucchelli

Kivinen

et al. 2007

Journal of Medical Genetics

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Background: Several members of the GIMAP gene family have been suggested as being involved in different aspects of the immune system in different species. Recently, a mutation in the GIMAP5 gene was shown to cause lymphopenia in a rat model of autoimmune insulin-dependent diabetes. Thus it was hypothesised that genetic variation in GIMAP5 may be involved in susceptibility to other autoimmune disorders where lymphopenia is a key feature, such as systemic lupus erythematosus (SLE). Material and methods: To investigate this, seven single nucleotide polymorphisms in GIMAP5 were analysed in five independent sets of family-based SLE collections, containing more than 2000 samples. Result: A significant increase in SLE risk associated with the most common GIMAP5 haplotype was found (OR 1.26, 95% CI 1.02 to 1.54, p = 0.0033). In families with probands diagnosed with trombocytopenia, the risk was increased (OR 2.11, 95% CI 1.09 to 4.09, p = 0.0153). The risk haplotype bears a polymorphic polyadenylation signal which alters the 39 part of GIMAP5 mRNA by producing an inefficient polyadenylation signal. This results in higher proportion of non-terminated mRNA for homozygous individuals (p,0.005), a mechanism shown to be causal in thalassaemias. To further assess the functional effect of the polymorphic polyadenylation signal in the risk haplotype, monocytes were treated with several cytokines affecting apoptosis. All the apoptotic cytokines induced GIMAP5 expression in two monocyte cell lines (1.5-6 times, p,0.0001 for all tests). Conclusion: Taken together, the data suggest the role of GIMAP5 in the pathogenesis of SLE.

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Mapping the Systematic Lupus Erythematosus Susceptibility Genes

Cited by 5 publications

References 62 publications

Alternative Polyadenylation in Human Diseases

Alternative Polyadenylation in Human Diseases

Association of PDCD1 genetic variation with risk and clinical manifestations of systemic lupus erythematosus in a multiethnic cohort

The human GIMAP5 gene has a common polyadenylation polymorphism increasing risk to systemic lupus erythematosus

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