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Genetic association of IRF5 with SLE in Mexicans: higher frequency of the risk haplotype and its homozygozity than Europeans
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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2007 (English)In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 121, no 6, 721-727 p.Article in journal (Refereed) Published
Abstract [en]

The IRF5 gene was found to be strongly associated with SLE. We identified two functional polymorphisms and recently an insertion/deletion together with a tag SNP defining the risk haplotype in individuals of European ancestry. We now analyzed sets of Mexican patients with SLE. Three polymorphisms in the IRF5 gene were genotyped in two sets of Mexican individuals with SLE and controls as well as in families including a set of pediatric SLE patients. A set of healthy Mexican Indians was also typed. Genetic association with SLE was found for all three polymorphisms. The genetic association was very strong in the case–control analysis in both sets (for SNP rs2070197, combined P = 1.26 × 10−21) and in families (combined P = 0.000004). Compared to healthy individuals with European ancestry, the frequency of the risk haplotype in healthy Mexican individuals was significantly higher and even higher in the healthy Mexican Indian group. Further, a much higher frequency of the risk haplotype and of individual homozygote for it was found among Mexican SLE patients. The significantly higher frequency of homozygote individuals for the risk haplotype among Mexican SLE patients could be the result of genetic admixture, and suggests the possibility that IRF5 could be involved in the more active disease and organ involvement known to occur among Mexican SLE patients.

Place, publisher, year, edition, pages
2007. Vol. 121, no 6, 721-727 p.
Keyword [en]
Adult, Alleles, Case-Control Studies, Child, Ethnic Groups/genetics, Europe, Female, Gene Frequency, Haplotypes, Homozygote, Humans, Indians; North American/genetics, Interferon Regulatory Factors/*genetics, Lupus Erythematosus; Systemic/*genetics/*immunology, Male, Mexico, Polymorphism; Single Nucleotide, Risk Factors
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-96500DOI: 10.1007/s00439-007-0367-6ISI: 000247239400008PubMedID: 17476532OAI: oai:DiVA.org:uu-96500DiVA: diva2:171096
Available from: 2007-11-21 Created: 2007-11-21 Last updated: 2011-02-09Bibliographically approved
In thesis
1. The Genetics of Systemic Lupus Erythematosus: The Specificity of IRF5 to SLE.
Open this publication in new window or tab >>The Genetics of Systemic Lupus Erythematosus: The Specificity of IRF5 to SLE.
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The breakdown of self-tolerance is the main driving force behind susceptibility to SLE. When this occurs, T and B cells are activated in an uncontrolled manner and produce autoantibodies against self fragmented DNA, RNA and sometimes other parts of the cell such as cardiolipin, phosphatidylserine, etc.

The mechanism behind the breakdown of self-tolerance may be genetic factors that are triggered by environmental factors. SLE is not caused by a single gene, but by many genes, and is thus a polygenic disease. So far only a few genes have been found to be associated with SLE including PDCD1, FcγRs, and PTPN22. The main aim of my thesis is to find susceptibility genes responsible for SLE.

Recently, a gene called IRF5 was found to be associated with SLE. In paper one, we performed a thorough study and confirmed its association to SLE. In addition, we found a few other SNPs in the gene that were associated to the disease. Among them, SNP rs2004640 is very strongly associated and was found to affect the splicing of the gene. Another SNP, rs2280714, correlated with overexpression of the gene, although SNP rs10954213 was much more highly correlated with expression adding to this, in paper two we found a few other SNPs that were associated to SLE and played crucial roles in gene function. An indel in exon 6, though not associated by itself, regulated which isoforms were expressed. Individuals with 2 repeats expressed isoforms V1 and V4, while individuals with 4 repeats expressed isoforms V5 and V6. SNP rs2070197 was also very strongly associated, but did not have a functional role. In paper three, the same polymorphisms were studied in a Mexican population, which showed an even stronger association when compared to a European population.

It is known that autoimmune diseases share susceptibility genes, therefore we wanted to see if the IRF5 gene is associated with any other autoimmune diseases. In papers four and five, we tested its association to RA (using three sets of patients and controls from Sweden, Argentina and Spain) and psoriasis (using a set of patients and controls from Sweden). Association was not found in either of the diseases. Therefore, we believe that this association may be SLE-specific.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 79 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 296
Molecular genetics, Systemic lupus erythematosus, Interferon regulatory factor 5, Transmission-Disequilibrium Test, Family-based association test, Linkage Disequilibrium, Hardy-Weinberg equilibrium, Genetik
urn:nbn:se:uu:diva-8332 (URN)978-91-554-7038-8 (ISBN)
Public defence
2007-12-12, Rudbecksalen, Rudbeck Laboratory, 09:15
Available from: 2007-11-21 Created: 2007-11-21Bibliographically approved

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