uu.seUppsala universitets publikationer
Ändra sökning
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Genetic Risk Factors for Systemic Lupus Erythematosus: From Candidate Genes to Functional Variants
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
2008 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The aim of this thesis has been to identify genetic variants that increase the susceptibility for Systemic Lupus Erythematosus (SLE), an autoimmune disease caused by a complex interplay between various genetic and environmental factors.

Five different candidate genes were selected through different strategies, and were analysed for association with SLE in an attempt to distinguish some of the underlying mechanisms of this disease. Two of these genes, PD-L1 and PD-L2, appeared not to contain any major risk factors for SLE in the analysed European and Latin American populations. In two other genes, CD24 and STAT4, there appeared to be population-specific effects. The A57V amino acid substitution in the CD24 gene, previously implicated with multiple sclerosis, was associated in a Spanish cohort, with a weak trend in German samples, and no association in Swedish. The previously reported and highly convincing association of the STAT4 transcription factor gene was confirmed in all our cohorts. Interestingly, the results indicate the presence of at least two independent risk variants: the first, represented by a previously reported SNP, was the strongest in individuals of Northern European ancestry, and the second was more pronounced in individuals from Southern Europe and Latin America. We also report the identification of a novel susceptibility gene. The BANK1 gene, encoding a scaffold protein involved in B-cell activation, contains functional variants affecting important domains, which are associated in all investigated cohorts from Europe and Latin America.

These results confirm the existence of replicable associations between genetic variants and SLE, which are common and present in many populations. The results also illustrate a certain degree of heterogeneity, where some risk factors could have variable effect in different populations.

Ort, förlag, år, upplaga, sidor
Uppsala: Universitetsbiblioteket , 2008. , s. 61
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 395
Nyckelord [en]
Systemic Lupus Erythematosus, SLE, association study, complex disease, genetic
Nationell ämneskategori
Medicinsk genetik
Identifikatorer
URN: urn:nbn:se:uu:diva-9367ISBN: 978-91-554-7336-5 (tryckt)OAI: oai:DiVA.org:uu-9367DiVA, id: diva2:172824
Disputation
2008-12-06, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 13:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2008-11-14 Skapad: 2008-11-14 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
Delarbeten
1. No evidence of association between genetic variants of the PDCD1 ligands and SLE
Öppna denna publikation i ny flik eller fönster >>No evidence of association between genetic variants of the PDCD1 ligands and SLE
Visa övriga...
2007 (Engelska)Ingår i: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 8, nr 1, s. 69-74Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

PDCD1, an immunoreceptor involved in peripheral tolerance has previously been shown to be genetically associated with systemic lupus erythematosus (SLE). PDCD1 has two ligands whose genes are located in close proximity on chromosome 9p24. Our attention was drawn to these ligands after finding suggestive linkage to a marker (gata62f03, Z=2.27) located close to their genes in a genome scan of Icelandic families multiplex for SLE. Here, we analyse Swedish trios (N=149) for 23 single nucleotide polymorphisms (SNPs) within the genes of the PDCD1 ligands. Initially, indication of association to eight SNPs was observed, and these SNPs were therefore also analysed in Mexican trios (N=90), as well as independent sets of patients and controls from Sweden (152 patients, 448 controls) and Argentina (288 patients, 288 controls). We do not find support for genetic association to SLE. This is the first genetic study of SLE and the PDCD1 ligands and the lack of association in several cohorts implies that these genes are not major risk factors for SLE.

Nyckelord
systemic lupus erythematosus, genetic association, linkage disequilibrium, autoimmunity, PD-L1, PD-L2
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-97760 (URN)10.1038/sj.gene.6364360 (DOI)000243783500009 ()17136123 (PubMedID)
Tillgänglig från: 2008-11-14 Skapad: 2008-11-14 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
2. Association of a CD24 Gene Polymorphism with Susceptibility to Systemic Lupus Erythematosus
Öppna denna publikation i ny flik eller fönster >>Association of a CD24 Gene Polymorphism with Susceptibility to Systemic Lupus Erythematosus
Visa övriga...
2007 (Engelska)Ingår i: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 56, nr 9, s. 3080-3086Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Objective. To determine the potential role of the CD24 A57V gene polymorphism in systemic lupus erythematosus (SLE).

Methods. We studied 3 cohorts of Caucasian patients and controls. The Spanish cohort included 696 SLE patients and 539 controls, the German cohort included 257 SLE patients and 317 controls, and the Swedish cohort included 310 SLE patients and 247 controls. The CD24 A57V polymorphism was genotyped by polymerase chain reaction, using a predeveloped TaqMan allele discrimination assay. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.

Results. In the Spanish cohort there was a statistically significant difference in the distribution of the CD24 V allele between SLE patients and controls (OR 3.6 [95% CI 2.13-6.16], P < 0.0001). In addition, frequency of the CD24 V/V genotype was increased in SLE patients compared with controls (OR 3.7 [95% CI 2.16-6.34], P < 0.00001). We sought to replicate this association with SLE in a German population and a Swedish population. A similar trend was found in the German group. The CD24 V/V genotype and the CD24 V allele were more frequent in SLE patients than in controls, although this difference was not statistically significant. No differences were observed in the Swedish group. A meta-analysis of the Spanish and German cohorts demonstrated that the CD24 V allele has a risk effect in SLE patients (pooled OR 1.25 [95% Cl 1.08-1.46], P = 0.003). In addition, homozygosity for the CD24 V risk allele significantly increased the effect (pooled OR 2.1,9 [95% Cl 1.50-3.22], P = 0.00007).

Conclusion. These findings suggest that the CD24 A57V polymorphism plays a role in susceptibility to SLE in a Spanish population.

Nyckelord
Antigens; CD24/*genetics, Cohort Studies, Female, Genetic Predisposition to Disease, Humans, Lupus Erythematosus; Systemic/*genetics, Male, Polymorphism; Genetic
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-97761 (URN)10.1002/art.22871 (DOI)000249832600030 ()17763438 (PubMedID)
Tillgänglig från: 2008-11-14 Skapad: 2008-11-14 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
3. Functional Variants in the B-Cell Gene BANK1 are Associated with Systemic Lupus Erythematosus
Öppna denna publikation i ny flik eller fönster >>Functional Variants in the B-Cell Gene BANK1 are Associated with Systemic Lupus Erythematosus
Visa övriga...
2008 (Engelska)Ingår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 40, nr 2, s. 211-216Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by production of autoantibodies and complex genetic inheritance(1-3). In a genome-wide scan using 85,042 SNPs, we identified an association between SLE and a nonsynonymous substitution (rs10516487, R61H) in the B-cell scaffold protein with ankyrin repeats gene, BANK1. We replicated the association in four independent case-control sets (combined P = 3.7 x 10(-10); OR = 1.38). We analyzed BANK1 cDNA and found two isoforms, one full-length and the other alternatively spliced and lacking exon 2 (Delta 2), encoding a protein without a putative IP3R-binding domain. The transcripts were differentially expressed depending on a branch point-site SNP, rs17266594, in strong linkage disequilibrium (LD) with rs10516487. A third associated variant was found in the ankyrin domain (rs3733197, A383T). Our findings implicate BANK1 as a susceptibility gene for SLE, with variants affecting regulatory sites and key functional domains. The disease-associated variants could contribute to sustained B cell-receptor signaling and B-cell hyperactivity characteristic of this disease.

Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-97762 (URN)10.1038/ng.79 (DOI)000252732900020 ()
Tillgänglig från: 2008-11-14 Skapad: 2008-11-14 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
4. STAT4 Associates with SLE through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk
Öppna denna publikation i ny flik eller fönster >>STAT4 Associates with SLE through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk
Visa övriga...
2009 (Engelska)Ingår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 68, nr 11, s. 1746-1753Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

OBJECTIVES: To confirm and define the genetic association of STAT4 and systemic lupus erythematosus, investigate the possibility of correlations with differential splicing and/or expression levels, and genetic interaction with IRF5. METHODS: 30 tag SNPs were genotyped in an independent set of Spanish cases and controls. SNPs surviving correction for multiple tests were genotyped in 5 new sets of cases and controls for replication. STAT4 cDNA was analyzed by 5'-RACE PCR and sequencing. Expression levels were measured by quantitative PCR. RESULTS: In the fine-mapping, four SNPs were significant after correction for multiple testing, with rs3821236 and rs3024866 as the strongest signals, followed by the previously associated rs7574865, and by rs1467199. Association was replicated in all cohorts. After conditional regression analyses, two major independent signals represented by SNPs rs3821236 and rs7574865, remained significant across the sets. These SNPs belong to separate haplotype blocks. High levels of STAT4 expression correlated with SNPs rs3821236, rs3024866 (both in the same haplotype block) and rs7574865 but not with other SNPs. We also detected transcription of alternative tissue-specific exons 1, indicating presence of tissue-specific promoters of potential importance in the expression of STAT4. No interaction with associated SNPs of IRF5 was observed using regression analysis. CONCLUSIONS: These data confirm STAT4 as a susceptibility gene for SLE and suggest the presence of at least two functional variants affecting levels of STAT4. Our results also indicate that both genes STAT4 and IRF5 act additively to increase risk for SLE.

Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-102290 (URN)10.1136/ard.2008.097642 (DOI)000270700900016 ()19019891 (PubMedID)
Tillgänglig från: 2009-05-06 Skapad: 2009-05-06 Senast uppdaterad: 2017-12-13Bibliografiskt granskad

Open Access i DiVA

fulltext(1368 kB)977 nedladdningar
Filinformation
Filnamn FULLTEXT01.pdfFilstorlek 1368 kBChecksumma MD5
7f69de62512cfcdb0191becc4eb6bc79ac9f059321fd84c30f0ef282887c132fabfb1cea
Typ fulltextMimetyp application/pdf
omslag(108 kB)124 nedladdningar
Filinformation
Filnamn COVER01.pdfFilstorlek 108 kBChecksumma MD5
e73824beea6eb985da5a4c4e320f57b97b51f34b8acfea6108c46abf582002faad3ba9c5
Typ coverMimetyp application/pdf
Köp publikationen >>

Av organisationen
Institutionen för genetik och patologi
Medicinsk genetik

Sök vidare utanför DiVA

GoogleGoogle Scholar
Totalt: 977 nedladdningar
Antalet nedladdningar är summan av nedladdningar för alla fulltexter. Det kan inkludera t.ex tidigare versioner som nu inte längre är tillgängliga.

isbn
urn-nbn

Altmetricpoäng

isbn
urn-nbn
Totalt: 2180 träffar
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf