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  • 1.
    Abelson, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Delgado-Vega, Angélica Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kozyrev, Sergey V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sánchez, Elena
    Velázquez-Cruz, Rafael
    Eriksson, Niclas
    Wojcik, Jerome
    Linga Reddy, Prasad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lima, Guadalupe
    D'Alfonso, Sandra
    Migliaresi, Sergio
    Baca, Vicente
    Orozco, Lorena
    Witte, Torsten
    Ortego-Centeno, Norberto
    Abderrahim, Hadi
    Pons-Estel, Bernardo A.
    Gutiérrez, Carmen
    Suárez, Ana
    González-Escribano, Maria Francisca
    Martin, Javier
    Alarcón-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    STAT4 Associates with SLE through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk2009In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 68, no 11, p. 1746-1753Article in journal (Refereed)
    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.

  • 2.
    Abelson, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Johansson, Cecilia M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kozyrev, Sergey V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kristjansdottir, Helga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gunnarsson, Iva
    Svenungsson, Elisabet
    Jönsen, Andreas
    Lima, Guadalupe
    Scherbarth, Hugo R
    Gamron, Susana
    Allievi, Alejandro
    Palatnik, Sergio A
    Alvarellos, Antonio
    Paira, Sergio
    Graf, Cesar
    Guillerón, Carlos
    Catoggio, Luis J
    Prigione, Carlos
    Battagliotti, Cesar G
    Berbotto, Guillermo A
    García, Mercedes A
    Perandones, Carlos E
    Truedsson, Lennart
    Steinsson, Kristjan
    Sturfelt, Gunnar
    Pons-Estel, Bernardo
    Alarcón-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    No evidence of association between genetic variants of the PDCD1 ligands and SLE2007In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 8, no 1, p. 69-74Article in journal (Refereed)
    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.

  • 3.
    Alarcon-Riquelme, Marta E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kozyrev, Sergey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Shared genes in rheumatic diseases: The role of PDCD1 and RUNX genes in disease susceptibility2006In: Hereditary Basis of Rheumatic Diseases, Basel: Birkhäuser , 2006, p. 79-85Chapter in book (Other academic)
  • 4.
    Alarcón-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Recent advances in the genetics of autoimmune diseases2007In: AUTOIMMUNITY, PT B: NOVEL APPLICATIONS OF BASIC RESEARCH / [ed] Gershwin ME, Shoenfeld Y, 2007, Vol. 1110, p. 1-9Conference paper (Refereed)
    Abstract [en]

    Autoimmune diseases in general are complex genetic diseases where genes and environment interact in unknown ways. In recent years technologies have advanced our knowledge and new genes are being identified very rapidly. We can expect that most genes of major importance for the various autoimmune diseases will be discovered in the coming 5 years. The real challenge comes when we try to understand the mechanisms through which these genes confer disease susceptibility and how the interaction with environment takes place such that clinical expression of the disease results.

  • 5.
    Alarcón-Riquelme, Marta E
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    The genetics of systemic lúpus erythematosus: The path ahead.2007In: Autoimmunity, ISSN 1607-842X, Vol. 40, no 8, p. 549-Article, review/survey (Other (popular scientific, debate etc.))
  • 6. Bennet, Anna M.
    et al.
    Alarcón-Riquelme, Marta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wiman, Björn
    de Faire, Ulf
    Prokunina-Olsson, Ludmila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Decreased risk for myocardial infarction and lower tumor necrosis factor-alpha levels in carriers of variants of the PDCD1 gene2006In: Human Immunology, ISSN 0198-8859, E-ISSN 1879-1166, Vol. 67, no 9, p. 700-705Article in journal (Refereed)
    Abstract [en]

    Increasing interest has been directed toward the inflammatory mechanisms involved in the pathogenesis of myocardial infarction (MI). In the search for genetic mechanisms underlying these inflammatory components, we studied variants of programmed cell death-1 (PDCD1), an immunoinhibitory receptor that inhibits lymphocyte activation and cytokine production, previously shown to be associated with several autoimmune disorders. The PD1.1, PD1.3, and PD1.6 polymorphisms of the PDCD1 gene were typed in the Stockholm Heart Epidemiology Program, a population-based clinical material consisting of 1179 first-time MI case patients and 1528 unaffected control subjects. Individual alleles and haplotypes were studied for association with levels of the inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-6, and C-reactive protein and risk for MI. We observed a weak protective effect of PD1.3A allele for MI (odds ratio: 0.78, 95% confidence interval: 0.61-0.98). We also observed decreased levels of TNF-alpha in carriers of the PD1.1A/PD1.3G/PD1.6A haplotype, which is consistent with our previous observation that this haplotype may be protective from autoimmune conditions. Carriers of variants of the PDCD1 gene exhibit a decreased risk for nonfatal myocardial infarction, and PDCD1 mediates variation in TNF-alpha levels.

  • 7.
    Delgado-Vega, Angelica M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Abelson, A-K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sánchez, E.
    Witte, T.
    D'Alfonso, S.
    Galeazzi, M.
    Jiménez-Alonso, J.
    Pons-Estel, B. A.
    Martin, J.
    Alarcón-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Replication of the TNFSF4 (OX40L) promoter region association with systemic lupus erythematosus2009In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 10, no 3, p. 248-253Article in journal (Refereed)
    Abstract [en]

    The tumor necrosis factor ligand superfamily member 4 gene (TNFSF4) encodes the OX40 ligand (OX40L), a costimulatory molecule involved in T-cell activation. A recent study demonstrated the association of TNFSF4 haplotypes located in the upstream region with risk for or protection from systemic lupus erythematosus (SLE). To replicate this association, five single nucleotide polymorphisms (SNPs) tagging the previously associated haplotypes and passing the proper quality-control filters were tested in 1312 cases and 1801 controls from Germany, Italy, Spain and Argentina. The association of TNFSF4 with SLE was replicated in all the sets except Spain. There was a unique risk haplotype tagged by the minor alleles of the SNPs rs1234317 (pooled odds ratio (OR)=1.39, P=0.0009) and rs12039904 (pooled OR=1.38, P=0.0012). We did not observe association to a single protective marker (rs844644) or haplotype as the first study reported; instead, we observed different protective haplotypes, all carrying the major alleles of both SNPs rs1234317 and rs12039904. Association analysis conditioning on the haplotypic background confirmed that these two SNPs explain the entire haplotype effect. This first replication study confirms the association of genetic variation in the upstream region of TNFSF4 with susceptibility to SLE.

  • 8. Douglas, K. B.
    et al.
    Windels, D. C.
    Zhao, J.
    Gadeliya, A. V.
    Wu, H.
    Kaufman, K. M.
    Harley, J. B.
    Merrill, J.
    Kimberly, R. P.
    Alarcón, G. S.
    Brown, E. E.
    Edberg, J. C.
    Ramsey-Goldman, R.
    Petri, M.
    Reveille, J. D.
    Vilá, L. M.
    Gaffney, P. M.
    James, J. A.
    Moser, K. L.
    Alarcón-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Vyse, T .J.
    Gilkeson, G. S.
    Jacob, C. O.
    Ziegler, J. T.
    Langefeld, C. D.
    Ulgiati, D.
    Tsao, B. P.
    Boackle, Susan A.
    Complement receptor 2 polymorphisms associated with systemic lupus erythematosus modulate alternative splicing2009In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 10, no 5, p. 457-469Article in journal (Refereed)
    Abstract [en]

    Genetic factors influence susceptibility to systemic lupus erythematosus (SLE). A recent family-based analysis in Caucasian and Chinese populations provided evidence for association of single-nucleotide polymorphisms (SNPs) in the complement receptor 2 (CR2/CD21) gene with SLE. Here we confirmed this result in a case-control analysis of an independent European-derived population including 2084 patients with SLE and 2853 healthy controls. A haplotype formed by the minor alleles of three CR2 SNPs (rs1048971, rs17615, rs4308977) showed significant association with decreased risk of SLE (30.4% in cases vs 32.6% in controls, P=0.016, OR=0.90 (0.82-0.98)). Two of these SNPs are in exon 10, directly 5' of an alternatively spliced exon preferentially expressed in follicular dendritic cells (FDC), and the third is in the alternatively spliced exon. Effects of these SNPs and a fourth SNP in exon 11 (rs17616) on alternative splicing were evaluated. We found that the minor alleles of these SNPs decreased splicing efficiency of exon 11 both in vitro and ex vivo. These findings further implicate CR2 in the pathogenesis of SLE and suggest that CR2 variants alter the maintenance of tolerance and autoantibody production in the secondary lymphoid tissues where B cells and FDCs interact.

  • 9. Fawwaz, S.
    et al.
    Nikamo, P.
    Törn, C.
    Landin-Olsson, M.
    Lernmark, A.
    Alarcón-Riquelme, Marta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kockum, I.
    No evidence of association of the PDCD1 gene with Type 1 diabetes2007In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 24, no 12, p. 1473-1477Article in journal (Refereed)
    Abstract [en]

    Aims: To test the association between the immunoreceptor PD-1 (PDCD1) gene and Type 1 diabetes mellitus (T1DM). This gene has been reported to be associated with other autoimmune diseases such as systemic lupus erythematosus (SLE) as well as T1DM. Methods: Genotyping of single nucleotide polymorphisms (SNPs) in the PDCD1 gene was performed using polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP), pyrosequencing and TaqMan in two separate cohorts of Swedish patients and control subjects: a family study consisting of 184 multiplex and eight simplex families and a case-control study consisting of 586 patients and 836 control subjects. Three SNPs were genotyped: PD-1 7146, PD-1 7785 and PD-1 8738. Results: We did not detect any association or linkage between SNPs in PDCD1 and T1DM. We further performed a meta-analysis for association of PD-1 7146, PD-1 7785 and PD-1 8738 to T1DM. We detected heterogeneity in association with weak evidence for overall association. Conclusions: We conclude that PDCD1 is unlikely to be a major susceptibility gene for T1DM.

  • 10. Forabosco, P.
    et al.
    Gorman, J. D.
    Cleveland, C.
    Kelly, J. A.
    Fisher, S. A.
    Ortmann, W. A.
    Johansson, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Johanneson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Moser, K. L.
    Gaffney, P. M.
    Tsao, B. P.
    Cantor, R. M.
    Alarcón-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Behrens, T. W.
    Harley, J. B.
    Lewis, C. M.
    Criswell, Lindsey A.
    Meta-analysis of genome-wide linkage studies of systemic lupus erythematosus2006In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 7, no 7, p. 609-614Article in journal (Refereed)
    Abstract [en]

    A genetic contribution to the development of systemic lupus erythematosus (SLE) is well established. Several genome-wide linkage scans have identified a number of putative susceptibility loci for SLE, some of which have been replicated in independent samples. This study aimed to identify the regions showing the most consistent evidence for linkage by applying the genome scan meta-analysis (GSMA) method. The study identified two genome-wide suggestive regions on 6p21.1-q15 and 20p11-q13.13 (P-value=0.0056 and P-value=0.0044, respectively) and a region with P-value<0.01 on 16p13-q12.2.The region on chromosome 6 contains the human leukocyte antigen cluster, and the chromosome 16 and 20 regions have been replicated in several cohorts. The potential importance of the identified genomic regions are also highlighted. These results, in conjunction with data emerging from dense single nucleotide polymorphism typing of specific regions or future genome-wide association studies will help guide efforts to identify the actual predisposing genetic variation contributing to this complex genetic disease.

  • 11. Han, Shizhong
    et al.
    Kim-Howard, Xana
    Deshmukh, Harshal
    Kamatani, Yoichiro
    Viswanathan, Parvathi
    Guthridge, Joel M.
    Thomas, Kenaz
    Kaufman, Kenneth M.
    Ojwang, Joshua
    Rojas-Villarraga, Adriana
    Baca, Vicente
    Orozco, Lorena
    Rhodes, Benjamin
    Choi, Chan-Bum
    Gregersen, Peter K.
    Merrill, Joan T.
    James, Judith A.
    Gaffney, Patrick M.
    Moser, Kathy L.
    Jacob, Chaim O.
    Kimberly, Robert P.
    Harley, John B.
    Bae, Sang-Choel
    Anaya, Juan-Manuel
    Alarcón-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Matsuda, Koichi
    Vyse, Timothy J.
    Nath, Swapan K.
    Evaluation of imputation-based association in and around the integrin-alpha-M (ITGAM) gene and replication of robust association between a non-synonymous functional variant within ITGAM and systemic lupus erythematosus (SLE)2009In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 18, no 6, p. 1171-1180Article in journal (Refereed)
    Abstract [en]

    We recently identified a novel non-synonymous variant, rs1143679, at exon 3 of the ITGAM gene associated with systemic lupus erythematosus (SLE) susceptibility in European-Americans (EAs) and African-Americans. Using genome-wide association approach, three other studies also independently reported an association between SLE susceptibility and ITGAM or ITGAM-ITGAX region. The primary objectives of this study are to assess whether single or multiple causal variants from the same gene or any nearby gene(s) are involved in SLE susceptibility and to confirm a robust ITGAM association across nine independent data sets (n = 8211). First, we confirmed our previously reported association of rs1143679 (risk allele 'A') with SLE in EAs (P = 1.0 x 10(-8)) and Hispanic-Americans (P = 2.9 x 10(-5)). Secondly, using a comprehensive imputation-based association test, we found that ITGAM is one of the major non-human leukocyte antigen susceptibility genes for SLE, and the strongest association for EA is the same coding variant rs1143679 (log(10)Bayes factor=20, P = 6.17 x 10(-24)). Thirdly, we determined the robustness of rs1143679 association with SLE across three additional case-control samples, including UK (P = 6.2 x 10(-8)), Colombian (P = 3.6 x 10(-7)), Mexican (P = 0.002), as well as two independent sets of trios from UK (P(TDT) = 1.4 x 10(-5)) and Mexico (P(TDT) = 0.015). A meta-analysis combing all independent data sets greatly reinforces the association (P(meta) = 7.1 x 10(-50), odds ratio = 1.83, 95% confidence interval = 1.69-1.98, n = 10 046). However, this ITGAM association was not observed in the Korean or Japanese samples, in which rs1143679 is monomorphic for the non-risk allele (G). Taken together along with our earlier findings, these results demonstrate that the coding variant, rs1143679, best explains the ITGAM-SLE association, especially in European- and African-derived populations, but not in Asian populations.

  • 12. Harley, John B.
    et al.
    Alarcón-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Criswell, Lindsey A.
    Jacob, Chaim O.
    Kimberly, Robert P.
    Moser, Kathy L.
    Tsao, Betty P.
    Vyse, Timothy J.
    Langefeld, Carl D.
    Nath, Swapan K.
    Guthridge, Joel M.
    Cobb, Beth L.
    Mirel, Daniel B.
    Marion, Miranda C.
    Williams, Adrienne H.
    Divers, Jasmin
    Wang, Wei
    Frank, Summer G.
    Namjou, Bahram
    Gabriel, Stacey B.
    Lee, Annette T.
    Gregersen, Peter K.
    Behrens, Timothy W.
    Taylor, Kimberly E.
    Fernando, Michelle
    Zidovetzki, Raphael
    Gaffney, Patrick M.
    Edberg, Jeffrey C.
    Rioux, John D.
    Ojwang, Joshua O.
    James, Judith A.
    Merrill, Joan T.
    Gilkeson, Gary S.
    Seldin, Michael F.
    Yin, Hong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Baechler, Emily C.
    Li, Quan-Zhen
    Wakeland, Edward K.
    Bruner, Gail R.
    Kaufman, Kenneth M.
    Kelly, Jennifer A.
    Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci2008In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 40, no 2, p. 204-10Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (lambda(S) = approximately 30). We performed a genome-wide association scan using 317,501 SNPs in 720 women of European ancestry with SLE and in 2,337 controls, and we genotyped consistently associated SNPs in two additional independent sample sets totaling 1,846 affected women and 1,825 controls. Aside from the expected strong association between SLE and the HLA region on chromosome 6p21 and the previously confirmed non-HLA locus IRF5 on chromosome 7q32, we found evidence of association with replication (1.1 x 10(-7) < P(overall) < 1.6 x 10(-23); odds ratio = 0.82-1.62) in four regions: 16p11.2 (ITGAM), 11p15.5 (KIAA1542), 3p14.3 (PXK) and 1q25.1 (rs10798269). We also found evidence for association (P < 1 x 10(-5)) at FCGR2A, PTPN22 and STAT4, regions previously associated with SLE and other autoimmune diseases, as well as at > or =9 other loci (P < 2 x 10(-7)). Our results show that numerous genes, some with known immune-related functions, predispose to SLE.

  • 13. Kosoy, Roman
    et al.
    Nassir, Rami
    Tian, Chao
    White, Phoebe A.
    Butler, Lesley M.
    Silva, Gabriel
    Kittles, Rick
    Alarcon-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gregersen, Peter K.
    Belmont, John W.
    De La Vega, Francisco M.
    Seldin, Michael F.
    Ancestry informative marker sets for determining continental origin and admixture proportions in common populations in America2009In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 30, no 1, p. 69-78Article in journal (Refereed)
    Abstract [en]

    To provide a resource for assessing continental ancestry in a wide variety of genetic studies, we identified, validated, and characterized a set of 128 ancestry informative markers (AIMs). The markers were chosen for informativeness, genome-wide distribution, and genotype reproducibility on two platforms (TaqMan assays and Illumina arrays). We analyzed genotyping data from 825 subjects with diverse ancestry, including European, East Asian, Amerindian, African, South Asian, Mexican, and Puerto Rican. A comprehensive set of 128 AIMs and subsets as small as 24 AIMs are shown to be useful tools for ascertaining the origin of subjects from particular continents, and to correct for population stratification in admixed population sample sets. Our findings provide general guidelines for the application of specific AIM subsets as a resource for wide application. We conclude that investigators can use TaqMan assays for the selected AIMs as a simple and cost efficient tool to control for differences in continental ancestry when conducting association studies in ethnically diverse populations.

  • 14.
    Kozyrev, Sergey V.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Alarcon-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    The genetics and biology of Irf5-mediated signaling in lupus2007In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 40, no 8, p. 591-601Article in journal (Refereed)
    Abstract [en]

    Recently much attention was attracted to the importance of the type I interferon pathway in the initiation and development of the autoimmune disease systemic lupus erythematosus (SLE). Many SLE patients have increased serum levels of IFN-α and display an IFN gene expression "signature" characterized by strong overexpression of IFN-responsive genes in leukocytes and target tissues. Moreover, about 20% of cancer patients treated with IFN-α therapy manifest symptoms resembling SLE and some later develop the disease. One of the key genes of the IFN-α pathway, IRF5, was found to be strongly associated with SLE. Two functional SNPs lead to alternative splicing and altered steady-state level of IRF5 gene expression. Besides, the gene has a polymorphic inserion/deletion in exon 6, which contributes to the diversity in the isoform pattern of IRF5. Interestingly, recent studies have not found association of IRF5 with the other autoimmune diseases, such as rheumatoid arthritis or psoriasis, suggesting the unique role for IRF5 in the development of lupus. Here, we present the current knowledge on IRF5 genetics and its biological function and discuss the possible ways in which IRF5 contributes to susceptibility to SLE.

  • 15.
    Linga Reddy, M. V. Prasad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Velázquez-Cruz, Rafael
    Baca, Vicente
    Lima, Guadalupe
    Granados, Julio
    Orozco, Lorena
    Alarcón-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Genetic association of IRF5 with SLE in Mexicans: higher frequency of the risk haplotype and its homozygozity than Europeans2007In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 121, no 6, p. 721-727Article in journal (Refereed)
    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.

  • 16. Liu, Kui
    et al.
    Li, Quan-Zhen
    Delgado-Vega, Angelica M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Abelson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sánchez, Elena
    Kelly, Jennifer A.
    Li, Li
    Liu, Yang
    Zhou, Jinchun
    Yan, Mei
    Ye, Qiu
    Liu, Shenxi
    Xie, Chun
    Zhou, Xin J.
    Chung, Sharon A.
    Pons-Estel, Bernardo
    Witte, Torsten
    de Ramón, Enrique
    Bae, Sang-Cheol
    Barizzone, Nadia
    Sebastiani, Gian Domenico
    Merrill, Joan T.
    Gregersen, Peter K.
    Gilkeson, Gary G.
    Kimberly, Robert P.
    Vyse, Timothy J.
    Kim, Il
    D'Alfonso, Sandra
    Martin, Javier
    Harley, John B.
    Criswell, Lindsey A.
    Wakeland, Edward K.
    Alarcón-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Mohan, Chandra
    Danieli, M.G.
    Galeazzi, M.
    Querini, P.R.
    Migliaresi, S.
    Scherbarth, H.R.
    Lopez, J.A.
    Motta, E.L.
    Gamron, S.
    Drenkard, C.
    Menso, E.
    Allievi, A.
    Tate, G.A.
    Presas, J.L.
    Palatnik, S.A.
    Abdala, M.
    Bearzotti, M.
    Alvarellos, A.
    Caeiro, F.
    Bertoli, A.
    Paira, S.
    Roverano, S.
    Graf, C.E.
    Bertero, E.
    Caprarulo, C.
    Buchanan, G.
    Guillerón, C.
    Grimaudo, S.
    Manni, J.
    Catoggio, L.J.
    Soriano, E.R.
    Santos, C.D.
    Prigione, C.
    Ramos, F.A.
    Navarro, S.M.
    Berbotto, G.A.
    Jorfen, M.
    Romero, E.J.
    Garcia, M.A.
    Marcos, J.C.
    Marcos, A.I.
    Perandones, C.E.
    Eimon, A.
    Battagliotti, C.G.
    Armadi-Simab, K.
    Gross, W.L.
    Gromica-Ihle, E.
    Peter, H.H.
    Manger, K.
    Schnarr, S.
    Zeidler, H.
    Schmidt, R.E.
    Ortego, N.
    Callejas, J.L.
    Jiménez-Alonso, J.
    Sabio, M.
    Sánchez-Román, J.
    Garcia-Hernandez, F.J.
    Camps, M.
    López-Nevot, M.A.
    González-Escribano, M.F.
    Harley, J.H.
    Riquelme, M.A.
    Kimberly, R.
    Criswell, L.
    Langefeld, C.
    Tsao, B.
    Jacob, C.
    Kallikrein genes are associated with lupus and glomerular basement membrane-specific antibody-induced nephritis in mice and humans2009In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 119, no 4, p. 911-923Article in journal (Refereed)
    Abstract [en]

    Immune-mediated nephritis contributes to disease in systemic lupus erythematosus, Goodpasture syndrome (caused by antibodies specific for glomerular basement membrane [anti-GBM antibodies]), and spontaneous lupus nephritis. Inbred mouse strains differ in susceptibility to anti-GBM antibody-induced and spontaneous lupus nephritis. This study sought to clarify the genetic and molecular factors that maybe responsible for enhanced immune-mediated renal disease in these models. When the kidneys of 3 mouse strains sensitive to anti-GBM antibody-induced nephritis were compared with those of 2 control strains using microarray analysis, one-fifth of the underexpressed genes belonged to the kallikrein gene family,which encodes serine esterases. Mouse strains that upregulated renal and urinary kallikreins exhibited less evidence of disease. Antagonizing the kallikrein pathway augmented disease, while agonists dampened the severity of anti-GBM antibody-induced nephritis. In addition, nephritis-sensitive mouse strains had kallikrein haplotypes that were distinct from those of control strains, including several regulatory polymorphisms,some of which were associated with functional consequences. Indeed, increased susceptibility to anti-GBM antibody-induced nephritis and spontaneous lupus nephritis was achieved by breeding mice with a genetic interval harboring the kallikrein genes onto a disease-resistant background. Finally, both human SLE and spontaneous lupus nephritis were found to be associated with kallikrein genes, particularly KLK1 and the KLK3 promoter, when DNA SNPs from independent cohorts of SLE patients and controls were compared. Collectively, these studies suggest that kallikreins are protective disease-associated genes in anti-GBM antibody-induced nephritis and lupus.

  • 17. Lu, R
    et al.
    Vidal, G S
    Kelly, J A
    Delgado-Vega, Angelica M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Howard, X K
    Macwana, S R
    Dominguez, N
    Klein, W
    Burrell, C
    Harley, I T
    Kaufman, K M
    Bruner, G R
    Moser, K L
    Gaffney, P M
    Gilkeson, G S
    Wakeland, E K
    Li, Q-Z
    Langefeld, C D
    Marion, M C
    Divers, J
    Alarcón, G S
    Brown, E E
    Kimberly, R P
    Edberg, J C
    Ramsey-Goldman, R
    Reveille, J D
    McGwin, G
    Vilá, L M
    Petri, M A
    Bae, S-C
    Cho, S-K
    Bang, S-Y
    Kim, I
    Choi, C-B
    Martin, J
    Vyse, T J
    Merrill, J T
    Harley, J B
    Alarcón-Riquelme, Marta E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nath, S K
    James, J A
    Guthridge, J M
    Genetic associations of LYN with systemic lupus erythematosus2009In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 10, no 5, p. 397-403Article in journal (Refereed)
    Abstract [en]

    We targeted LYN, a src-tyosine kinase involved in B-cell activation, in case-control association studies using populations of European-American, African-American and Korean subjects. Our combined European-derived population, consisting of 2463 independent cases and 3131 unrelated controls, shows significant association with rs6983130 in a female-only analysis with 2254 cases and 2228 controls (P=1.1 x 10(-4), odds ratio (OR)=0.81 (95% confidence interval: 0.73-0.90)). This single nucleotide polymorphism (SNP) is located in the 5' untranslated region within the first intron near the transcription initiation site of LYN. In addition, SNPs upstream of the first exon also show weak and sporadic association in subsets of the total European-American population. Multivariate logistic regression analysis implicates rs6983130 as a protective factor for systemic lupus erythematosus (SLE) susceptibility when anti-dsDNA, anti-chromatin, anti-52 kDa Ro or anti-Sm autoantibody status were used as covariates. Subset analysis of the European-American female cases by American College of Rheumatology classification criteria shows a reduction in the risk of hematological disorder with rs6983130 compared with cases without hematological disorders (P=1.5 x 10(-3), OR=0.75 (95% CI: 0.62-0.89)). None of the 90 SNPs tested show significant association with SLE in the African American or Korean populations. These results support an association of LYN with European-derived individuals with SLE, especially within autoantibody or clinical subsets.

  • 18. Meroni, Pier Luigi
    et al.
    Tincani, A.
    Alarcón-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Shoenfeld, Y.
    Borghi, M. O.
    European Forum on Antiphospholipid Antibodies: research in progress2009In: Lupus, ISSN 0961-2033, E-ISSN 1477-0962, Vol. 18, no 10, p. 924-929Article in journal (Refereed)
    Abstract [en]

    The research projects of the European Forum on Antiphospholipid Antibodies are representative of how dynamic is this area of investigation. The present review is focused on the most recent projects of the Forum on the aetiopathogenic aspects of the antiphospholipid syndrome (APS). Studies on the genetic background of the APS are ongoing in order to better define the proximity between APS and full-blown systemic lupus erythematosus. However, the analysis of the polymorphisms of genes coding for inflammatory mediators may offer new information on the role of inflammatory processes in triggering thrombotic events as well as the whole susceptibility for developing the vascular manifestations. A systematic and wide detection of serological markers of infectious processes will give new insight on the role of infectious agents in favouring autoimmunity in APS. Owing to the well-known role of vitamin D(3) defect in autoimmune disease, the detection of vitamin plasma levels in APS patients will offer the rationale for a possible therapeutic supplementation. Additional projects are aimed to better characterize the diagnostic/prognostic value of antiphospholipid antibodies (aPL) by defining their epitope specificity and binding avidity. Pregnancy complications represent the obstetric side of APS. Research projects are focussed on the role of complement activation in placenta damage and on the potential ability of aPL to affect the fertility. Finally, a study has been planned in order to draw definitive conclusions on the associations between aPL and atherosclerosis.

  • 19. Namjou, Bahram
    et al.
    Sestak, Andrea L.
    Armstrong, Don L.
    Zidovetzki, Raphael
    Kelly, Jennifer A.
    Jacob, Noam
    Ciobanu, Voicu
    Kaufman, Kenneth M.
    Ojwang, Joshua O.
    Ziegler, Julie
    Quismorio, Francesco P.
    Reiff, Andreas
    Myones, Barry L.
    Guthridge, Joel M.
    Nath, Swapan K.
    Bruner, Gail R.
    Mehrian-Shai, Ruth
    Silverman, Earl
    Klein-Gitelman, Marisa
    McCurdy, Deborah
    Wagner-Weiner, Linda
    Nocton, James J.
    Putterman, Chaim
    Bae, Sang-Cheol
    Kim, Yun Jung
    Petri, Michelle
    Reveille, John D.
    Vyse, Timothy J.
    Gilkeson, Gary S.
    Kamen, Diane L.
    Alarcón-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gaffney, Patrick M.
    Moser, Kathy L.
    Merrill, Joan T.
    Scofield, R. Hal
    James, Judith A.
    Langefeld, Carl D.
    Harley, John B.
    Jacob, Chaim O.
    High-density genotyping of STAT4 reveals multiple haplotypic associations with systemic lupus erythematosus in different racial groups2009In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 60, no 4, p. 1085-1095Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disorder, with complex etiology and a strong genetic component. Recently, gene products involved in the interferon pathway have been under intense investigation in terms of the pathogenesis of SLE. STAT-1 and STAT-4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for involvement in SLE susceptibility. METHODS: Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 on chromosome 2 were genotyped using the Illumina platform, as part of an extensive association study in a large collection of 9,923 lupus patients and control subjects from different racial groups. DNA samples were obtained from the peripheral blood of patients with SLE and control subjects. Principal components analyses and population-based case-control association analyses were performed, and the P values, false discovery rate q values, and odds ratios with 95% confidence intervals were calculated. RESULTS: We observed strong genetic associations with SLE and multiple SNPs located within STAT4 in different ethnic groups (Fisher's combined P = 7.02 x 10(-25)). In addition to strongly confirming the previously reported association in the third intronic region of this gene, we identified additional haplotypic association across STAT4 and, in particular, a common risk haplotype that is found in multiple racial groups. In contrast, only a relatively weak suggestive association was observed with STAT1, probably due to its proximity to STAT4. CONCLUSION: Our findings indicate that STAT4 is likely to be a crucial component in SLE pathogenesis in multiple racial groups. Knowledge of the functional effects of this association, when they are revealed, might improve our understanding of the disease and provide new therapeutic targets.

  • 20. Nath, Swapan K.
    et al.
    Han, Shizhong
    Kim-Howard, Xana
    Kelly, Jennifer A.
    Viswanathan, Parvathi
    Gilkeson, Gary S.
    Chen, Wei
    Zhu, Cheng
    McEver, Rodger P.
    Kimberly, Robert P.
    Alarcón-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Vyse, Timothy J.
    Li, Quan-Zhen
    Wakeland, Edward K.
    Merrill, Joan T.
    James, Judith A.
    Kaufman, Kenneth M.
    Guthridge, Joel M.
    Harley, John B.
    A nonsynonymous functional variant in integrin-alpha(M) (encoded by ITGAM) is associated with systemic lupus erythematosus2008In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 40, no 2, p. 152-154Article in journal (Refereed)
    Abstract [en]

    We identified and replicated an association between ITGAM (CD11b) at 16p11.2 and risk of systemic lupus erythematosus (SLE) in 3,818 individuals of European descent. The strongest association was at a nonsynonymous SNP, rs1143679 (P = 1.7 x 10(-17), odds ratio = 1.78). We further replicated this association in two independent samples of individuals of African descent (P = 0.0002 and 0.003; overall meta-analysis P = 6.9 x 10(-22)). The genetic association between ITGAM and SLE implicates the alpha(M)beta2-integrin adhesion pathway in disease development.

  • 21. Orozco, G.
    et al.
    Sanchez, E.
    Gomez, L. M.
    Gonzalez-Gay, M. A.
    Lopez-Nevot, M. A.
    Torres, B.
    Ortego-Centeno, N.
    Jimenez-Alonso, J.
    de Ramon, E.
    Sanchez Roma¡n, J.
    Anaya, J. M.
    Sturfelt, G.
    Gunnarsson, I.
    Svennungsson, E.
    Alarcón-Riquelme, Marta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gonzalez-Escribano, M. F.
    Marti­n, J.
    Study of the role of functional variants of SLC22A4, RUNX1 and SUMO4 in systemic lupus erythematosus2006In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 65, no 6, p. 791-5Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Functional polymorphisms of the solute carrier family 22, member 4 (SLC22A4), runt related transcription factor 1 (RUNX1) and small ubiquitin-like modifier 4 (SUMO4) genes have been shown to be associated with several autoimmune diseases. OBJECTIVE: To test the possible role of these variants in susceptibility to or severity of systemic lupus erythematosus (SLE), on the basis that common genetic bases are shared by autoimmune disorders. METHODS: 597 SLE patients and 987 healthy controls of white Spanish origin were studied. Two additional cohorts of 228 SLE patients from Sweden and 122 SLE patients from Colombia were included. A case-control association study was carried out with six single nucleotide polymorphisms (SNP) spanning the SLC22A4 gene, one SNP in RUNX1 gene, and one additional SNP in SUM04 gene. RESULTS: No significant differences were observed between SLE patients and healthy controls when comparing the distribution of the genotypes or alleles of any of the SLC22A4, RUNX1, or SUMO4 polymorphisms tested. Significant differences were found in the distribution of the SUMO4 genotypes and alleles among SLE patients with and without nephritis, but after multiple testing correction, the significance of the association was lost. The association of SUMO4 with nephritis could not be verified in two independent SLE cohorts from Sweden and Colombia. CONCLUSIONS: These results suggest that the SLC22A4, RUNX1, and SUMO4 polymorphisms analysed do not play a role in the susceptibility to or severity of SLE.

  • 22. Orozco, Gisela
    et al.
    Abelson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    González-Gay, Miguel A.
    Balsa, Alejandro
    Pascual-Salcedo, Dora
    García, Antonio
    Fernández-Gutierrez, Benjamín
    Petersson, Ingemar
    Pons-Estel, Bernardo
    Eimon, Alicia
    Paira, Sergio
    Scherbarth, Hugo R.
    Alarcón-Riquelme, Marta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Martín, Javier
    Study of functional variants of the BANK1 gene in rheumatoid arthritis2009In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 60, no 2, p. 372-379Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate 1 functional (rs17266594) and 2 potentially functional (rs10516487 and rs3733197) BANK1 variants, which were previously identified as systemic lupus erythematosus (SLE) susceptibility markers, to test whether they are associated with rheumatoid arthritis (RA). METHODS: Four different cohorts were included in the study: 1,080 RA patients and 1,368 healthy controls from Spain, 278 RA patients and 568 healthy controls from Sweden, 288 RA patients and 287 healthy controls from Argentina, and 288 RA patients and 288 healthy controls from Mexico. Samples were genotyped for BANK1 single-nucleotide polymorphisms (SNPs) using a TaqMan 5'-allele discrimination assay. Statistical analysis comparing allele and genotype distributions was performed with the chi-square test. RESULTS: We did not find a significant association between RA and the rs10516487 and rs17266594 BANK1 polymorphisms. However, there was an increase in the major alleles among RA patients. Similarly, for rs3733197, there was an increase in the major allele among patients in every cohort. Nevertheless, this skewing reached statistical significance in the Spanish (P = 0.01, odds ratio [OR] 1.17 [95% confidence interval (95% CI) 1.03-1.32]) and Argentinean (P = 0.04, OR 1.31 [95% CI 1.00-1.72]) populations. We found a significant association of rs10516487 (P = 0.005, OR 1.15 [95% CI 1.04-1.28]) and rs3733197 (P = 0.0009, OR 1.17 [95% CI 1.07-1.29]) with RA in the pooled analysis. In a 3-SNP haplotype analysis, we found that the major TGG haplotype was significantly associated with RA (P = 0.005, OR 1.14 [95% CI 1.04-1.25]). In addition, we found a common CAA haplotype that was protective against RA (P = 0.0004, OR 0.82 [95% CI 0.74-0.92]). CONCLUSION: These results suggest that BANK1 SNPs and haplotypes may contribute to RA susceptibility with a low risk.

  • 23. Orozco, Gisela
    et al.
    Alizadeh, Behrooz Z.
    Delgado-Vega, Angélica M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    González-Gay, Miguel A.
    Balsa, Alejandro
    Pascual-Salcedo, Dora
    Fernández-Gutierrez, Benjamín
    González-Escribano, María F.
    Petersson, Ingemar F.
    van Riel, Piet L. C. M.
    Barrera, Pilar
    Coenen, Marieke J. H.
    Radstake, Timothy R. D. J.
    van Leeuwen, Miek A.
    Wijmenga, Cisca
    Koeleman, Bobby P. C.
    Alarcón-Riquelme, Marta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Martín, Javier
    Association of STAT4 with rheumatoid arthritis: a replication study in three European populations2008In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 58, no 7, p. 1974-1980Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: This study was undertaken to investigate the previously reported association of the STAT4 polymorphism rs7574865 with rheumatoid arthritis (RA) in 3 different European populations from Spain, Sweden, and The Netherlands, comprising a total of 2,072 patients and 2,474 controls. METHODS: Three different cohorts were included in the study: 923 RA patients and 1,296 healthy controls from Spain, 273 RA patients and 285 healthy controls from Sweden, and 876 RA patients and 893 healthy controls from The Netherlands. DNA from patients and controls was obtained from peripheral blood. Samples were genotyped for the STAT4 single-nucleotide polymorphism rs7574865 using a TaqMan 5'-allele discrimination assay. The chi-square test was performed to compare allele and genotype distributions. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: We observed a significantly increased frequency of the minor T allele in RA patients compared with healthy controls in the Spanish population (24.8% versus 20.8%; P = 0.001, OR 1.26 [95% CI 1.09-1.45]). This association was confirmed in both the Swedish population (P = 0.03, OR 1.35 [95% CI 1.03-1.77]) and the Dutch population (P = 0.03, OR 1.45 [95% CI 1.21-1.73]). The overall P value for all 3 populations was 9.79 x 10(-6) (OR 1.25 [95% CI 1.13-1.37]). No association between rs7574865 and the presence of rheumatoid factor or anti-cyclic citrullinated peptide autoantibodies was observed. A meta-analysis of all published STAT4 associations revealed an OR of 1.25 (95% CI 1.19-1.33) (P = 1 x 10(-5)). CONCLUSION: Our findings indicate an association between the STAT4 polymorphism rs7574865 and RA in 3 different populations, from Spain, Sweden, and The Netherlands, thereby confirming previous data.

  • 24. Orrú, Valeria
    et al.
    Tsai, Sophia J.
    Rueda, Blanca
    Fiorillo, Edoardo
    Stanford, Stephanie M.
    Dasgupta, Jhimli
    Hartiala, Jaana
    Zhao, Lei
    Ortego-Centeno, Norberto
    D'Alfonso, Sandra
    Arnett, Frank C.
    Wu, Hui
    Gonzalez-Gay, Miguel A.
    Tsao, Betty P.
    Pons-Estel, Bernardo
    Alarcon-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    He, Yantao
    Zhang, Zhong-Yin
    Allayee, Hooman
    Chen, Xiaojiang S.
    Martin, Javier
    Bottini, Nunzio
    A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus2009In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 18, no 3, p. 569-579Article in journal (Refereed)
    Abstract [en]

    A gain-of-function R620W polymorphism in the PTPN22 gene, encoding the lymphoid tyrosine phosphatase LYP, has recently emerged as an important risk factor for human autoimmunity. Here we report that another missense substitution (R263Q) within the catalytic domain of LYP leads to reduced phosphatase activity. High-resolution structural analysis revealed the molecular basis for this loss of function. Furthermore, the Q263 variant conferred protection against human systemic lupus erythematosus, reinforcing the proposal that inhibition of LYP activity could be beneficial in human autoimmunity.

  • 25.
    Prokunina, Ludmila
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Castillejo-Lopez, Casimiro
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology.
    Öberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gunnarsson, Iva
    Berg, Louise
    Magnusson, Veronica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Brookes, Anthony J.
    Tentler, Dmitry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kristjansdottir, Helga
    Gröndal, Gerdur
    Bolstad, Anne Isine
    Svenungsson, Elisabet
    Lundberg, Ingrid
    Sturfelt, Gunnar
    Jönssen, Andreas
    Truedsson, Lennart
    Lima, Guadelupe
    Alcocer-Varela, Jorge
    Jonsson, Roland
    Gyllensten, Ulf B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Harley, John B.
    Alarcon-Segovia, Donato
    Steinsson, Kristján
    Alarcon-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans2002In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 32, no 4, p. 666-669Article, book review (Other academic)
    Abstract [en]

    Systemic lupus erythematosus (SLE, OMIM 152700) is a complex autoimmune disease that affects 0.05% of the Western population, predominantly women. A number of susceptibility loci for SLE have been suggested in different populations, but the nature of the susceptibility genes and mutations is yet to be identified. We previously reported a susceptibility locus (SLEB2) for Nordic multi-case families. Within this locus, the programmed cell death 1 gene (PDCD1, also called PD-1) was considered the strongest candidate for association with the disease. Here, we analyzed 2,510 individuals, including members of five independent sets of families as well as unrelated individuals affected with SLE, for single-nucleotide polymorphisms (SNPs) that we identified in PDCD1. We show that one intronic SNP in PDCD1 is associated with development of SLE in Europeans (found in 12% of affected individuals versus 5% of controls; P = 0.00001, r.r. (relative risk) = 2.6) and Mexicans (found in 7% of affected individuals versus 2% of controls; P = 0.0009, r.r. = 3.5). The associated allele of this SNP alters a binding site for the runt-related transcription factor 1 (RUNX1, also called AML1) located in an intronic enhancer, suggesting a mechanism through which it can contribute to the development of SLE in humans.

  • 26. Rueda, Blanca
    et al.
    Reddy, M. V. Prasad Linga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    González-Gay, Miguel A.
    Balsa, Alejandro
    Pascual-Salcedo, Dora
    Petersson, Ingemar F.
    Eimon, Alicia
    Paira, Sergio
    Scherbarth, Hugo R.
    Pons-Estel, Bernardo A.
    González-Escribano, Maria F.
    Alarcón-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Martín, Javier
    Analysis of IRF5 gene functional polymorphisms in rheumatoid arthritis2006In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 54, no 12, p. 3815-3819Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Recent findings suggest that interferon regulatory factor 5 (IRF-5) may play a crucial role in several cellular processes, including the transcription of genes for inflammatory cytokines. Two genetic variants of the IRF5 gene (rs2004640 in exon 1 and rs2280714 in the 3'-untranslated region) have been shown to exert functional modifications affecting IRF5 messenger RNA splicing and expression, and have been associated with genetic predisposition to systemic lupus erythematosus (SLE). The aim of this study was to analyze the possible contribution of the IRF5 gene to the predisposition to rheumatoid arthritis (RA). METHODS: Three case-control cohorts from Spain (724 RA patients and 542 healthy controls), Sweden (281 RA patients 474 healthy controls), and Argentina (284 RA patients and 286 healthy controls) were independently analyzed. Genotyping for IRF5 rs2004640 and rs2280714 was performed using a TaqMan 5' allele-discrimination assay. RESULTS: In the 3 cohorts studied, no statistically significant differences in allele or genotype frequencies of the rs2004640 and rs2280714 IRF5 polymorphisms were observed between RA patients and controls. Accordingly, haplotype analysis revealed that none of the IRF5 haplotypes was associated with genetic predisposition to RA. CONCLUSION: Our results suggest that the IRF5 functional polymorphisms analyzed do not seem to be implicated in genetic susceptibility to RA.

  • 27. Sawalha, Amr H.
    et al.
    Webb, Ryan
    Han, Shizhong
    Kelly, Jennifer A.
    Kaufman, Kenneth M.
    Kimberly, Robert P.
    Alarcón-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    James, Judith A.
    Vyse, Timothy J.
    Gilkeson, Gary S.
    Choi, Chan-Bum
    Scofield, R. Hal
    Bae, Sang-Cheol
    Nath, Swapan K.
    Harley, John B.
    Common variants within MECP2 confer risk of systemic lupus erythematosus2008In: PLoS ONE, ISSN 1932-6203, Vol. 3, no 3, p. e1727-Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is a predominantly female autoimmune disease that affects multiple organ systems. Herein, we report on an X-chromosome gene association with SLE. Methyl-CpG-binding protein 2 (MECP2) is located on chromosome Xq28 and encodes for a protein that plays a critical role in epigenetic transcriptional regulation of methylation-sensitive genes. Utilizing a candidate gene association approach, we genotyped 21 SNPs within and around MECP2 in SLE patients and controls. We identify and replicate association between SLE and the genomic element containing MECP2 in two independent SLE cohorts from two ethnically divergent populations. These findings are potentially related to the overexpression of methylation-sensitive genes in SLE.

  • 28. Seldin, M. F.
    et al.
    Qi, L.
    Scherbarth, H. R.
    Tian, C.
    Ransom, M.
    Silva, G.
    Belmont, J. W.
    Gamron, S.
    Allievi, A.
    Palatnik, S. A.
    Saurit, V.
    Paira, S.
    Graf, C.
    Guillerón, C.
    Catoggio, L. J.
    Prigione, C.
    Berbotto, G. A.
    García, M. A.
    Perandones, C. E.
    Truedsson, L.
    Abderrahim, H.
    Battagliotti, C. G.
    Pons-Estel, B. A.
    Alarcon-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Amerindian ancestry in Argentina is associated with increased risk for systemic lupus erythematosus2008In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 9, no 4, p. 389-393Article in journal (Refereed)
    Abstract [en]

    Previous studies have demonstrated that in admixed populations, West African ancestry is associated with an increased prevalence of systemic lupus erythematosus (SLE). In the current study, the effect of Amerindian ancestry in SLE was examined in an admixed population in Argentina. The Argentine population is predominantly European with approximately 20% Amerindian admixture, and a very small (<2%) contribution from West Africa. The results indicate that Amerindian admixture in this population is associated with a substantial increase in SLE susceptibility risk (Odds Ratio=7.94, P=0.00006). This difference was not due to known demographic factors, including site of collection, age and gender. In addition, there were trends towards significance for Amerindian ancestry influencing renal disease, age of onset and anti-SSA antibodies. These studies suggest that populations with Amerindian admixture, like those with West African admixture, should be considered in future studies to identify additional allelic variants that predispose to SLE.

  • 29. Seldin, Michael F.
    et al.
    Tian, Chao
    Shigeta, Russell
    Scherbarth, Hugo R.
    Silva, Gabriel
    Belmont, John W.
    Kittles, Rick
    Gamron, Susana
    Allevi, Alberto
    Palatnik, Simon A.
    Alvarellos, Alejandro
    Paira, Sergio
    Caprarulo, Cesar
    Guilleron, Carolina
    Catoggio, Luis J.
    Prigione, Cristina
    Berbotto, Guillermo A.
    Garci­a, Mercedes A.
    Perandones, Carlos E.
    Pons-Estel, Bernardo A.
    Alarcon-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Argentine population genetic structure: large variance in Amerindian contribution2007In: American Journal of Physical Anthropology, ISSN 0002-9483, E-ISSN 1096-8644, Vol. 132, no 3, p. 455-462Article in journal (Refereed)
    Abstract [en]

    Argentine population genetic structure was examined using a set of 78 ancestry informative markers (AIMs) to assess the contributions of European, Amerindian, and African ancestry in 94 individuals members of this population. Using the Bayesian clustering algorithm STRUCTURE, the mean European contribution was 78%, the Amerindian contribution was 19.4%, and the African contribution was 2.5%. Similar results were found using weighted least mean square method: European, 80.2%; Amerindian, 18.1%; and African, 1.7%. Consistent with previous studies the current results showed very few individuals (four of 94) with greater than 10% African admixture. Notably, when individual admixture was examined, the Amerindian and European admixture showed a very large variance and individual Amerindian contribution ranged from 1.5 to 84.5% in the 94 individual Argentine subjects. These results indicate that admixture must be considered when clinical epidemiology or case control genetic analyses are studied in this population. Moreover, the current study provides a set of informative SNPs that can be used to ascertain or control for this potentially hidden stratification. In addition, the large variance in admixture proportions in individual Argentine subjects shown by this study suggests that this population is appropriate for future admixture mapping studies.

  • 30. Sánchez, Elena
    et al.
    Palomino-Morales, Rogelio J.
    Ortego-Centeno, Norberto
    Jiménez-Alonso, Juan
    González-Gay, Miguel A.
    López-Nevot, Miguel A.
    Sánchez-Román, Julio
    de Ramón, Enrique
    González-Escribano, M. Francisca
    Pons-Estel, Bernardo A.
    D'Alfonso, Sandra
    Sebastiani, Gian Domenico
    Alarcón-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Martín, Javier
    Identification of a new putative functional IL18 gene variant through an association study in systemic lupus erythematosus2009In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 18, no 19, p. 3739-3748Article in journal (Refereed)
    Abstract [en]

    Interleukin-18 (IL-18) is a proinflammatory cytokine that plays an important role in chronic inflammation and autoimmune disorders. In this study, we aimed to determine the potential role of the IL18 gene in SLE. To define the genetic association of the IL18 and SLE, we have genotyped nine SNPs in an independent set of Spanish cases and controls. The IL18 polymorphisms were genotyped by PCR, using a predeveloped TaqMan allele discrimination assay. Two SNPs were still significant after fine mapping of the IL18 gene. The SNP (rs360719) surviving correction for multiple tests was genotyped in two replication cohorts from Italy and Argentina. After the analysis, a significance with rs360719 C-allele remained across the sets and after the meta-analysis (Pooled OR = 1.37, 95% CI 1.21-1.54, combined P = 3.8E-07, Pc = 1.16E-06). Quantitative real-time PCR was performed to assess IL18 mRNA expression in PBMC from subjects with different IL18 rs360719 genotypes. We tested the effect of the IL18 rs360719 polymorphism on the transcription of IL18 by electrophoretic mobility shift assay and western blot. We found a significant increase in the relative expression of IL18 mRNA in individuals carrying the rs360719 C-risk allele; in addition we show that the polymorphism creates a binding site for the transcriptional factor OCT-1. These findings suggest that the novel IL18 rs360719 variant may play an important role in determining the susceptibility to SLE and it could be a key factor in the expression of the IL18 gene.

  • 31.
    Teruel, Maria
    et al.
    Univ Granada, Andalusian Reg Govt, Ctr Genom & Oncol Res Pfizer, GENYO, Granada, Spain..
    Coit, Patrick
    Univ Michigan, Div Rheumatol, Ann Arbor, MI 48109 USA..
    Dozmorov, Mikhail
    Virginia Commonwealth Univ, Dept Biostat, Richmond, VA USA..
    Cardiel, Mario
    Ctr Invest Clin Morelia SC, Morelia, Michoacan, Mexico..
    Garcia-De La Torre, Ignacio
    Ctr Est Invest Bas & Clin SC, Immunol & Rheumatol, Guadalajara, Jalisco, Mexico..
    Maradiaga-Cecena, Marco A.
    Hosp Gen Culiacan, Culiacan, Mexico..
    Moctezuma, Jose Francisco
    Hosp Gen Mexico City, Serv Reumatol, Mexico City, DF, Mexico..
    Tusie-Luna, Maria Teresa
    Univ Nacl Autonoma Mexico, Med Genom & Toxicol Ambiental, Mexico City, DF, Mexico..
    Alarcón-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Univ Granada, Junta Andalucia, Pfizer, Ctr Genom & Invest Oncol, Granada, Spain..
    Sawalha, Amr H.
    Univ Michigan, Div Rheumatol, Ann Arbor, MI 48109 USA..
    Genome-Wide DNA Methylation Study in Lupus in an Admixed Mexican Population2017In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 69, no S10, article id 178Article in journal (Other academic)
  • 32. Thorburn, C. M.
    et al.
    Prokunina-Olsson, L.
    Sterba, K. A.
    Lum, R. F.
    Seldin, M. F.
    Alarcon-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Criswell, L. A.
    Association of PDCD1 genetic variation with risk and clinical manifestations of systemic lupus erythematosus in a multiethnic cohort2007In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 8, no 4, p. 279-287Article in journal (Refereed)
    Abstract [en]

    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=0.01). Among Hispanic families, two novel SNPs were associated with SLE risk (P=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.

  • 33. Webb, Ryan
    et al.
    Merrill, Joan T
    Kelly, Jennifer A
    Sestak, Andrea
    Kaufman, Kenneth M
    Langefeld, Carl D
    Ziegler, Julie
    Kimberly, Robert P
    Edberg, Jeffrey C
    Ramsey-Goldman, Rosalind
    Petri, Michelle
    Reveille, John D
    Alarcón, Graciela S
    Vilá, Luis M
    Alarcón-Riquelme, Marta E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    James, Judith A
    Gilkeson, Gary S
    Jacob, Chaim O
    Moser, Kathy L
    Gaffney, Patrick M
    Vyse, Timothy J
    Nath, Swapan K
    Lipsky, Peter
    Harley, John B
    Sawalha, Amr H
    A polymorphism within IL21R confers risk for systemic lupus erythematosus2009In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 60, no 8, p. 2402-2407Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Interleukin-21 (IL-21) is a member of the type I cytokine superfamily that has a variety of effects on the immune system, including B cell activation, plasma cell differentiation, and immunoglobulin production. The expression of IL-21 receptor (IL-21R) is reduced in the B cells of patients with systemic lupus erythematosus (SLE), while serum IL-21 levels are increased both in lupus patients and in some murine lupus models. We recently reported that polymorphisms within the IL21 gene are associated with increased susceptibility to SLE. The aim of this study was to examine the genetic association between single-nucleotide polymorphisms (SNPs) within IL21R and SLE. METHODS: We genotyped 17 SNPs in the IL21R gene in 2 large cohorts of lupus patients (a European-derived cohort and a Hispanic cohort) and in ethnically matched healthy controls. RESULTS: We identified and confirmed the association between rs3093301 within the IL21R gene and SLE in the 2 cohorts (meta-analysis odds ratio 1.16 [95% confidence interval 1.08-1.25], P=1.0x10(-4)). CONCLUSION: Our findings indicate that IL21R is a novel susceptibility gene for SLE.

  • 34. Webb, Ryan
    et al.
    Wren, Jonathan D.
    Jeffries, Matlock
    Kelly, Jennifer A.
    Kaufman, Kenneth M.
    Tang, Yuhong
    Frank, Mark Barton
    Merrill, Joan
    Kimberly, Robert P.
    Edberg, Jeffrey C.
    Ramsey-Goldman, Rosalind
    Petri, Michelle
    Reveille, John D.
    Alarcón, Graciela S.
    Vilá, Luis M.
    Alarcón-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    James, Judith A.
    Vyse, Timothy J.
    Moser, Kathy L.
    Gaffney, Patrick M.
    Gilkeson, Gary S.
    Harley, John B.
    Sawalha, Amr H.
    Variants within MECP2, a key transcription regulator, are associated with increased susceptibility to lupus and differential gene expression in patients with systemic lupus erythematosus2009In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 60, no 4, p. 1076-1084Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Both genetic and epigenetic factors play an important role in the pathogenesis of lupus. The aim of this study was to examine methyl-CpG-binding protein 2 gene (MECP2) polymorphisms in a large cohort of patients with lupus and control subjects, and to determine the functional consequences of the lupus-associated MECP2 haplotype. METHODS: We genotyped 18 single-nucleotide polymorphisms within MECP2, located on chromosome Xq28, in a large cohort of patients with lupus and control subjects of European descent. We studied the functional effects of the lupus-associated MECP2 haplotype by determining gene expression profiles in B cell lines in female lupus patients with and those without the lupus-associated MECP2 risk haplotype. RESULTS: We confirmed, replicated, and extended the genetic association between lupus and genetic markers within MECP2 in a large independent cohort of lupus patients and control subjects of European descent (odds ratio 1.35, P = 6.65 x 10(-11)). MECP2 is a dichotomous transcription regulator that either activates or represses gene expression. We identified 128 genes that are differentially expressed in lupus patients with the disease-associated MECP2 haplotype; most ( approximately 81%) were up-regulated. Genes that were up-regulated had significantly more CpG islands in their promoter regions compared with genes that were down-regulated. Gene ontology analysis using the differentially expressed genes revealed significant association with epigenetic regulatory mechanisms, suggesting that these genes are targets for MECP2 regulation in B cells. Furthermore, at least 13 of the 104 up-regulated genes are regulated by interferon. The disease-risk MECP2 haplotype was associated with increased expression of the MECP2 transcription coactivator CREB1 and decreased expression of the corepressor histone deacetylase 1. CONCLUSION: Polymorphism in the MECP2 locus is associated with lupus and, at least in part, contributes to the interferon signature observed in lupus patients.

  • 35. Yu, X.
    et al.
    Wieczorek, S.
    Franke, A.
    Yin, Hong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Pierer, M.
    Sina, C.
    Karlsen, T. H.
    Boberg, K. M.
    Bergquist, A.
    Kunz, M.
    Witte, T.
    Gross, W. L.
    Epplen, J. T.
    Alarcón-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Schreiber, S.
    Ibrahim, S. M.
    Association of UCP2 - 866 G/A polymorphism with chronic inflammatory diseases2009In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 10, no 6, p. 601-605Article in journal (Refereed)
    Abstract [en]

    We reported earlier that two mitochondrial gene polymorphisms, UCP2 -866 G/A (rs659366) and mtDNA nt13708 G/A (rs28359178), are associated with multiple sclerosis (MS). Here we aim to investigate whether these functional polymorphisms contribute to other eight chronic inflammatory diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Wegener' granulomatosis (WG), Churg-Strauss syndrome (CSS), Crohn's disease (CD), ulcerative colitis (UC), primary sclerosing cholangitis (PSC) and psoriasis. Compared with individual control panels, the UCP2 -866 G/A polymorphism was associated with RA and SLE, and the mtDNA nt13708 G/A polymorphism with RA. Compared with combined controls, the UCP2 -866 G/A polymorphism was associated with SLE, WG, CD and UC. When all eight disease panels and the original MS panel were combined in a meta-analysis, the UCP2 was associated with chronic inflammatory diseases in terms of either alleles (odds ratio (OR)=0.91, 95% confidence interval (95% CI): 0.86-0.96), P=0.0003) or genotypes (OR=0.88, (95% CI: 0.82-0.95), P=0.0008), with the -866A allele associated with a decreased risk to diseases. As the -866A allele increases gene expression, our findings suggest a protective role of the UCP2 protein in chronic inflammatory diseases.

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