Anna-Karin Lindqvist

Karolinska Institutet, Solna, Stockholm, Sweden

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Publications (17)86.48 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to investigate genetic variants in the gene neutrophil cytosolic factor 1 (NCF1) for association with rheumatoid arthritis (RA). In rodent models, a single-nucleotide polymorphism (SNP) in Ncf1 has been shown to be a major locus regulating severity of arthritis. Ncf1 encodes one of five subunits of the NADPH oxidase complex. In humans the genomic structure of NCF1 is complex, excluding it from genome-wide association screens and complicating genetic analysis. In addition to copy number variation of NCF1, there are also two nonfunctional pseudogenes, nearly identical in sequence to NCF1. We have characterized copy number variation and SNPs in NCF1, and investigated these variants for association with RA. We find that RA patients are less likely to have an increased copy number of NCF1, 7.6%, compared with 11.6% in controls; p=0.037. We also show that the T-allele of NCF1-339 (rs13447) is expressed in NCF1 and significantly reduces reactive oxygen species production. This is the first finding of genetic association of NCF1 with RA. The detailed characterization of genetic variants in NCF1 also helps elucidate the complexity of the NCF1 gene. These data suggest that an increased copy number of NCF1 can be protective against developing RA and add support to previous findings of a role of NCF1 and the phagocyte NADPH oxidase complex in RA pathogenesis.
    Antioxidants & Redox Signaling 07/2011; 16(1):71-8. · 8.20 Impact Factor
  • Kutty Selva Nandakumar, Anna-Karin B Lindqvist, Rikard Holmdahl
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    ABSTRACT: To investigate the genetic control of chronic arthritis and collagen epitope specific antibody responses in an experimental model for rheumatoid arthritis. The chronic collagen induced arthritis (CCIA) model was used, induced with collagen type II (CII) in mineral oil lacking mycobacterium in BALB/c (n=24), B10.Q (n=44), (BALB/c × B10.Q) F1 (n=85) and B10.Q × (BALB/c × B10.Q) N2 (n=684) mice. Genome-wide genotyping for 190 N2 mice was performed with extreme phenotypes: chronic arthritis that persisted for 4 months or non-affected. Statistical and linkage analysis were performed with R/qtl software using arthritis and serum subphenotypes. (BALB/c × B10.Q) F1 mice were highly prone to develop a chronic relapsing arthritis (66%), whereas both parental strains were relatively resistant: BALB/c (H-2(d); 0%) and B10.Q (H-2(q); 4.5%). CCIA experiments were performed on 684 mice backcrossed to B10.Q; 38% of the mice developed arthritis and more than half of them developed chronic arthritis phenotype. Genome-wide genotyping revealed mainly the major histocompatibility complex (MHC) locus that had an independent and dominant influence on the chronicity. Interestingly, the H2(d) allele had a dominant suppressive effect. This effect overrode the role of other loci as interaction analysis, after conditioning MHC, revealed additional loci, controlling arthritis and autoantibody phenotypes. A dominant negative influence of specific MHC haplotype (H2(d)) on CCIA was identified. Further, loci controlling the autoantibody response to different CII epitopes were also identified, and it has been shown that these are dependent on MHC and non-MHC genes.
    Annals of the rheumatic diseases 05/2011; 70(9):1664-70. · 8.11 Impact Factor
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    ABSTRACT: Psoriasis is a complex genetic disease of unresolved pathogenesis with both heritable and environmental factors contributing to onset and severity. In addition to a disfiguring skin inflammation, approximately 10-40% of psoriasis patients suffer from destructive joint involvement. Previously, we reported that the CD18 hypomorphic PL/J mouse carrying a mutation resulting in reduced expression of the common chain of beta(2) integrins (CD11/CD18) spontaneously develops a skin disease that closely resembles human psoriasis. In contrast, the same mutation on C57BL/6J background did not demonstrate this phenotype. By a genome-wide linkage analysis, two major loci were identified as contributing to the development of psoriasiform dermatitis under the condition of low CD18 expression. Using a congenic approach, we now demonstrate that the introduction of a 9-centimorgan fragment of chromosome 10 derived from the PL/J strain into the disease-resistant CD18 hypomorphic C57BL/6J was promoting the development of psoriasiform skin disease and notably also arthritis. We therefore designated this locus psoriasiform skin disease-associated locus 1 (PSD1). High numbers of CD4(+) T cells and TNF-alpha producing macrophages were detected both in inflamed skin and joints in these congenic mice, with a complete resolution upon TNF-alpha inhibitor therapy or depletion of CD4(+) T cells. For the first time, we have identified a distinct genetic element that contributes to the T cell-dependent development of both psoriasiform skin disease and associated arthritis. This congenic model will be suitable to further investigations of genetic and molecular pathways that cause psoriasiform dermatitis and arthritis, and it may also be relevant for other autoimmune diseases.
    The Journal of Immunology 05/2008; 180(8):5520-9. · 5.52 Impact Factor
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    ABSTRACT: The nonobese diabetic (NOD) Nss1 and Idd5 loci have been associated with sialadenitis development in mice. In this study the NOD Nss1 and Idd5 loci were backcrossed onto the healthy control strain B10.Q by using the speed congenic breeding strategy, resulting in three congenic strains: B10.Q.Nss1, B10.Q.Nss1/Idd5 heterozygous and B10.Q.Nss1/Idd5 homozygous. We investigated the effects of the Nss1 and Idd5 loci on sialadenitis and gene expression in NOD congenic mice. One submandibular salivary gland from each mouse was used for histological analysis of sialadenitis, whereas the contralateral salivary gland was used for gene expression profiling with the Applied Biosystems Mouse Genome Survey chip v.1.0. The results were validated using quantitative reverse transcriptase PCR. The NOD Nss1 and Idd5 loci had clear influence on the onset and progression of sialadenitis in congenic mice. Double congenic mice exhibited the most severe phenotype. We successfully identified several genes that are located in the NOD congenic regions to be differentially expressed between the congenic strains and the control strain. Several of these were found to be co-regulated, such as Stat1, complement component C1q genes and Tlr12. Also, a vast contingency of interferon-regulated genes (such as Ltb, Irf7 and Irf8) and cytokine and chemokine genes (such as Ccr7 and Ccl19) were differentially expressed between the congenic strains and the control strain. Over-representation of inflammatory signalling pathways was observed among the differentially expressed genes. We have found that the introgression of the NOD loci Nss1 and Idd5 on a healthy background caused sialadenitis in NOD congenic mouse strains, and we propose that genes within these loci are important factors in the pathogenesis. Furthermore, gene expression profiling has revealed several differentially expressed genes within and outside the NOD loci that are similar to genes found to be differentially expressed in patients with Sjögren's syndrome, and as such are interesting candidates for investigation to enhance our understanding of disease mechanisms and to develop future therapies.
    Arthritis research & therapy 02/2007; 9(5):R99. · 4.27 Impact Factor
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    ABSTRACT: Rheumatoid arthritis (RA) is a chronic inflammatory disease with a heritability of 60%. Genetic contributions to RA are made by multiple genes, but only a few gene associations have yet been confirmed. By studying animal models, reduced capacity of the NADPH-oxidase (NOX) complex, caused by a single nucleotide polymorphism (SNP) in one of its components (the NCF1 gene), has been found to increase severity of arthritis. To our knowledge, however, no studies investigating the potential role played by reduced reactive oxygen species production in human RA have yet been reported. In order to examine the role played by the NOX complex in RA, we investigated the association of 51 SNPs in five genes of the NOX complex (CYBB, CYBA, NCF4, NCF2, and RAC2) in a Swedish case-control cohort consisting of 1,842 RA cases and 1,038 control individuals. Several SNPs were found to be mildly associated in men in NCF4 (rs729749, P = 0.001), NCF2 (rs789181, P = 0.02) and RAC2 (rs1476002, P = 0.05). No associations were detected in CYBA or CYBB. By stratifying for autoantibody status, we identified a strong association for rs729749 (in NCF4) in autoantibody negative disease, with the strongest association detected in rheumatoid factor negative men (CT genotype versus CC genotype: odds ratio 0.34, 95% confidence interval 0.2 to 0.6; P = 0.0001). To our knowledge, this is the first genetic association identified between RA and the NOX complex, and it supports previous findings from animal models of the importance of reactive oxygen species production capacity to the development of arthritis.
    Arthritis research & therapy 02/2007; 9(5):R98. · 4.27 Impact Factor
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    ABSTRACT: Psoriasis is a frequently occurring inflammatory skin disease characterized by thickened erythematous skin that is covered with silvery scales. It is a complex genetic disease with both heritable and environmental factors contributing to onset and severity. The CD18 hypomorphic PL/J mouse reveals reduced expression of the common chain of beta(2) integrins (CD11/CD18) and spontaneously develops a skin disease that closely resembles human psoriasis. In contrast, CD18 hypomorphic C57BL/6J mice do not demonstrate this phenotype. In this study, we have performed a genome-wide scan to identify loci involved in psoriasiform dermatitis under the condition of low CD18 expression. Backcross analysis of a segregating cross between susceptible CD18 hypomorphic PL/J mice and the resistant CD18 hypomorphic C57BL/6J strain was performed. A genome-wide linkage analysis of 94 phenotypically extreme mice of the backcross was undertaken. Thereafter, a complementary analysis of the regions of interest from the genome-wide screen was done using higher marker density and further mice. We found two loci on chromosome 10 that were significantly linked to the disease and interacted in an additive fashion in its development. In addition, a locus on chromosome 6 that promoted earlier onset of the disease was identified in the most severely affected mice. For the first time, we have identified genetic regions associated with psoriasis in a mouse model resembling human psoriasis. The identification of gene regions associated with psoriasis in this mouse model might contribute to the understanding of genetic causes of psoriasis in patients and pathological mechanisms involved in development of disease.
    The Journal of Immunology 11/2006; 177(7):4612-9. · 5.52 Impact Factor
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    ABSTRACT: Genetic segregation analysis between NOD and C57BL strains have been used to identify loci associated with autoimmune disease. Only two loci (Cia2 and Cia9) had earlier been found to control development of arthritis, whereas none of the previously identified diabetes loci was of significance for arthritis. We have now made a high-powered analysis of a backcross of NOD genes on to the B10.Q strain for association with collagen-induced arthritis. We could confirm relevance of both Cia2 and Cia9 as well as the interaction between them, but we did not identify any other significant arthritis loci. Immune cellular subtyping revealed that Cia2 was also associated with the number of blood macrophages. Congenic strains of the Cia2 and Cia9 loci on the B10.Q background were made and used to establish a partial advanced intercross (PAI). Testing the PAI mice for development of collagen-induced arthritis confirmed the loci and the interactions and also indicated that at least two genes contribute to the Cia9 locus. Furthermore, it clearly showed that Cia2 is dominant protective but that the protection is not complete. Because these results may indicate that the Cia2 effect on arthritis is not only due to the deficiency of the complement C5, we analyzed complement functions in the Cia2 congenics as well as the PAI mice. These data show that not only arthritis but also C5-dependent complement activity is dominantly suppressed, confirming that C5 is one of the major genes explaining the Cia2 effect.
    The Journal of Immunology 10/2006; 177(6):3952-9. · 5.52 Impact Factor
  • Kutty Selva Nandakumar, Anna-Karin B. Lindqvist, Rikard Holmdahl
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    ABSTRACT: To investigate the genetic control of chronic development of arthritis, we used a variant of collagen-induced arthritis induced after immunization of type II collagen (CII) lacking mycobacteria adjuvant. F1 mice of BALB/c and B10.Q are highly prone to develop a chronic relapsing arthritis (66%) whereas both parentals are relatively resistant; BALB/c (H-2d; 0%) and B10.Q (H-2q; 4.5%). As this suggest the involvement of dominant regulatory loci, we performed a CIA experiment on 684 N2 backcross mice, backcrossed to B10.Q; 38% of the backcrossed mice developed arthritis and more than half of these mice developed a chronic form of arthritis that persisted for a minimum period of 4 months. For genome-wide genotyping, 190 animals with the most severe phenotype were selected. Despite the high statistical power, only the MHC locus had independently a significant dominant influence on the chronicity. Interestingly, the H2d allele had a dominant suppressive effect. This effect overridded the role of other loci as interation analysis, conditioning MHC, revealed additional loci on chromosomes 5, 8, 9, 11, 13 and 15. Importantly, the observed genetic regulation is operating through autoimmunity as we also found several loci linked to anti-CII autoantibody response.
    1st International MUGEn Conference on Animal Models for Human Immunological Disease, Athens, Greece; 09/2006
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    ABSTRACT: Rheumatoid arthritis (RA) affects millions of people world wide causing considerable human suffering and large socioeconomic costs. Increased knowledge of pathological pathways involved in RA will enable development of modern drugs, with reduced side effects. The mouse models offer an attractive approach to dissect the genetic and molecular mechanisms of RA.
    Trends in Genetics 06/2002; 18(6):S7-S13. · 9.77 Impact Factor
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    ABSTRACT: We have previously identified a locus on mouse chromosome 15 (eae2) that regulates susceptibility to experimental autoimmune encephalomyelitis in a cross between the susceptible strain B10.RIII and the resistant strain RIIIS/J. In an effort to verify the protective effect from having two RIIIS/J alleles at eae2, the resistant locus was bred into the susceptible strain in homozygous form. However, the expected effect was not as clear as in the original study. This might be due to an epistatic effect conferred by several unidentified genes in the genome of the resistant strain or due to the environment by genotype interactions, possibly overcoming the effect of protective alleles at eae2. To further the genetic understanding in this disease, a genome-wide linkage screening approach was employed on an F(2) intercross that carried the protective allele at eae2in homozygous form while the rest of the genome segregated between the B10.RIII and RIIIS/J strains as in the original investigation. In the present study we find one region on chromosome 7, not previously identified in this strain combination, that affects the disease at significant logarithm of the odds score and six regions showing suggestive evidence for linkage to disease phenotypes.
    International Immunology 02/2002; 14(1):79-85. · 3.14 Impact Factor
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    ABSTRACT: The non-obese diabetic (NOD) mouse spontaneously develops diabetes and sialadenitis. The sialadenitis is characterized by histopathological changes in salivary glands and functional deficit similar to Sjögren's syndrome. In humans, Sjögren's syndrome could be associated with other connective tissue disorders, such as rheumatoid arthritis. In the present study the genetic control of sialadenitis in mice was compared to that of arthritis. We have previously reported a NOD locus, identified in an F2 cross with the H2(q) congenic NOD (NOD.Q) and C57BL/10.Q (B10.Q) strains, that promoted susceptibility to collagen-induced arthritis. The sialadenitis in NOD.Q showed a similar histological phenotype as in NOD, whereas no submandibular gland infiltration was found in B10.Q. The development of sialadenitis was independent of immunization with type II collagen and established arthritis. To identify the genetic control of sialadenitis, a gene segregation experiment was performed on an (NOD.QxB10.Q)F2 cross and genetic mapping of 353 F2 mice revealed one significant locus associated with sialadenitis on chromosome 4, LOD score 4.7. The NOD.Q allele-mediated susceptibility under a recessive inheritance pattern. The genetic control of sialadenitis seemed to be unique in comparison to diabetes and arthritis, as no loci associated with these diseases have been identified at the same location.
    European Journal of Immunology 02/2002; 32(1):243-50. · 4.97 Impact Factor
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    ABSTRACT: The non-obese diabetic (NOD) mouse spontaneously develops diabetes and sialadenitis. The sialadenitis is characterized by histopathological changes in salivary glands and functional deficit similar to Sjögren's syndrome. In humans, Sjögren's syndrome could be associated with other connective tissue disorders, such as rheumatoid arthritis. In the present study the genetic control of sialadenitis in mice was compared to that of arthritis. We have previously reported a NOD locus, identified in an F2 cross with the H2q congenic NOD (NOD.Q) and C57BL/10.Q (B10.Q) strains, that promoted susceptibility to collagen-induced arthritis. The sialadenitis in NOD.Q showed a similar histological phenotype as in NOD, whereas no submandibular gland infiltration wasfound in B10.Q. The development of sialadenitis was independent of immunization with type II collagen and established arthritis. To identify the genetic control of sialadenitis, a gene segregation experiment was performed on an (NOD.Q×B10.Q)F2 cross and genetic mapping of 353 F2 mice revealed one significant locus associated with sialadenitis on chromosome 4, LOD score 4.7. The NOD.Q allele-mediated susceptibility under a recessive inheritance pattern. The genetic control of sialadenitis seemed to be unique in comparison to diabetes and arthritis, as no loci associated with these diseases have been identified at the same location.
    European Journal of Immunology 01/2002; 32(1):243 - 250. · 4.97 Impact Factor
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    ABSTRACT: The nonobese diabetic (NOD) mouse spontaneously develops autoimmune-mediated diseases such as diabetes and Sjögren′s syndrome. To investigate whether NOD genes also promote autoimmune-mediatedarthritis we established a NOD strain with an MHC class II fragment containing the Aq class II gene predisposing for collagen induced arthritis (NOD.Q). However, this mouse was resistant to arthritis in contrast to other Aq expressing strains such as B10.Q and DBA/1. To determine the major resistance factor/s, a genetic analysis was performed. (NOD.Q×B10.Q)F1 mice were resistant, whereas 27% of the (NOD.Q×B10.Q)F2 mice developed severe arthritis. Genetic mapping of 353 F2 mice revealed two loci associated with arthritis. One locus was found on chromosome 2 (LOD score 9.8), at the location of the complement factor 5 (C5) gene. The susceptibility allele was from B10.Q, which contains a productive C5 encoding gene in contrast to NOD.Q. The other significant locus was found on chromosome 1 (LOD score 5.6) close to the Fc-gamma receptor IIb gene, where NOD carried the susceptible allele. An interaction between the two loci was observed, indicating that they operate on the same or on interacting pathways. The genetic control of arthritis is unique in comparison to diabetes, since none of these loci have been identified in analysis of diabetes susceptibility.
    European Journal of Immunology 05/2001; 31(6):1847 - 1856. · 4.97 Impact Factor
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    ABSTRACT: To identify chromosomal regions containing susceptibility loci for systemic lupus erythematosus (SLE), we performed genome scans in families with multiple SLE patients from Iceland, a geographical and genetic isolate, and from Sweden. A number of chromosomal regions showed maximum lod scores (Z) indicating possible linkage to SLE in both the Icelandic and Swedish families. In the Icelandic families, five regions showed lod scores greater than 2.0, three of which (4p15–13, Z=3.20; 9p22, Z=2.27; 19q13, Z=2.06) are homologous to the murine regions containing the lmb2, sle2 and sle3 loci, respectively. The fourth region is located on 19p13 (D19S247, Z=2.58) and the fifth on 2q37 (D2S125, Z=2.06). Only two regions showed lod scores above 2.0 in the Swedish families: on chromosome 2q11 (D2S436, Z=2.13) and 2q37 (D2S125, Z=2.18). The combination of both family sets gave a highly signifi-cant lod score at D2S125 of Z=4.24 in favor of linkage for 2q37. This region represents a new locus for SLE. Our results underscore the importance of studying well-defined populations for genetic analysis of complex diseases such as SLE.
    Journal of Autoimmunity 01/2000; 14:169-178. · 8.15 Impact Factor
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    ABSTRACT: The association of variation at the HLA class I1 loci DQAl, DQBl, DRBl and DPBl with malaria infection and antibody titers was studied in two endemic populations, Trat and Pongnamron, in Thailand. Presence of P. falciparunz was determined by microscopy and PCR. Significant allele frequency differences were found between infected and uninfected individuals for two alleles in the sample from Trat collected in 1991, while an independent sample from the same locality in 1994 did not show any association. A set of 10 families from Pongnamron were studied for infection status and the antibody titers against the whole parasite (PARIF) and against the P. fulciparum membrane antigen (Pfl55/RESA) (EMIF) were measured. Using the TDT test significant deviation from equal probability of transmission of parental HLA alleles was detected only for the DPB1*0202 allele and the antibody response to the whole parasite. Due to the large number of tests performed we cannot exclude that the significances observed represents statistical type I errors. Thus, the results do not provide evidence of an involvement of HLA class I1 loci in either malaria infection or response versus the two malaria antigens in the two Thai populations.
    Hereditas 01/2000; 132(132):119-127. · 0.96 Impact Factor
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    ABSTRACT: Systemic lupus erythematosus is a disease of unknown etiology. Multiple genetic factors are believed to be involved in its pathogenesis. In addition, and due to genetic heterogeneity, these factors and/or their combinations may be different in different ethnic groups, while some might be shared between populations. We have performed genome scans in multicase families from three different population groups, two from Northern Europe, with a high degree of homogeneity, and the third from a recently admixed population of Mexican Mestizos. Although our family material is relatively small, the results presented here show that using family sets from well defined populations are sufficient to detect susceptibility loci for SLE. Our results also reveal the chromosomal regions most likely to contain susceptibility genes for SLE.
    Journal of Autoimmunity 01/1999; 13:137-141. · 8.15 Impact Factor
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Publication Stats

181 Citations
86.48 Total Impact Points

Institutions

  • 2011
    • Karolinska Institutet
      • Institutionen för medicinsk biokemi och biofysik
      Solna, Stockholm, Sweden
  • 2001–2011
    • Lund University
      • Department of Experimental Medical Science
      Lund, Skane, Sweden
  • 2002
    • Haukeland University Hospital
      • Centre for Medical Genetics and Molecular Medicine
      Bergen, Hordaland, Norway
  • 1999–2000
    • Uppsala University
      • • The Rudbeck Laboratory
      • • Department of Immunology, Genetics and Pathology
      Uppsala, Uppsala, Sweden