Sari Koskenmies

Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease caused by both genetic and environmental factors. Genome scans in families with SLE point to multiple potential chromosomal regions that harbor SLE susceptibility genes, and association studies in different populations have suggested several susceptibility alleles for SLE. Increased production of type I interferon (IFN) and expression of IFN-inducible genes is commonly observed in SLE and may be pivotal in the molecular pathogenesis of the disease. We analyzed 44 single-nucleotide polymorphisms (SNPs) in 13 genes from the type I IFN pathway in 679 Swedish, Finnish, and Icelandic patients with SLE, in 798 unaffected family members, and in 438 unrelated control individuals for joint linkage and association with SLE. In two of the genes--the tyrosine kinase 2 (TYK2) and IFN regulatory factor 5 (IRF5) genes--we identified SNPs that displayed strong signals in joint analysis of linkage and association (unadjusted P<10(-7)) with SLE. TYK2 binds to the type I IFN receptor complex and IRF5 is a regulator of type I IFN gene expression. Thus, our results support a disease mechanism in SLE that involves key components of the type I IFN system.

Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus

TREX1 acts in concert with the SET complex in granzyme A–mediated apoptosis, and mutations in TREX1 cause Aicardi-Goutières syndrome and familial chilblain lupus. Here, we report monoallelic frameshift or missense mutations and one 3′ UTR variant of TREX1 present in 9/417 individuals with systemic lupus erythematosus but absent in 1,712 controls (P = 4.1 × 10−7). We demonstrate that two mutant TREX1 alleles alter subcellular targeting. Our findings implicate TREX1 in the pathogenesis of SLE.

Evidence for Genetic Association and Interaction Between the TYK2 and IRF5 Genes in Systemic Lupus Erythematosus

Objective. Several candidate genes have been implicated in susceptibility for systemic lupus erythematosus (SLE), a complex autoimmune disease. The proposed genes include members of the type I interferon (IFN) pathway and genes involved in immunological defense functions. Our aim was to systematically replicate 6 such genes, TYK2, IRF5, CTLA4, PDCD1, FCGR2A, and NOD2. Methods. Single-nucleotide polymorphisms in TYK2, IRF5, CTLA4, PDCD1, FCGR2A, and NOD2 were genotyped in 277 SLE patients and 356 healthy controls from Finland, giving a power of 42%–70% for different genes at published allele frequencies. Results. Significant association was seen for rs2304256 (p = 0.0001) and rs12720270 (p = 0.0031) in TYK2 and rs10954213 (p = 0.0043) in IRF5 in our samples, but not for the other genes. We found evidence for genetic interaction (p = 0.014) between rs2304256 in TYK2 and rs10954213 in IRF5, both members of the type I IFN pathway, strengthening the role of the type I IFN pathway in the pathogenesis of SLE. Conclusion. The IFN pathway genes IRF5 and TYK2 may act epistatically in increasing risk for SLE, but our lack of replication does not exclude effects of the other genes studied.

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

Background: Several members of the GIMAP gene family have been suggested as being involved in different aspects of the immune system in different species. Recently, a mutation in the GIMAP5 gene was shown to cause lymphopenia in a rat model of autoimmune insulin-dependent diabetes. Thus it was hypothesised that genetic variation in GIMAP5 may be involved in susceptibility to other autoimmune disorders where lymphopenia is a key feature, such as systemic lupus erythematosus (SLE). Material and methods: To investigate this, seven single nucleotide polymorphisms in GIMAP5 were analysed in five independent sets of family-based SLE collections, containing more than 2000 samples. Result: A significant increase in SLE risk associated with the most common GIMAP5 haplotype was found (OR 1.26, 95% CI 1.02 to 1.54, p = 0.0033). In families with probands diagnosed with trombocytopenia, the risk was increased (OR 2.11, 95% CI 1.09 to 4.09, p = 0.0153). The risk haplotype bears a polymorphic polyadenylation signal which alters the 3′ part of GIMAP5 mRNA by producing an inefficient polyadenylation signal. This results in higher proportion of non-terminated mRNA for homozygous individuals (p<0.005), a mechanism shown to be causal in thalassaemias. To further assess the functional effect of the polymorphic polyadenylation signal in the risk haplotype, monocytes were treated with several cytokines affecting apoptosis. All the apoptotic cytokines induced GIMAP5 expression in two monocyte cell lines (1.5–6 times, p<0.0001 for all tests). Conclusion: Taken together, the data suggest the role of GIMAP5 in the pathogenesis of SLE.

Tyrosine kinase 2 and interferon regulatory factor 5 polymorphisms are associated with discoid and subacute cutaneous lupus erythematosus

Please cite this paper as: Tyrosine kinase 2 and interferon regulatory factor 5 polymorphisms are associated with discoid and subacute cutaneous lupus erythematosus. Experimental Dermatology 2010; 19: 123–131.

Replication of GWAS-identified systemic lupus erythematosus susceptibility genes affirms B-cell receptor pathway signalling and strengthens the role of IRF5 in disease susceptibility in a Northern European population

OBJECTIVE A large number of genes, including several not previously implicated in SLE susceptibility, have recently been identified or confirmed by genome-wide association studies (GWAS). In this study, we sought to replicate some of these results in Finnish SLE patients (n = 275) and control individuals (n = 356). METHODS We genotyped 32 single nucleotide polymorphisms (SNPs) in 12 of the best-supported GWAS-identified SLE genes and loci. We further investigated gene-gene interactions between the loci included in the study. RESULTS The strongest evidence of association was found at the IRF5-TNPO3 locus, with the most significant P-value being 2.0 × 10(-7) and an odds ratio of 1.95 (95% CI 1.51, 2.50). Association between SLE and TNFAIP3, FAM167A-BLK, BANK1 and KIAA1542 was also confirmed, although at a lower significance level and contribution to individual risk. No significant association was found with 1q25.1, PXK, ATG5, ICA1, XKR6, LYN and SCUBE1. Furthermore, no significant gene-gene interactions were detected. CONCLUSION Replication of previous GWAS findings across diverse populations is of importance to validate these associations and to get a better understanding of potential genetic heterogeneity between populations in SLE susceptibility. Our results attest the importance of B-cell receptor pathway and IFN signalling in SLE pathogenesis.

Polymorphisms of the ITGAM Gene Confer Higher Risk of Discoid Cutaneous than of Systemic Lupus Erythematosus

Background Lupus erythematosus (LE) is a heterogeneous disease ranging from mainly skin-restricted manifestations (discoid LE [DLE] and subacute cutaneous LE) to a progressive multisystem disease (systemic LE [SLE]). Genetic association studies have recently identified several strong susceptibility genes for SLE, including integrin alpha M (ITGAM), also known as CD11b, whereas the genetic background of DLE is less clear. Principal Findings To specifically investigate whether ITGAM is a susceptibility gene not only for SLE, but also for cutaneous DLE, we genotyped 177 patients with DLE, 85 patients with sporadic SLE, 190 index cases from SLE families and 395 population control individuals from Finland for nine genetic markers at the ITGAM locus. SLE patients were further subdivided by the presence or absence of discoid rash and renal involvement. In addition, 235 Finnish and Swedish patients positive for Ro/SSA-autoantibodies were included in a subphenotype analysis. Analysis of the ITGAM coding variant rs1143679 showed highly significant association to DLE in patients without signs of systemic disease (P-value  = 4.73×10−11, OR  = 3.20, 95% CI  = 2.23–4.57). Significant association was also detected to SLE patients (P-value  = 8.29×10−6, OR  = 2.14, 95% CI  = 1.52–3.00), and even stronger association was found when stratifying SLE patients by presence of discoid rash (P-value  = 3.59×10−8, OR  = 3.76, 95% CI  = 2.29–6.18). Significance We propose ITGAM as a novel susceptibility gene for cutaneous DLE. The risk effect is independent of systemic involvement and has an even stronger genetic influence on the risk of DLE than of SLE.

Linkage mapping of systemic lupus erythematosus (SLE) in Finnish families multiply affected by SLE

Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse and variable clinical manifestations and unknown aetiology. Epidemiological and animal studies indicate that environmental and genetic factors are involved in the development of the disease. Several candidate gene loci (including the human leucocyte antigen ( HLA ) region, Fcγ receptors, and complement components) have been implicated through association studies, and multiple susceptibility loci have been detected in inbred mouse models of SLE.1,2 Until now, six groups have published genomewide scans with SLE as a phenotype in different ethnic groups.3–8 Recently, linkage to chromosome 2q37 (logarithm of odds (LOD) 4.24) in a Swedish population resulted in the identification of a new susceptibility gene PDCD1 in a large multinational study by Prokunina et al .8,9 The SLE associated allele of this immunoreceptor gene alters a binding site for the runt related transcription factor 1 ( RUNX1 ), which is found in an intronic enhancer. Stratification of pedigrees based on clinical manifestations has been used in recent studies that involved genomewide scans.10–16 The aim was to achieve genetically and clinically homogeneous sets of families and to increase the power to detect susceptibility genes for different subphenotypes of SLE. Altogether, 17 regions have been linked significantly to SLE with model based and non-parametric approaches; 11 of these in stratified studies. In addition, several other regions with suggestive linkage have been identified, but only some of those loci have been implicated in more than one study.6,18 The data suggest that multiple genes are involved in conferring susceptibility to SLE. In our study, we conducted a nationwide and genomewide scan for SLE susceptibility loci in Finnish families multiply affected by SLE. The extensive hospital registration system in Finland allowed us to identify and recruit approximately 85% of all patients with …

Matrix metalloproteinases as mediators of tissue injury in different forms of cutaneous lupus erythematosus

Background  Matrix metalloproteinases (MMPs) contribute to tissue destruction, regeneration, inflammation and apoptosis and several of them are upregulated by ultraviolet (UV) radiation in skin. Although some MMPs associate with organ manifestations of systemic lupus erythematosus (SLE), their role in cutaneous lupus erythematosus (LE) is elusive.

The association of antibodies to cardiolipin, beta 2-glycoprotein I, prothrombin, and oxidized low-density lipoprotein with thrombosis in 292 patients with familial and sporadic systemic lupus erythematosus.

Objective: To determine the prevalence of antibodies to phospholipid‐binding plasma proteins (aPL) and to oxidized low‐density lipoprotein (OX‐LDL), and to study the association of these antibodies with thrombosis and coronary heart disease (CHD) in patients with systemic lupus erythematosus (SLE). Methods: Clinical data and sera from 89 Finnish patients with familial and 203 with sporadic SLE were available for the study. Enzyme‐linked immunosorbent assays (ELISA) were used for antibody determination. Results: The occurrence of thrombosis in our SLE patients was 13.7% (40/292) and of clinically diagnosed CHD was 1.4% (4/292). All antibody assays, except IgM‐aCL, were significantly associated with thrombosis. IgG‐aCL alone or in combination with anti β2‐GPI or with anti OX‐LDL were reasonably sensitive (38%, 48%, and 58%, respectively) and specific (87%, 80% and 72%, respectively) for a history of thrombosis. A high risk of arterial thrombosis (TIA or stroke) was associated with positivity of IgG‐aCL, anti β2‐GPI, and anti‐prothrombin. Venous thrombosis was significantly associated with all other assays except IgM‐aCL and anti‐prothrombin. No test correlated with CHD, but the number of affected patients was small. There were three multiplex SLE families with two patients having a history of thrombosis: no consistent pattern of aPL or anti OX‐LDL was found in these patients. Conclusion: IgG‐aCL alone or in combination with anti β2‐GPI or anti OX‐LDL are sensitive and specific tests for detecting SLE patients at increased risk of thrombosis. The aetiopathogenesis of thrombosis in familial SLE appears to be multifactorial.