We analyzed a comprehensive set of single-nucleotide polymorphisms (SNPs) and length polymorphisms in the interferon regulatory factor 5 (IRF5) gene for their association with the autoimmune disease systemic lupus erythematosus (SLE) in 485 Swedish patients and 563 controls. We found 16 SNPs and two length polymorphisms that display association with SLE (P < 0.0005, OR > 1.4). Using a Bayesian model selection and averaging approach we identified parsimonious models with exactly two variants of IRF5 that are independently associated with SLE. The variants of IRF5 with the highest posterior probabilities (1.00 and 0.71, respectively) of being causal in SLE are a SNP (rs10488631) located 3' of IRF5, and a novel CGGGG insertion-deletion (indel) polymorphism located 64 bp upstream of the first untranslated exon (exon 1A) of IRF5. The CGGGG indel explains the association signal from multiple SNPs in the IRF5 gene, including rs2004640, rs10954213 and rs729302 previously considered to be causal variants in SLE. The CGGGG indel contains three or four repeats of the sequence CGGGG with the longer allele containing an additional SP1 binding site as the risk allele for SLE. Using electrophoretic mobility shift assays we show increased binding of protein to the risk allele of the CGGGG indel and using a minigene reporter assay we show increased expression of IRF5 mRNA from a promoter containing this allele. Increased expression of IRF5 protein was observed in peripheral blood mononuclear cells from SLE patients carrying the risk allele of the CGGGG indel. We have found that the same IRF5 allele also confers risk for inflammatory bowel diseases and multiple sclerosis, suggesting a general role for IRF5 in autoimmune diseases.
The interferon regulatory factor 5 (IRF5) gene encodes a transcription factor that plays an important role in the innate as well as in the cell-mediated immune responses. The IRF5 gene has been shown to be associated with systemic lupus erythematosus and rheumatoid arthritis. We studied whether the IRF5 gene is also associated with inflammatory bowel diseases (IBD), Crohn disease (CD) and ulcerative colitis (UC). Twelve polymorphisms in the IRF5 gene were genotyped in a cohort of 1007 IBD patients (748 CD and 254 UC) and 241 controls from Wallonia, Belgium. The same polymorphisms were genotyped in a confirmatory cohort of 311 controls and 687 IBD patients (488 CD and 192 UC) from Leuven, Belgium. A strong signal of association [P = 1.9 x 10(-5), odds ratio (OR) 1.81 (1.37-2.39)] with IBD was observed for a 5 bp indel (CGGGG) polymorphism in the promoter region of the IRF5 gene. The association was detectable also in CD patients (P = 6.8 x 10(-4)) and was particularly strong among the UC patients [P = 5.3 x 10(-8), OR = 2.42 (1.76-3.34)]. The association of the CGGGG indel was confirmed in the second cohort [P = 3.2 x 10(-5), OR = 1.59 (1.28-1.98)]. The insertion of one CGGGG unit is predicted to create an additional binding site for the transcription factor SP1. Using an electrophoretic mobility shift assay, we show allele-specific differences in protein binding to this repetitive DNA-stretch, which suggest a potential function role for the CGGGG indel.
The study considers numerous factors potentially related to suicide ideation in adults, including life stress, stress perceptions, social support, personality, alcohol use, chronic conditions, distress symptoms and sociodemographic background. Using data from a health survey of 825 adult residents in the urban Reykjavik area of Iceland, the study finds that financial hardship, legal stress, family difficulties, stress perceptions and low material support are significantly related to thoughts of committing suicide. Multiple chronic conditions, frequent alcohol use and various forms of distress (e.g. depression, anxiety, hopelessness, pain) are also related to suicide ideation. Furthermore, low self-esteem and external locus of control (low sense of mastery) are both associated with suicidal thoughts. No significant relationships were found between sociodemographic background and suicide ideation. The meaning of the results, and their implications for continued theoretical and clinical work in this area, are discussed. Suicide research has primarily focused on completed suicides (e.g. Durkheim [1897] 1951; Fisher et al. 1993; Henry and Short 1954; Lester 1974; Pritchard 1996) or suicide attempts (e.g. Diekstra 1982; Maris 1981; Slap et al. 1989; Smith and Crawford 1986; Stack and Wasserman 1995). Relatively few studies have focused on thoughts of own death or suicide, or suicide planning. Nevertheless, there is a growing understanding that ideation and planning are important steps in a process of suicide, characterised by a stepwise hierarchy of actions with an underlying gradient of severity (Beck 1986; Bonner and Rich 1987; Diekstra 1993; Smith and Crawford 1986). Ideation precedes planning, which may result in an attempt leading to death. If nonfatal, the attempt may increase the likelihood of subsequent ideation, planning and attempt (see paths a-e in Fig. 1). It should therefore be of theoretical as well as clinical value to consider the risk factors associated with suicide ideation and planning.
Background:IRF5 is a transcription factor involved both in the type I interferon and the toll-like receptor signalling pathways. Previously, IRF5 has been found to be associated with systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel diseases. Here we investigated whether polymorphisms in the IRF5 gene would be associated with yet another disease with features of autoimmunity, multiple sclerosis (MS).Methods:We genotyped nine single nucleotide polymorphisms and one insertion-deletion polymorphism in the IRF5 gene in a collection of 2337 patients with MS and 2813 controls from three populations: two case–control cohorts from Spain and Sweden, and a set of MS trio families from Finland.Results:Two single nucleotide polymorphism (SNPs) (rs4728142, rs3807306), and a 5 bp insertion-deletion polymorphism located in the promoter and first intron of the IRF5 gene, showed association signals with values of p<0.001 when the data from all cohorts were combined. The predisposing alleles were present on the same common haplotype in all populations. Using electrophoretic mobility shift assays we observed allele specific differences in protein binding for the SNP rs4728142 and the 5 bp indel, and by a proximity ligation assay we demonstrated increased binding of the transcription factor SP1 to the risk allele of the 5 bp indel.Conclusion:These findings add IRF5 to the short list of genes shown to be associated with MS in more than one population. Our study adds to the evidence that there might be genes or pathways that are common in multiple autoimmune diseases, and that the type I interferon system is likely to be involved in the development of these diseases.
Primary Sjö gren's syndrome (SS) shares many features with systemic lupus erythematosus (SLE). Here we investigated the association of the three major polymorphisms in IRF5 and STAT4 found to be associated with SLE, in patients from Sweden and Norway with primary SS. These polymorphisms are a 5-bp CGGGG indel in the promoter of IRF5, the single nucleotide polymorphism (SNP) rs10488631 downstream of IRF5 and the STAT4 SNP rs7582694, which tags the major risk haplotype of STAT4. We observed strong signals for association between all three polymorphisms and primary SS, with odds ratios (ORs) 41.4 and P-values o0.01. We also found a strong additive effect of the three risk alleles of IRF5 and STAT4 with an overall significance between the number of risk alleles and primary SS of P ¼ 2.5 Â 10 À9 . The OR for primary SS increased in an additive manner, with an average increase in OR of 1.78. For carriers of two risk alleles, the OR for primary SS is 1.43, whereas carriers of five risk alleles have an OR of 6.78. IRF5 and STAT4 are components of the type I IFN system, and our findings emphasize the importance of this system in the etiopathogenesis of primary SS.
Kristjansdottir G, Vilhjalmsson R. Sociodemographic differences in patterns of sedentary and physically active behavior in older children and adolescents. Acta Paediatr 2001: 90: 429-435. Stockholm. ISSN 0803-5253 Numerous studies have found that involvement in moderate-intensity and strenuous activity has positive effects on health. This study considered the prevalence of different aspects of physical activity and sedentary behavior in 11-16-y-olds based on a representative national survey of 3270 Icelandic primary schoolchildren (91% response rate). All-day sedentary behavior was extremely rare (< 1%), and the vast majority (91%) were physically active ( ¶3 times per week) during school or leisure time, thanks largely to school physical education. Only 39% were physically active ( ¶3 times per week) during leisure time, and only 29% engaged in regular ( ¶3 times per week) leisure time strenuous exercise. Girls were more sedentary, less leisure time physically active, and less involved in leisure time strenuous exercise. Sedentary behavior increased and physically active behavior decreased with age, especially after early adolescence. However, there were no age differences in strenuous leisure time exercise. Upper-class students were less sedentary and more physically active during leisure time than working-class students. Finally, rural students were more sedentary during leisure time, and less physically active than students from urban areas. An interaction was found between age and residence when predicting leisure time physical activity, indicating that the inverse age-activity relationship in urban areas is partly reversed in rural areas.Conclusion: Compulsory school physical education frequently failed to translate into voluntary physical involvement. Sociodemographic differences in physical activity were greater during leisure time, than during school and leisure time combined.
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