Marriage, cohabitation and incidence trends of invasive penile squamous cell carcinoma in Denmark 1978-2010.

Few population-based studies have investigated the relation between living arrangements and risk of invasive penile squamous cell carcinoma (iP-SCC). Using long-term national cancer registry data in Denmark we examined incidence trends of iP-SCC. Furthermore, we examined the relation between marital status, cohabitation status and risk of iP-SCC using hazard ratios (HRs) with 95% confidence intervals (CIs) obtained in Cox proportional hazards regression analyses as our measure of relative risk. Overall, 1,292 cases of iP-SCC were identified during 65.6 million person-years of observation between 1978 and 2010. During this period, the WHO world age-standardized incidence remained relatively stable (p-trend = 0.41) with an average incidence of 1.05 cases per 100,000 person-years. When compared to married men, those who were unmarried (HR 1.37; 95% CI: 1.13-1.66), divorced (HR 1.49; 95% CI: 1.24-1.79) or widowed (HR 1.36; 95% CI: 1.13-1.63) were at increased risk of iP-SCC. Regarding cohabitation status, single-living men were at increased risk of iP-SCC compared to men in opposite-sex cohabitation (HR 1.43; 95% CI: 1.26-1.62). Risk increased with increasing numbers of prior opposite-sex (p-trend = 0.02) and same-sex (p-trend < 0.001) cohabitations. In conclusion, single-living Danish men and men who are not currently married are at increased risk of iP-SCC, and the risk increases with the number of prior cohabitations, perhaps reflecting less stable sexual relations in these subgroups.

Cluster of highly expressed interferon-stimulated genes associate more with African ancestry than disease activity in patients with systemic lupus erythematosus. A systematic review of cross-sectional studies.

Type I interferons (IFN) are central players in the pathogenesis of systemic lupus erythematosus (SLE) and the up-regulation of interferon-stimulated genes (ISGs) in SLE patients is subjected to increasing scrutiny as for its use in diagnosis, stratification and monitoring of SLE patients. Determinants of this immunological phenomenon are yet to be fully charted. The purpose of this systematic review was to characterize expressions of ISGs in blood of SLE patients and to analyze if they associated with core demographic and clinical features of SLE. Twenty cross-sectional, case-control studies comprising 1033 SLE patients and 602 study controls could be included. ISG fold-change expression values (SLE vs controls), demographic and clinical data were extracted from the published material and analyzed by hierarchical cluster analysis and generalized linear modelling. ISG expression varied substantially within each study with IFI27, IFI44, IFI44L, IFIT4 and RSAD2, being the top-five upregulated ISGs. Analysis of inter-study variation showed that IFI27, IFI44, IFI44L, IFIT1, PRKR and RSAD2 expression clustered with the fraction of SLE cases having African ancestry or lupus nephritis. Generalized linear models adjusted for prevalence of lupus nephritis and usage of hydroxychloroquine confirmed the observed association between African ancestry and IFI27, IFI44L, IFIT1, PRKR and RSAD2, whereas disease activity was associated with expression of IFI27 and RNASE2. In conclusion, this systematic review revealed that expression of ISGs often used for deriving an IFN signature in SLE patients were influenced by African ancestry rather than disease activity. This underscores the necessity of taking ancestry into account when employing the IFN signature for clinical research in SLE.

Epstein-Barr virus-associated infectious mononucleosis and risk of systemic lupus erythematosus.

OBJECTIVES: Elevated levels of serological markers of EBV infection in patients with SLE and observations that infectious mononucleosis (IM) may precede some cases of SLE suggest a possible role of EBV in the aetiology of SLE. We evaluated the relationship between EBV-associated IM and subsequent risk of SLE in a population-based cohort study. METHODS: We followed cohorts of Danes tested serologically for IM using the Paul-Bunnell (PB) heterophile antibody test between 1939 and 1989, and patients hospitalized with IM between 1977 and 2007 for subsequent first hospitalizations with SLE in the period 1977-2008. Standardized incidence ratios (SIRs) with 95% CI served as measures of relative risk. RESULTS: Risk of SLE was not increased either in individuals with a positive PB test (SIR = 1.1; 95% CI 0.8, 1.6; n = 27) or in individuals hospitalized with IM (SIR = 1.3; 95% CI 0.7, 2.2; n = 12). However, SLE risk in PB-negative individuals was significantly increased (SIR = 2.6; 95% CI 2.1, 3.2; n = 82), a risk that was particularly high 1-4 years after the PB test (SIR = 6.6; 95% CI 3.3, 13.2) and remained significantly elevated for >25 years. CONCLUSIONS: EBV-associated IM does not seem to be a risk factor for SLE. The temporal pattern of increased SLE risk in individuals with a negative PB test suggests that some patients who go on to develop SLE may present with unspecific symptoms, for which they may be tested for IM, long in advance of their SLE diagnosis.

Twin DNA Methylation Profiling Reveals Flare-Dependent Interferon Signature and B Cell Promoter Hypermethylation in Systemic Lupus Erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE) has limited monozygotic twin concordance, implying a role for pathogenic factors other than genetic variation, such as epigenetic changes. Using the disease-discordant twin model, we investigated genome-wide DNA methylation changes in sorted CD4+ T cells, monocytes, granulocytes, and B cells in twin pairs with at least 1 SLE-affected twin. METHODS: Peripheral blood obtained from 15 SLE-affected twin pairs (6 monozygotic and 9 dizygotic) was processed using density-gradient centrifugation for the granulocyte fraction. CD4+ T cells, monocytes, and B cells were further isolated using magnetic beads. Genome-wide DNA methylation was analyzed using Infinium HumanMethylation450K BeadChips. When comparing probes from SLE-affected twins and co-twins, differential DNA methylation was considered statistically significant when the P value was less than 0.01 and biologically relevant when the median DNA methylation difference was >7%. Findings were validated by pyrosequencing and replicated in an independent case-control sample. RESULTS: In paired analyses of twins discordant for SLE restricted to the gene promoter and start region, we identified 55, 327, 247, and 1,628 genes with differentially methylated CpGs in CD4+ T cells, monocytes, granulocytes, and B cells, respectively. All cell types displayed marked hypomethylation in interferon-regulated genes, such as IFI44L, PARP9, and IFITM1, which was more pronounced in twins who experienced a disease flare within the past 2 years. In contrast to what was observed in the other cell types, differentially methylated CpGs in B cells were predominantly hypermethylated, and the most important upstream regulators included TNF and EP300. CONCLUSION: Hypomethylation of interferon-regulated genes occurs in all major cellular compartments in SLE-affected twins. The observed B cell promoter hypermethylation is a novel finding with potential significance in SLE pathogenesis.

Histone variants and melanoma: facts and hypotheses.

Melanoma is the most aggressive form of skin cancer with rising incidence and morbidity. Despite advances in treatment, the 10-yr survival for patients with metastatic disease is less than 10%. During the past few years, ongoing research on different epigenomic aberrations in melanoma has catalyzed better understanding of its pathogenesis and identification of new therapeutics. In our review, we will focus on the role of histone variants, key epigenetic players in melanoma initiation and progression. Specifically, incorporation of histone variants enables additional layers of chromatin structure, and here, we will describe how alterations in this epigenetic behavior impact melanoma.

Infections and antineutrophil cytoplasmic antibodies: triggering mechanisms.

The precise cause of the antineutrophil cytoplasmic antibodies (ANCA) autoimmunity is not known and is likely to be multifactorial. Infections may trigger formation of ANCA and a fraction of the patients with infection-triggered ANCA develop ANCA-associated vasculitis. Here we discuss some of the proposed mechanisms of ANCA formation during the course of infection. They include initiation of autoimmune response by microbial peptides that are complementary to autoantigens; epigenetic silencing and antigen complementarity leading to upregulation of autoantigen genes; molecular mimicry between bacterial and self-antigens; formation of neutrophil extracellular traps that stimulate immune processes including production of ANCA; and interaction of bacterial components with Toll-like receptors, which leads to formation of mediators affecting the immune responses to infections and can trigger ANCA production. Further work is needed to clarify these mechanisms and develop preventive measures and therapeutic interventions.

Reproductive factors and risk of systemic lupus erythematosus: nationwide cohort study in Denmark.

OBJECTIVE: The female predominance in systemic lupus erythematosus (SLE) suggests the possible involvement of reproductive factors in its etiology. We evaluated the relationship between parity and pregnancy losses and subsequent risk of SLE in a population-based cohort study. METHODS: We followed 4.4 million Danes aged 15-69 years for first inpatient hospitalizations for SLE between 1977 and 2004. As measures of relative risk, we used Poisson regression-derived hospitalization rate ratios (RR) with 95% confidence intervals (CI) for cohort members with different reproductive histories. RESULTS: Overall, 1614 women and 274 men were hospitalized with SLE during 88.9 million person-years of followup. Number of children was unrelated to SLE risk in men, but women with at least one liveborn child were at lower risk than nulliparous women (RR 0.74; 95% CI 0.64-0.86), and women with 2 or more children were at lower risk than 1-child mothers. Recurrent idiopathic pregnancy losses, including spontaneous abortions, missed abortions, and stillbirths, were associated with markedly increased SLE risk (RR 3.50; 95% CI 2.38-4.96, for 2+ vs none; p < 0.001). CONCLUSION: Nulliparous women, 1-child mothers, and women who experience spontaneous abortions, missed abortions, or stillbirths are at increased SLE risk. Theoretically, immunological processes involved in subfertility or idiopathic pregnancy losses might act as initiating or contributing factors in some cases of SLE. However, considering the well established excess of pregnancy complications in women with established SLE, the observed associations more likely reflect the effect of subclinical immunological processes in women destined to develop SLE.