Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy

Contains fulltext : 97006.pdf (publisher's version ) (Open Access)The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32x10(-12), OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 x 10(-6), OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39x10(-7), OR = 1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79x10(-61), OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57x10(-76), OR = 8.84), and in NOTCH4 with ACA P = 8.84x10(-21), OR = 0.55) and ATA (P = 1.14x10(-8), OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc

Combination Pressure : The Paid Work–Family Balance of Men and Women in European Countries

People today lead busy, hurried lives with competing time claims between the spheres of paid work and the household. The aim of this article is to provide more insight into the way men and women experience the multiple claims on their time and to attempt to understand the differences between European countries in this respect. Are we able to draw a sharp line in the work–family balance experienced in eastern and western Europe? Expectations are formulated at the individual level (work and home-related factors) and at the contextual level (gender culture and family policy). Data were gathered in 2001 within the international research programme ‘Households, Work and Flexibility’, financed by the European Union. The eight countries included in the analyses are Sweden, the Netherlands, UK, Slovenia, Hungary, Czech Republic, Romania and Bulgaria, and hypotheses are tested using multivariate regression analyses. At the contextual level, results reflect more support for the gender culture hypothesis than for the family friendly policy hypothesis. The multiplicity of options in western European countries due to the emancipation process causes time pressure. Individual factors are especially important in explaining combination pressure in the three western European countries: long working hours, overtime work, demanding job and having young children all add to the pressure men and women experience.

The impact of childhood sexual trauma on intimacy and sexuality needs among people with non-affective psychosis

Background: Childhood trauma, in particular childhood sexual abuse (CSA), and unmet sexuality and intimacy needs are prevalent among people with psychosis spectrum disorders. The association between CSA and sexuality and intimacy needs over time in adults with psychosis spectrum disorders were examined. Method: Patients (n = 1119) were recruited as part of the Genetic Risk and OUtcome of Psychosis (GROUP) study, a representative cohort of patients with non-affective psychotic disorder. At baseline, three-year and six-year follow-up, sexuality and intimacy needs were assessed with the Camberwell Assessment of Needs. CSA was assessed with the Childhood Trauma Questionnaire. Results: At baseline, sexuality (26%) and intimacy (40%) needs were prevalent; 90% of these needs remained unmet. Cross-sectionally, CSA was associated with sexuality needs (OR = 1.68, 95% CI: 1.13-2.04) and intimacy needs (OR = 1.75, 95% CI: 1.04-1.77). Childhood emotional abuse (CEA) was also cross-sectionally associated with sexuality and intimacy needs. Others forms of trauma were not. Prospectively, CSA predicted incidence of a sexuality need (HR = 2.1, 95% CI: 1.23-3.74) as well as an intimacy need (HR = 1.7, 95% CI: 1.11-2.66), as did CEA (sexuality: HR = 1.8, 95% CI: 1.11-2.89; intimacy: HR = 1.4, 95% CI: 1.03-1.96). CSA and CEA were not associated with persistence of sexuality or intimacy. Conclusion: CSA and CEA are associated with a higher prevalence and incidence of sexuality and intimacy needs in patients with psychotic disorders. High rates of unmet sexuality and intimacy needs may indicate an under-lying need for trauma-related treatment as well as a need for novel interventions targeting these needs

Inflammatory mediators in human epilepsy : A systematic review and meta-analysis

Background: Accumulating evidence suggests a role for inflammation in the pathophysiology of epilepsy. Methods: We performed a systematic review and meta-analysis of studies that investigated inflammatory mediators in human epilepsy. Studies reporting on inflammatory mediators in serum, cerebrospinal fluid or brain tissue of epilepsy patients were included. Studies comparing patients to controls were included in a meta-analysis. Results: 66 articles reporting on 1934 patients were included. IL-1ra, IL-1β, IL-6, IL-10, IFN-γ and TNF-α were the most extensively investigated proteins. Elevated levels for IL-1ra, IL-1β, IL-6 and CXCL8/IL-8 were reported in several different epilepsy etiologies and media, while other proteins were specifically increased for one etiology. IL-1α, IL-7 and IL-13, as well as the chemokines CCL2-5, -19 and -22, were increased exclusively in brain tissue. In an aggregate meta-analysis, we found significantly different protein levels for serum IL-6, IL-17 and CSF IL-1β and IL-10. Conclusion: Inflammatory pathways are involved in epilepsy. Future studies may further clarify their role, and prove potential of targeted anti-inflammatory treatment