Systemic lupus erythematosus (SLE) is a prototypic autoimmune disorder with a complex pathogenesis in which genetic, hormonal and environmental factors have a role. Rare mutations in the TREX1 gene, the major mammalian 3 0 -5 0 exonuclease, have been reported in sporadic SLE cases. Some of these mutations have also been identified in a rare pediatric neurological condition featuring an inflammatory encephalopathy known as Aicardi-Goutiè res syndrome (AGS). We sought to investigate the frequency of these mutations in a large multi-ancestral cohort of SLE cases and controls. A total of 40 single-nucleotide polymorphisms (SNPs), including both common and rare variants, across the TREX1 gene, were evaluated in B8370 patients with SLE and B7490 control subjects. Stringent quality control procedures were applied, and principal components and admixture proportions were calculated to identify outliers for removal from analysis. Population-based case-control association analyses were performed. P-values, false-discovery rate q values, and odds ratios (OR) with 95% confidence intervals (CI) were calculated. The estimated frequency of TREX1 mutations in our lupus cohort was 0.5%. Five heterozygous mutations were detected at the Y305C polymorphism in European lupus cases but none were observed in European controls. Five African cases incurred heterozygous mutations at the E266G polymorphism and, again, none were observed in the African controls. A rare homozygous R114H mutation was identified in one Asian SLE patient, whereas all genotypes at this mutation in previous reports for SLE were heterozygous. Analysis of common TREX1 SNPs (minor allele frequency (MAF)410%) revealed a relatively common risk haplotype in European SLE patients with neurological manifestations, especially seizures, with a frequency of 58% in lupus cases compared with 45% in normal controls (P ¼ 0.0008, OR ¼ 1.73, 95% CI ¼ 1.25-2.39). Finally, the presence or absence of specific autoantibodies in certain populations produced significant genetic associations. For example, a strong association with anti-nRNP was observed in the European cohort at a coding synonymous variant rs56203834 (P ¼ 2.99EÀ13, OR ¼ 5.2, 95% CI ¼ 3.18-8.56). Our data confirm and expand previous reports and provide additional support for the involvement of TREX1 in lupus pathogenesis.

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Background: Chronic stress worsens the quality of life (QOL) of lupus patients by affecting their physical and psychological status. The effectiveness of a cognitive-behavioural intervention in a group of patients with lupus and high levels of daily stress was investigated. Methods: Forty-five patients with lupus and high levels of daily stress were randomly assigned to a control group (CG) or a therapy group (TG); they received cognitive behavioural therapy (CBT) which consisted of ten consecutive weekly sessions. The following variables were evaluated at baseline and at 3, 9 and 15 months: (1) stress, anxiety, depression, (2) Systemic Lupus Erythematosus Disease Activity Index, somatic symptoms, number of flares, (3) anti-nDNA antibodies, complement fractions C3 and C4 and (4) QOL. A multivariate analysis of repeated measures and various analyses of variance were carried out. Results: We found a significant reduction in the level of depression, anxiety and daily stress in the TG compared to the CG and a significant improvement in QOL and somatic symptoms in the TG throughout the entire follow-up period. We did not find any significant changes in the immunological parameters. Conclusions: CBT is effective in dealing with patients suffering from lupus and high levels of daily stress as it significantly reduces the incidence of psychological disorders associated with lupus and improves and maintains patients’ QOL, despite there being no significant reduction in the disease activity index.

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Objectives Systemic lupus erythematosus (SLE) is a sexually dimorphic autoimmune disease which is more common in women, but affected men often experience a more severe disease. The genetic basis of sexual dimorphism in SLE is not clearly defined. A study was undertaken to examine sex-specific genetic effects among SLE susceptibility loci. Methods A total of 18 autosomal genetic susceptibility loci for SLE were genotyped in a large set of patients with SLE and controls of European descent, consisting of 5932 female and 1495 male samples. Sex-specific genetic association analyses were performed. The sex–gene interaction was further validated using parametric and nonparametric methods. Aggregate differences in sex-specific genetic risk were examined by calculating a cumulative genetic risk score for SLE in each individual and comparing the average genetic risk between male and female patients. Results A significantly higher cumulative genetic risk for SLE was observed in men than in women. (P = 4.52×10−8) A significant sex–gene interaction was seen primarily in the human leucocyte antigen (HLA) region but also in IRF5, whereby men with SLE possess a significantly higher frequency of risk alleles than women. The genetic effect observed in KIAA1542 is specific to women with SLE and does not seem to have a role in men. Conclusions The data indicate that men require a higher cumulative genetic load than women to develop SLE. These observations suggest that sex bias in autoimmunity could be influenced by autosomal genetic susceptibility loci.