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.     

Genetic heterogeneity in Finnish hereditary prostate cancer using ordered subset analysis

Prostate cancer (PrCa) is the most common male cancer in developed countries and the second most common cause of cancer death after lung cancer. We recently reported a genome-wide linkage scan in 69 Finnish hereditary PrCa (HPC) families, which replicated the HPC9 locus on 17q21-q22 and identified a locus on 2q37. The aim of this study was to identify and to detect other loci linked to HPC. Here we used ordered subset analysis (OSA), conditioned on nonparametric linkage to these loci to detect other loci linked to HPC in subsets of families, but not the overall sample. We analyzed the families based on their evidence for linkage to chromosome 2, chromosome 17 and a maximum score using the strongest evidence of linkage from either of the two loci. Significant linkage to a 5-cM linkage interval with a peak OSA nonparametric allele-sharing LOD score of 4.876 on Xq26.3-q27 (ΔLOD=3.193, empirical P=0.009) was observed in a subset of 41 families weakly linked to 2q37, overlapping the HPCX1 locus. Two peaks that were novel to the analysis combining linkage evidence from both primary loci were identified; 18q12.1-q12.2 (OSA LOD=2.541, ΔLOD=1.651, P=0.03) and 22q11.1-q11.21 (OSA LOD=2.395, ΔLOD=2.36, P=0.006), which is close to HPC6. Using OSA allows us to find additional loci linked to HPC in subsets of families, and underlines the complex genetic heterogeneity of HPC even in highly aggregated families.     

Cervical artery dissection goes frequently undiagnosed

Cervical artery dissection (CeAD) is a frequent cause of stroke among young patients. It is unclear how many CeADs occur asymptomatically or cause subtle and unspecific clinical symptoms. We hypothesize that CeAD remains often unrecognized. Accordingly, the incidence of CeAD might be higher and the stroke risk lower than generally assumed. Lack of CeAD-indicating clinical symptoms is regarded as the main cause of missed diagnoses. We further hypothesize that underrepresentation of asymptomatic and oligosymptomatic patients in CeAD studies may have biased the association between ischemia and local symptoms in CeAD patients as well as the associations of CeAD with risk factors or co-morbidities. We finally hypothesize that symptomatic CeAD may be preceded by an initial asymptomatic phase. According to this final hypothesis, the time of onset of CeAD should be considered uncertain. The issue of unrecognized CeAD is relevant, as it may affect the associations between CeAD and putative risk factors. Furthermore, the existence of clinically silent CeADs may explain why recurrent and familial CeAD have been rarely observed.     

Parametric merging of MEG and fMRI reveals spatiotemporal differences in cortical processing of spoken words and environmental sounds in background noise

There is an increasing interest to integrate electrophysiological and hemodynamic measures for characterizing spatial and temporal aspects of cortical processing. However, an informative combination of responses that have markedly different sensitivities to the underlying neural activity is not straightforward, especially in complex cognitive tasks. Here, we used parametric stimulus manipulation in magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) recordings on the same subjects, to study effects of noise on processing of spoken words and environmental sounds. The added noise influenced MEG response strengths in the bilateral supratemporal auditory cortex, at different times for the different stimulus types. Specifically for spoken words, the effect of noise on the electrophysiological response was remarkably nonlinear. Therefore, we used the single-subject MEG responses to construct parametrization for fMRI data analysis and obtained notably higher sensitivity than with conventional stimulus-based parametrization. fMRI results showed that partly different temporal areas were involved in noise-sensitive processing of words and environmental sounds. These results indicate that cortical processing of sounds in background noise is stimulus specific in both timing and location and provide a new functionally meaningful platform for combining information obtained with electrophysiological and hemodynamic measures of brain function.     

Prevalence of restless legs symptoms according to depressive symptoms and depression type: a cross-sectional study

Background: Restless legs syndrome is a sensorimotor disorder and it is associated with several other diseases especially mental illnesses.

Aims: To analyze the relationship between the symptoms of restless legs syndrome and the severity of depressive symptoms and the prevalence of restless legs symptoms in depression subtypes.

Methods: A cross-sectional study of primary care patients in the Central Finland Hospital District. The prevalence of restless legs symptoms was studied in 706 patients with increased depressive symptoms and 426 controls without a psychiatric diagnosis by using a structured questionnaire. The depressive symptoms were evaluated with the Beck Depression Inventory (BDI) and the psychiatric diagnosis was confirmed by means of a diagnostic interview (Mini-International Neuropsychiatric Interview). The subjects with increased depressive symptoms were divided into three groups (subjects with depressive symptoms without a depression diagnosis, melancholic depression and non-melancholic depression).

Results: In the whole study population, the prevalence of restless legs symptoms increased with the severity of depressive symptoms. The prevalence of restless legs symptoms was highest in the melancholic and non-melancholic depressive patients (52 and 46%, respectively) and then in subjects with depressive symptoms without a depression diagnosis (43.4%), but the prevalence was also substantial (24.6%) in subjects without a psychiatric diagnosis.

Conclusions: Restless legs symptoms are very common in primary care among subjects with depression, regardless of the depression type. The prevalence of restless legs symptoms increased with increasing severity of depressive symptoms, regardless of the diagnosis. These findings should be considered in clinical evaluation and treatment of patients visiting their physician due to restless legs or depressive symptoms.     

Descriptive epidemiology of spinal muscular atrophy type I in Estonia

Spinal muscular atrophy is the second most frequent autosomal-recessive disorder in Europeans. There are no published epidemiological data on SMA in Estonia and other Baltic countries. The aim of this study was to estimate the incidence of SMA I in Estonia. All patients with SMA I diagnosed between January 1994 and December 2003 were included in the study. The diagnosis was established on the basis of neurological evaluation, ENMG findings, molecular studies and muscle biopsy. PCR and restriction enzyme analysis was used to detect the homozygous deletion of the SMN1 gene. A total of 9 cases of SMA I were identified during this 10-year period. The incidence of SMA I in Estonia is 1 in 14,400 live births, which is similar to the result from Hungary but lower than average incidence in the world. Only one of the patients was female. Typical SMN1 gene deletion was found in all cases.     

Incidence and prevalence of dementia in elderly adults with mental retardation without down syndrome

Rates of dementia in adults with mental retardation without Down syndrome were equivalent to or lower than would be expected compared to general population rates, whereas prevalence rates of other chronic health concerns varied as a function of condition. Given that individual differences in vulnerability to Alzheimer's disease have been hypothesized to be due to variation in cognitive reserve, adults with mental retardation, who have long-standing intellectual and cognitive impairments, should be at increased risk. This suggests that factors determining intelligence may have little or no direct relationship to risk for dementia and that dementia risk for individuals with mental retardation will be comparable to that of adults without mental retardation unless predisposing risk factors for dementia are also present.     

Lifestyle and late effects after poliomyelitis. A risk factor study of two populations

BACKGROUND: Patients with polio often experience new symptoms (muscle weakness, pain, fatigue and respiratory problems) many years after the acute disease. This study examined possible interactions between lifestyle factors (overweight, physical inactivity, smoking) and late polio with new symptoms. METHODS: A total of 148 patients hospitalized for acute polio in 1950-1954 at Haukeland University Hospital, Norway and 128 patients, hospitalized for acute polio in 1958 at Tartu University Hospital, Estonia responded to a mailed questionnaire regarding lifestyle and late polio with new symptoms. Multiple regression analysis, two samples t-test and chi-square analysis were undertaken. RESULTS: Mean body mass index (BMI) and percentage of smokers did not differ in the two cohorts, while polio patients were physically less active in Estonia. The physically active patients in both cohorts had significantly lower odds for experiencing polio-related late muscle pain (OR = 0.21; 95% CI = 0.08-0.55) and fatigue (OR = 0.32; 95% CI = 0.14-0.75). With increasing age the patients had significantly higher odds for experiencing new muscle weakness (OR = 1.03; 95% CI = 1.00-1.07), fatigue (OR = 1.04;95% CI = 1.01-1.07) and breath shortness (OR = 1.04; 95% CI = 1.00-1.07). CONCLUSION: Physically inactive patients are at a higher risk for late polio-related symptoms. An active lifestyle should be recommended for patients with polio sequels.