Identification of cis-regulatory variation influencing protein abundance levels in human plasma

Proteins are central to almost all cellular processes, and dysregulation of expression and function is associated with a range of disorders. A number of studies in human have recently shown that genetic factors significantly contribute gene expression variation. In contrast, very little is known about the genetic basis of variation in protein abundance in man. Here, we assayed the abundance levels of proteins in plasma from 96 elderly Europeans using a new aptamer-based proteomic technology and performed genome-wide local (cis-) regulatory association analysis to identify protein quantitative trait loci (pQTL). We detected robust cis-associations for 60 proteins at a false discovery rate of 5%. The most highly significant single nucleotide polymorphism detected was rs7021589 (false discovery rate, 2.5 × 10(-12)), mapped within the gene coding sequence of Tenascin C (TNC). Importantly, we identified evidence of cis-regulatory variation for 20 previously disease-associated genes encoding protein, including variants with strong evidence of disease association show significant association with protein abundance levels. These results demonstrate that common genetic variants contribute to the differences in protein abundance levels in human plasma. Identification of pQTLs will significantly enhance our ability to discover and comprehend the biological and functional consequences of loci identified from genome-wide association study of complex traits. This is the first large-scale genetic association study of proteins in plasma measured using a novel, highly multiplexed slow off-rate modified aptamer (SOMAmer) proteomic platform.     

The intercellular adhesion molecule-1 (ICAM-1) gene polymorphism K469E in end-stage renal disease patients with cardiovascular disease

The intercellular adhesion molecule-1 (ICAM-1) mediates interaction of activated endothelial cells with leukocytes. It plays an important role in the pathogenesis of atherosclerosis. A functionally important polymorphism of the ICAM-1 gene, K469E, has been described. We investigated whether this polymorphism influences the risk of CVD in end-stage renal disease (ESRD) patients. The groups of 1016 ESRD patients and 824 healthy individuals were genotyped by PCR and allele specific oligonucleotide technique. The T allele of the K469E polymorphism was significantly more frequent in ESRD CVD+ patients than CVD- and controls (OR 2.26, 95% CI 1.87-2.72 and 1.82, 95% CI 1.55-2.11, respectively). The TT genotype was also more frequent in CVD+ patients (OR 9.90, 95% CI 6.17-15.88 vs. CVD- subgroup). When patients were stratified according to clinical outcome of CVD, there was a tendency towards higher frequencies of the T allele and TT genotype in patients with myocardial infarction (OR for T allele 1, 57, 95% CI 1.12-2.18 vs. patients without MI). In the multivariate regression analysis the carrier status of T allele of K469E was an independent risk factor of susceptibility to CVD. Our data suggest that the ICAM-1 K469E polymorphism is associated with CVD in ESRD patients.     

Decreased markers of atopy in children with presumed early exposure to allergens, unhygienic conditions, and infections.

BACKGROUND: Several risk factors for the development of asthma and atopic disease in children have been described. Furthermore, there is consistent evidence that the prevalence of atopy increases with higher socioeconomic status. The knowledge about risk factors and preventive factors for atopy needs to be improved. OBJECTIVE: To compare 2 child populations (foster care and reference children) with different risk and protective factors for the development of atopy. METHODS: The study group consisted of 415 children, living in all 10 community foster homes in Lodz, a large industrial city in Poland. The study was performed from April 2, 2004, to April 30, 2006. The reference group consisted of 500 children, living with their parents at home, recruited from primary care centers. The primary outcome measures were skin prick test results and specific IgE in serum. Secondary outcomes included symptoms of allergic diseases and family history, including life conditions in early childhood. RESULTS: The full analysis set included 408 study children and 402 reference children. Significant differences were observed in the prevalence of atopy between the study and reference groups (11.3% vs 25.9%). We observed more positive skin prick test results in children from the reference group than in study children. To explain this phenomenon, we selected 16 variables that differ in both groups in early life and relate these to atopy. We found that the more cumulative features characteristic of the foster home population (poor living conditions), the lower the risk of atopy. CONCLUSION: Extremely unfavorable environmental circumstances, which are characteristic of the foster home population during early childhood, might prevent from atopy.     

Cognitive inhibition in patients with medial orbitofrontal damage

Inhibition underlies cognitive processes such as overcoming habitual responses, suppressing of goal-irrelevant information, and switching of attention between stimuli or task rules. These processes are thought to depend on the frontal lobes. However, the precise role of the ventral frontal regions (orbitofrontal cortex) in these processes remains elusive. In the present study, our goal was to clarify the role of the orbitofrontal cortex in cognitive inhibition by examining the effects of focal lesions to the medial orbitofrontal cortex (posterior part of the gyrus rectus) on performance in tasks that required inhibitory control. Patients who had undergone surgery for an anterior communicating artery aneurysm and normal control subjects (C) participated in the study. The patients were subdivided into three groups: those with resection of the left (LGR+) or right (RGR+) gyrus rectus, and without such a resection (GR-). The Stroop Color-Word test, Trail Making B test, and the Category test were used as instruments for assessing response inhibition, switching between concrete stimuli, and switching between abstract task rules, respectively. In addition, the Digit Symbol test was used to examine sustained attention and processing speed. In the Stroop Color-Word test, the RGR+ group performed worse than all other groups. In the Trail Making B test, the RGR+ and LGR+ groups performed worse than both the GR- and C groups. In the Category test and Digit Symbol test, the groups did not differ significantly from each other. Our study indicates a specific contribution of the medial orbitofrontal cortex to response inhibition and stimulus-based switching of attention.     

Psychosocial impairment associated with bipolar II disorder

BACKGROUND: Significant research has looked at the psychosocial impairment associated with bipolar I disorder and major depressive disorder. Far less is known about the impact of bipolar II disorder. The present study assessed the social and work impairment associated with bipolar II disorder and whether these are more or less severe than those associated with bipolar I disorder or major depressive disorder. METHODS: Psychiatric outpatients with bipolar II disorder (n=89), bipolar I disorder (n=45) and major depressive disorder (n=1251) were assessed cross-sectionally by highly trained raters using semi-structured interviews. Participants were in a major depressive episode. Groups were compared on a series of indicators of psychosocial functioning. RESULTS: Bipolar I and II disorder were associated with greater absenteeism from work due to psychopathology compared to major depressive disorder. The bipolar disorders also had higher rates of hospitalization and suicide attempts. Bipolar II disorder had fewer hospitalization than bipolar I disorder which may have led to slightly less severe work impairment. Both conditions had similar rates of serious suicide attempts. LIMITATIONS: The study was cross-sectional and retrospective. Furthermore, the sample consisted of outpatients seeking treatment, limiting generalizability to other settings. CONCLUSION: Bipolar II disorder is associated with serious work impairment and a high number of serious suicide attempts. The level of impairment is more similar than it is different from that associated with bipolar I disorder. Clinicians would be mistaken to presume that the "softer" bipolar spectrum, specifically bipolar II disorder, is less impairing than bipolar I disorder.     

Cyclin D1 and t(11;14)-positive B-cell neoplasms resembling marginal zone B-cell lymphoma: a morphological variant of mantle cell lymphoma

We describe 3 unusual B-cell non-Hodgkin's lymphomas in which the entire tumors histologically mimicked marginal zone B-cell lymphoma. All patients were male (mean age, 65 years). Excisional biopsy from lymph node (2 of 3) and parotid gland (1 of 3) showed proliferation of monocytoid B-cells with plasmacytoid features (2 of 3) and conspicuous absence of large lymphoma cells (3 of 3). By immunohistochemistry, cyclin D1 was positive (3 of 3), CD23 was negative (3 of 3), and aberrant expression of CD5/CD43 was present in 1 case. Ki67 labeling was greater than 50% in 1 case and 10% to 25% in the other 2 cases. Evidence of the t(11;14) was detectable in all by molecular techniques. One patient died within 15 months, and the other 2 patients had widely disseminated diseases at the last follow-up (8 months). Based on these features, we believed that the best classification for these lesions is the marginal zone B-cell lymphoma-like mantle cell lymphoma.     

CHRNA3/5, IREB2, and ADCY2 are associated with severe chronic obstructive pulmonary disease in Poland

We examined the association between single-nucleotide polymorphisms (SNPs) previously associated with chronic obstructive pulmonary disease (COPD) and/or lung function with COPD and COPD-related phenotypes in a novel cohort of patients with severe to very severe COPD. We examined 315 cases of COPD and 330 Caucasian control smokers from Poland. We included three SNPs previously associated with COPD: rs7671167 (FAM13A), rs13180 (IREB2), and rs8034191 (CHRNA 3/5), and four SNPs associated with lung function in a genome-wide association study of general population samples: rs2070600 (AGER), rs11134242 (ADCY2), rs4316710 (THSD4), and rs17096090 (INTS12). We tested for associations with severe COPD and COPD-related phenotypes, including lung function, smoking behavior, and body mass index. Subjects with COPD were older (average age 62 versus 58 years, P < 0.01), with more pack-years of smoking (45 versus 33 pack-years, P < 0.01). CHRNA3/5 (odds ratio [OR], 1.89; 95% confidence interval [CI], 1.5-2.4; P = 7.4 × 10(-7)), IREB2 (OR, 0.69; 95% CI, 0.5-0.9; P = 3.4 × 10(-3)), and ADCY2 (OR, 1.35; 95% CI, 1.1-1.7; P = 0.01) demonstrated significant associations with COPD. FAM13A (OR, 0.8; 95% CI, 0.7-1.0; P = 0.11) approached statistical significance. FAM13A and ADCY2 also demonstrated a significant association with lung function. Thus, in severe to very severe COPD, we demonstrate a replication of association between two SNPs previously associated with COPD (CHRNA3/5 and IREB2), as well as an association with COPD of one locus initially associated with lung function (ADCY2).     

Can increased spatial resolution solve the crossing fiber problem for diffusion MRI?

It is now widely recognized that voxels with crossing fibers or complex geometrical configurations present a challenge for diffusion MRI (dMRI) reconstruction and fiber tracking, as well as microstructural modeling of brain tissues. This “crossing fiber” problem has been estimated to affect anywhere from 30% to as many as 90% of white matter voxels, and it is often assumed that increasing spatial resolution will decrease the prevalence of voxels containing multiple fiber populations. The aim of this study is to estimate the extent of the crossing fiber problem as we progressively increase the spatial resolution, with the goal of determining whether it is possible to mitigate this problem with higher resolution spatial sampling. This is accomplished using ex vivo MRI data of the macaque brain, followed by histological analysis of the same specimen to validate these measurements, as well as to extend this analysis to resolutions not yet achievable in practice with MRI. In both dMRI and histology, we find unexpected results: the prevalence of crossing fibers increases as we increase spatial resolution. The problem of crossing fibers appears to be a fundamental limitation of dMRI associated with the complexity of brain tissue, rather than a technical problem that can be overcome with advances such as higher fields and stronger gradients.     

Behavioural genetics of Alzheimer's disease: a comprehensive review

Behavioural and psychological symptoms of dementia (BPSD) are present in the course of the illness in up to 90% of patients with Alzheimer''s disease (AD). They are the main source of caregiver burden and one of the major factors contributing to early institutionalization. The involvement of a genetic component in BPSD aetiology seems beyond controversy, though the exact significance of particular polymorphisms is uncertain in the majority of cases. Multiple genes have been assessed for their putative influence on BPSD risk. In this paper we review the behavioural genetics of AD, particularly the importance, with respect to BPSD risk, of genes coding for apolipoprotein E and proteins involved in the process of neurotransmission: serotonin receptors, serotonin transporter, COMT, MAO-A, tryptophan hydroxylase and dopamine receptors. A general conclusion is the striking inconsistency of the findings, unsurprising in the field of psychiatric genetics. The potential reasons for such discrepancy are exhaustively discussed.     

Is there a relation between vitamin D,interleukin-17, and bone mineral density in patients with inflammatory bowel disease?

IntroductionIn inflammatory bowel diseases (IBD), osteopenia and osteoporosis constitute a significant medical problem. Cytokines, especially IL-17, play an important role in the pathogenesis of IBD and osteoporosis. Vitamin D is a regulator of bone metabolism, and helps maintain immune system homeostasis.Material and methodsThe research sample consisted of 208 persons: 83 patients (age 35 ±11.99 years) with Crohn’s disease (CD); 86 patients (age 39.58 ±14.74 years) with ulcerative colitis (UC); and 39 persons (age 30.74 ±8.63 years) in the control group (CG). Clinical data on bone mineral density of the lumbar spine (L2-L4), bone mineral density of the femoral neck (FN), and body mass index (BMI) were collected. 25OHD and IL-17 serum concentrations were also measured.ResultsBody mass index (kg/m²) results: in CD, 21.51 ±3.68; in UC, 23.31 ±4.38; and in CG, 24.57 ±3.45 (p < 0.01). Densitometry results for L2–L4 T-score SD: in CD –0.83 ±1.45; in UC –0.47 ±1.15; in CG 0.09 ±0.70. Densitometry results for FN T-score SD: in CD –0.62 ±1.26; in UC –0.29±1.17; in CG 0.41 ±1.03 25OHD (ng/ml) serum concentrations: in CD, 21.33±12.50; in UC, 22.04±9.56; in CG, 21.56±9.11 (ns). IL-17 (pg/ml) serum concentrations: in CD, 8.55±10.99; in UC, 11.67±12.97; in CG, 5.16±9.11 (ns).ConclusionsInflammatory bowel diseases patients and persons from the CG did not differ in vitamin D or IL-17 levels. Patients with a mild course of the disease had a higher vitamin D concentration and bone mineral density. In UC, higher vitamin D concentrations were associated with lower IL-17 concentrations. The IBD patients with a severe course of the disease had a lower body mass than those in the CG and the patients with a mild course of the disease.