A Genome-Wide Association Study of Psoriasis and Psoriatic Arthritis Identifies New Disease Loci

A genome-wide association study was performed to identify genetic factors involved in susceptibility to psoriasis (PS) and psoriatic arthritis (PSA), inflammatory diseases of the skin and joints in humans. 223 PS cases (including 91 with PSA) were genotyped with 311,398 single nucleotide polymorphisms (SNPs), and results were compared with those from 519 Northern European controls. Replications were performed with an independent cohort of 577 PS cases and 737 controls from the U.S., and 576 PSA patients and 480 controls from the U.K.. Strongest associations were with the class I region of the major histocompatibility complex (MHC). The most highly associated SNP was rs10484554, which lies 34.7 kb upstream from HLA-C (P = 7.8×10−11, GWA scan; P = 1.8×10−30, replication; P = 1.8×10−39, combined; U.K. PSA: P = 6.9×10−11). However, rs2395029 encoding the G2V polymorphism within the class I gene HCP5 (combined P = 2.13×10−26 in U.S. cases) yielded the highest ORs with both PS and PSA (4.1 and 3.2 respectively). This variant is associated with low viral set point following HIV infection and its effect is independent of rs10484554. We replicated the previously reported association with interleukin 23 receptor and interleukin 12B (IL12B) polymorphisms in PS and PSA cohorts (IL23R: rs11209026, U.S. PS, P = 1.4×10−4; U.K. PSA: P = 8.0×10−4; IL12B:rs6887695, U.S. PS, P = 5×10−5 and U.K. PSA, P = 1.3×10−3) and detected an independent association in the IL23R region with a SNP 4 kb upstream from IL12RB2 (P = 0.001). Novel associations replicated in the U.S. PS cohort included the region harboring lipoma HMGIC fusion partner (LHFP) and conserved oligomeric golgi complex component 6 (COG6) genes on chromosome 13q13 (combined P = 2×10−6 for rs7993214; OR = 0.71), the late cornified envelope gene cluster (LCE) from the Epidermal Differentiation Complex (PSORS4) (combined P = 6.2×10−5 for rs6701216; OR 1.45) and a region of LD at 15q21 (combined P = 2.9×10−5 for rs3803369; OR = 1.43). This region is of interest because it harbors ubiquitin-specific protease-8 whose processed pseudogene lies upstream from HLA-C. This region of 15q21 also harbors the gene for SPPL2A (signal peptide peptidase like 2a) which activates tumor necrosis factor alpha by cleavage, triggering the expression of IL12 in human dendritic cells. We also identified a novel PSA (and potentially PS) locus on chromosome 4q27. This region harbors the interleukin 2 (IL2) and interleukin 21 (IL21) genes and was recently shown to be associated with four autoimmune diseases (Celiac disease, Type 1 diabetes, Grave's disease and Rheumatoid Arthritis)

Through a Glass, Darkly:The CIA and Oral History

This article broaches the thorny issue of how we may study the history of the CIA by utilizing oral history interviews. This article argues that while oral history interviews impose particular demands upon the researcher, they are particularly pronounced in relation to studying the history of intelligence services. This article, nevertheless, also argues that while intelligence history and oral history each harbour their own epistemological perils and biases, pitfalls which may in fact be pronounced when they are conjoined, the relationship between them may nevertheless be a productive one. Indeed, each field may enrich the other provided we have thought carefully about the linkages between them: this article's point of departure. The first part of this article outlines some of the problems encountered in studying the CIA by relating them to the author's own work. This involved researching the CIA's role in US foreign policy towards Afghanistan since a landmark year in the history of the late Cold War, 1979 (i.e. the year the Soviet Union invaded that country). The second part of this article then considers some of the issues historians must confront when applying oral history to the study of the CIA. To bring this within the sphere of cognition of the reader the author recounts some of his own experiences interviewing CIA officers in and around Washington DC. The third part then looks at some of the contributions oral history in particular can make towards a better understanding of the history of intelligence services and the CIA

Metacognitive ability correlates with hippocampal and prefrontal microstructure

The ability to introspectively evaluate our experiences to form accurate metacognitive beliefs, or insight, is an essential component of decision-making. Previous research suggests individuals vary substantially in their level of insight, and that this variation is related to brain volume and function, particularly in the anterior prefrontal cortex (aPFC). However, the neurobiological mechanisms underlying these effects are unclear, as qualitative, macroscopic measures such as brain volume can be related to a variety of microstructural features. Here we leverage a high-resolution (800 µm isotropic) multi-parameter mapping technique in 48 healthy individuals to delineate quantitative markers of in vivo histological features underlying metacognitive ability. Specifically, we examined how neuroimaging markers of local grey matter myelination and iron content relate to insight as measured by a signal-theoretic model of subjective confidence. Our results revealed a pattern of microstructural correlates of perceptual metacognition in the aPFC, precuneus, hippocampus, and visual cortices. In particular, we extend previous volumetric findings to show that right aPFC myeloarchitecture positively relates to metacognitive insight. In contrast, decreased myelination in the left hippocampus correlated with better metacognitive insight. These results highlight the ability of quantitative neuroimaging to reveal novel brainbehaviour correlates and may motivate future research on their environmental and developmental underpinnings

Identifying candidate genes affecting developmental time in Drosophila melanogaster: pervasive pleiotropy and gene-by-environment interaction

<p>Abstract</p> <p>Background</p> <p>Understanding the genetic architecture of ecologically relevant adaptive traits requires the contribution of developmental and evolutionary biology. The time to reach the age of reproduction is a complex life history trait commonly known as developmental time. In particular, in holometabolous insects that occupy ephemeral habitats, like fruit flies, the impact of developmental time on fitness is further exaggerated. The present work is one of the first systematic studies of the genetic basis of developmental time, in which we also evaluate the impact of environmental variation on the expression of the trait.</p> <p>Results</p> <p>We analyzed 179 co-isogenic single <it>P[GT1]-</it>element insertion lines of <it>Drosophila melanogaster </it>to identify novel genes affecting developmental time in flies reared at 25°C. Sixty percent of the lines showed a heterochronic phenotype, suggesting that a large number of genes affect this trait. Mutant lines for the genes <it>Merlin </it>and <it>Karl </it>showed the most extreme phenotypes exhibiting a developmental time reduction and increase, respectively, of over 2 days and 4 days relative to the control (a co-isogenic <it>P</it>-element insertion free line). In addition, a subset of 42 lines selected at random from the initial set of 179 lines was screened at 17°C. Interestingly, the gene-by-environment interaction accounted for 52% of total phenotypic variance. Plastic reaction norms were found for a large number of developmental time candidate genes.</p> <p>Conclusion</p> <p>We identified components of several integrated time-dependent pathways affecting egg-to-adult developmental time in <it>Drosophila</it>. At the same time, we also show that many heterochronic phenotypes may arise from changes in genes involved in several developmental mechanisms that do not explicitly control the timing of specific events. We also demonstrate that many developmental time genes have pleiotropic effects on several adult traits and that the action of most of them is sensitive to temperature during development. Taken together, our results stress the need to take into account the effect of environmental variation and the dynamics of gene interactions on the genetic architecture of this complex life-history trait.</p

Interrogating and Predicting Tolerated Sequence Diversity in Protein Folds: Application to E. elaterium Trypsin Inhibitor-II Cystine-Knot Miniprotein

Cystine-knot miniproteins (knottins) are promising molecular scaffolds for protein engineering applications. Members of the knottin family have multiple loops capable of displaying conformationally constrained polypeptides for molecular recognition. While previous studies have illustrated the potential of engineering knottins with modified loop sequences, a thorough exploration into the tolerated loop lengths and sequence space of a knottin scaffold has not been performed. In this work, we used the Ecballium elaterium trypsin inhibitor II (EETI) as a model member of the knottin family and constructed libraries of EETI loop-substituted variants with diversity in both amino acid sequence and loop length. Using yeast surface display, we isolated properly folded EETI loop-substituted clones and applied sequence analysis tools to assess the tolerated diversity of both amino acid sequence and loop length. In addition, we used covariance analysis to study the relationships between individual positions in the substituted loops, based on the expectation that correlated amino acid substitutions will occur between interacting residue pairs. We then used the results of our sequence and covariance analyses to successfully predict loop sequences that facilitated proper folding of the knottin when substituted into EETI loop 3. The sequence trends we observed in properly folded EETI loop-substituted clones will be useful for guiding future protein engineering efforts with this knottin scaffold. Furthermore, our findings demonstrate that the combination of directed evolution with sequence and covariance analyses can be a powerful tool for rational protein engineering

Multiple Loci within the Major Histocompatibility Complex Confer Risk of Psoriasis

Psoriasis is a common inflammatory skin disease characterized by thickened scaly red plaques. Previously we have performed a genome-wide association study (GWAS) on psoriasis with 1,359 cases and 1,400 controls, which were genotyped for 447,249 SNPs. The most significant finding was for SNP rs12191877, which is in tight linkage disequilibrium with HLA-Cw*0602, the consensus risk allele for psoriasis. However, it is not known whether there are other psoriasis loci within the MHC in addition to HLA-C. In the present study, we searched for additional susceptibility loci within the human leukocyte antigen (HLA) region through in-depth analyses of the GWAS data; then, we followed up our findings in an independent Han Chinese 1,139 psoriasis cases and 1,132 controls. Using the phased CEPH dataset as a reference, we imputed the HLA-Cw*0602 in all samples with high accuracy. The association of the imputed HLA-Cw*0602 dosage with disease was much stronger than that of the most significantly associated SNP, rs12191877. Adjusting for HLA-Cw*0602, there were two remaining association signals: one demonstrated by rs2073048 (p = 2×10−6, OR = 0.66), located within c6orf10, a potential downstream effecter of TNF-alpha, and one indicated by rs13437088 (p = 9×10−6, OR = 1.3), located 30 kb centromeric of HLA-B and 16 kb telomeric of MICA. When HLA-Cw*0602, rs2073048, and rs13437088 were all included in a logistic regression model, each of them was significantly associated with disease (p = 3×10−47, 6×10−8, and 3×10−7, respectively). Both putative loci were also significantly associated in the Han Chinese samples after controlling for the imputed HLA-Cw*0602. A detailed analysis of HLA-B in both populations demonstrated that HLA-B*57 was associated with an increased risk of psoriasis and HLA-B*40 a decreased risk, independently of HLA-Cw*0602 and the C6orf10 locus, suggesting the potential pathogenic involvement of HLA-B. These results demonstrate that there are at least two additional loci within the MHC conferring risk of psoriasis

Meta-Profiles of Gene Expression during Aging: Limited Similarities between Mouse and Human and an Unexpectedly Decreased Inflammatory Signature

Background: Skin aging is associated with intrinsic processes that compromise the structure of the extracellular matrix while promoting loss of functional and regenerative capacity. These processes are accompanied by a large-scale shift in gene expression, but underlying mechanisms are not understood and conservation of these mechanisms between humans and mice is uncertain. Results: We used genome-wide expression profiling to investigate the aging skin transcriptome. In humans, age-related shifts in gene expression were sex-specific. In females, aging increased expression of transcripts associated with T-cells, B-cells and dendritic cells, and decreased expression of genes in regions with elevated Zeb1, AP-2 and YY1 motif density. In males, however, these effects were contrasting or absent. When age-associated gene expression patterns in human skin were compared to those in tail skin from CB6F1 mice, overall human-mouse correspondence was weak. Moreover, inflammatory gene expression patterns were not induced with aging of mouse tail skin, and well-known aging biomarkers were in fact decreased (e.g., Clec7a, Lyz1 and Lyz2). These unexpected patterns and weak human-mouse correspondence may be due to decreased abundance of antigen presenting cells in mouse tail skin with age. Conclusions: Aging is generally associated with a pro-inflammatory state, but we have identified an exception to this pattern with aging of CB6F1 mouse tail skin. Aging therefore does not uniformly heighten inflammatory status across all mouse tissues. Furthermore, we identified both intercellular and intracellular mechanisms of transcriptome aging, including those that are sex- and species-specific

The importance of disease associations and concomitant therapy for the long-term management of psoriasis patients

It is well established that several inflammatory-type conditions, such as arthritis, diabetes, cardiovascular disease, and irritable bowel disease exist comorbidly and at an increased incidence in patients with psoriasis. Psoriasis and other associated diseases are thought to share common inflammatory pathways. Conditions such as these, with similar pathogenic mechanisms involving cytokine dysregulation, are referred to as immune-mediated inflammatory diseases (IMIDs). Considerable evidence for the genetic basis of cormobidities in psoriasis exists. The WHO has reported that the occurrence of chronic diseases, including IMIDs, are a rising global burden. In addition, conditions linked with psoriasis have been associated with increasing rates of considerable morbidity and mortality. The presence of comorbid conditions in psoriasis patients has important implications for clinical management. QoL, direct health care expenditures and pharmacokinetics of concomitant therapies are impacted by the presence of comorbid conditions. For example, methotrexate is contraindicated in hepatic impairment, while patients on ciclosporin should be monitored for kidney function. In addition, some agents, such as beta blockers, lithium, synthetic antimalarial drugs, NSAIDs and tetracycline antibiotics, have been implicated in the initiation or exacerbation of psoriasis. Consequently, collaboration between physicians in different specialties is essential to ensuring that psoriasis treatment benefits the patient without exacerbating associated conditions