Genome-wide association studies have identified thousands of loci for common diseases, but, for the majority of these, the mechanisms underlying disease susceptibility remain unknown. Most associated variants are not correlated with protein-coding changes, suggesting that polymorphisms in regulatory regions probably contribute to many disease phenotypes. Here we describe the Genotype-Tissue Expression (GTEx) project, which will establish a resource database and associated tissue bank for the scientific community to study the relationship between genetic variation and gene expression in human tissues

Understanding the functional consequences of genetic variation, and how it affects complex human disease and quantitative traits, remains a critical challenge for biomedicine. We present an analysis of RNA sequencing data from 1641 samples across 43 tissues from 175 individuals, generated as part of the pilot phase of the Genotype-Tissue Expression (GTEx) project. We describe the landscape of gene expression across tissues, catalog thousands of tissue-specific and shared regulatory expression quantitative trait loci (eQTL) variants, describe complex network relationships, and identify signals from genome-wide association studies explained by eQTLs. These findings provide a systematic understanding of the cellular and biological consequences of human genetic variation and of the heterogeneity of such effects among a diverse set of human tissues.

Inflammatory cytokines play an important role in human immune responses to malarial disease. However, the role of these mediators in disease pathogenesis, and the relationship between host protection and injury remains unclear. A total of 248 cases of severe Plasmodium falciparum malaria among children aged 3 months to 14 years residing in Bandiagara, Mali, were matched to cases of uncomplicated malaria and healthy controls. Using modified World Health Organization criteria for defining severe malaria, we identified 100 cases of cerebral malaria (coma, seizure, and obtundation), 17 cases of severe anemia (hemoglobin, <5 g/dl), 18 cases combined cerebral malaria with severe anemia, and 92 cases with hyperparasitemia (asexual trophozoites, >500,000/mm3). Significantly elevated levels (given as geometric mean concentrations in picograms/milliliter) of interleukin-6 (IL-6; 485.2 versus 54.1; P = <0.001), IL-10 (1,099.3 versus 14.1; P = <0.001), tumor necrosis factor alpha (10.1 versus 7.7; P = <0.001), and IL-12(p70) (48.9 versus 31.3; P = 0.004) in serum were found in severe cases versus healthy controls. Significantly elevated levels of IL-6 (485.2 versus 141.0; P = <0.001) and IL-10 (1,099.3 versus 133.9; P = <0.001) were seen in severe malaria cases versus uncomplicated malaria controls. Cerebral malaria was associated with significantly elevated levels of IL-6 (754.5 versus 311.4; P = <0.001) and IL-10 (1,405.6 versus 868.6; P = 0.006) compared to severe malaria cases without cerebral manifestations. Conversely, lower levels of IL-6 (199.2 versus 487.6; P = 0.03) and IL-10 (391.1 versus 1,160.9; P = 0.002) were noted in children with severe anemia compared to severe malaria cases with hemoglobin at >5 g/dl. Hyperparasitemia was associated with significantly lower levels of IL-6 (336.6 versus 602.1; P = 0.002). These results illustrate the complex relationships between inflammatory cytokines and disease in P. falciparum malaria.

Aging is one of the most important biological processes and is a known risk factor for many age-related diseases in human. Studying age-related transcriptomic changes in tissues across the whole body can provide valuable information for a holistic understanding of this fundamental process. In this work, we catalogue age-related gene expression changes in nine tissues from nearly two hundred individuals collected by the Genotype-Tissue Expression (GTEx) project. In general, we find the aging gene expression signatures are very tissue specific. However, enrichment for some well-known aging components such as mitochondria biology is observed in many tissues. Different levels of cross-tissue synchronization of age-related gene expression changes are observed, and some essential tissues (e.g., heart and lung) show much stronger “co-aging” than other tissues based on a principal component analysis. The aging gene signatures and complex disease genes show a complex overlapping pattern and only in some cases, we see that they are significantly overlapped in the tissues affected by the corresponding diseases. In summary, our analyses provide novel insights to the co-regulation of age-related gene expression in multiple tissues; it also presents a tissue-specific view of the link between aging and age-related diseases.

Objective To assess the efficacy and safety of high‐purity synthetic trans‐capsaicin (CNTX‐4975) in patients with chronic moderate‐to‐severe osteoarthritis (OA)–associated knee pain. Methods In this phase II multicenter double‐blind study, patients ages 45–80 years who had stable knee OA were randomized in a 2:1:2 ratio to receive a single intraarticular injection of placebo, CNTX‐4975 0.5 mg, or CNTX‐4975 1.0 mg. The primary efficacy end point was area under the curve (AUC) for change from baseline in daily Western Ontario and McMaster Universities Osteoarthritis Index pain with walking score (range 0–10, 0 = none and 10 = extreme) through week 12. Secondary efficacy end points included a similar AUC analysis of outcomes in patients treated with CNTX‐4975 0.5 mg, and evaluations extending to 24 weeks. Results Efficacy was evaluated in 172 patients (placebo group, n = 69; CNTX‐4975 0.5 mg group, n = 33; CNTX‐4975 1.0 mg group, n = 70). At week 12, greater decreases in the AUC for the pain score were observed with CNTX‐4975 in the 0.5 mg and 1.0 mg groups versus placebo (0.5 mg group least squares mean difference [LSMD] −0.79, P = 0.0740; 1.0 mg group LSMD −1.6, P < 0.0001). Significant improvements were maintained at week 24 in the 1.0 mg group (LSMD −1.4, P = 0.0002). Treatment‐emergent adverse events were similar in the placebo and CNTX‐4975 1.0 mg groups. Conclusion In this study, CNTX‐4975 provided dose‐dependent improvement in knee OA–associated pain. CNTX‐4975 1.0 mg produced a significant decrease in OA knee pain through 24 weeks; CNTX‐4975 0.5 mg significantly improved pain at 12 weeks, but the effect was not evident at 24 weeks.

Understanding HLA-restricted adaptive host immunity to defined epitopes of malarial antigens may be required for the development of successful malaria vaccines. Fourteen epitopes of preerythrocytic malarial antigens known to mediate cytotoxic T-lymphocyte responses against target cells expressing HLA-A2-restricted epitopes were synthesized and pooled based on antigen: thrombospondin-related anonymous protein (TRAP), circumsporozoite protein (CSP), and export protein 1 (Exp-1) peptides. HLA-A2 supertype (*0201, *0202, *0205, *6802) peripheral blood mononuclear cells collected from 774 Malian children, aged 3 months to 14 years, with severe Plasmodium falciparum malaria matched to uncomplicated malaria or healthy controls were stimulated with the HLA-A2-restricted peptide pools. Significant gamma interferon production, determined by enzyme-linked immunospot assay to at least one of the three peptide pools, was observed in 24/58 (41%) of the severe malaria cases, 24/57 (42%) of the uncomplicated malaria cases, and 34/51 (67%) of the healthy controls. Significant lymphoproliferation to these peptides was observed in 12/44 (27%) of the severe malaria cases, 13/55 (24%) of the uncomplicated malaria cases, and 18/50 (36%) of the healthy controls. Responses to individual peptide pools were limited. These studies confirm the presence of adaptive cell-mediated immunity to preerythrocytic malaria antigens in volunteers from Mali and demonstrate that suballeles of the HLA-A2 supertype can effectively present antigenic epitopes. However, whether these immune responses to TRAP, CSP, and Exp-1 malarial proteins play a substantial role in protection remains a matter of controversy.Despite technological advances, malaria remains a major threat to worldwide health, and the mechanisms underlying protective immunity to the causative parasite remain largely undefined. Naturally acquired sterile malaria immunity appears to be uncommon although sterile immunity to Plasmodium spp. has been achieved in mice, monkeys, and humans after irradiated-sporozoite injection (8, 21, 26). Irradiatedsporozoite development is arrested at the level of the hepatocyte, abrogating processing to the erythrocytic stage of parasite development. Evidence points to major histocompatibility complex-restricted CD8 ϩ T-cell-mediated responses as being crucial in mediating immunity to malaria, though CD4 ϩ T cells, cytokines, and antibodies may act in concert to prevent disease (18,36).Due to the impracticality of immunizing humans with irradiated sporozoites and the difficulties of including wholelength malaria proteins in current vaccines, the use of epitopebased, preerythrocytic-stage malaria vaccines is being evaluated.HLA polymorphisms complicate this approach. The presence of heterozygous class I alleles, variation in HLA binding affinities, and parasite diversity to escape recognition greatly increase the complexity of developing a successful vaccine. Nevertheless, the importance of HLA haplotypes in protection from natural infection is indirectly demonst...

The original version of this Article contained a typographical error in the spelling of the author Jakob Goldmann which was incorrectly given as Jakob Goldman. This has now been corrected in both the PDF and HTML versions of the Article.

BackgroundOsteoarthritis causes joint pain, stiffness, and reduced function, leading to disability. CNTX-4975, a highly purified, synthetic trans-capsaicin, targets the transient receptor potential vanilloid 1, producing analgesia via reversible deactivation of end terminals of primary afferent pain fibers within the joint and capsule.ObjectivesThis 24-week dose-ranging study evaluated CNTX-4975 efficacy and safety in subjects with chronic, moderate to severe osteoarthritis-associated knee pain.MethodsSubjects aged 45–80 years with chronic knee osteoarthritis, stable moderate to severe knee pain, and intolerability to oral or intra-articular analgesics were randomized to a single injection of placebo, CNTX-4975 0.5 mg, or CNTX-4975 1.0 mg. The primary efficacy endpoint was the area under the curve (AUC) for change from baseline in daily Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A1 score through week 12. Least squares mean differences (LSMD) for CNTX-4975 vs placebo were calculated for the primary endpoint and the average weekly AUC WOMAC A1 scores using analysis of covariance. Additional efficacy endpoints, mean change from baseline in weekly WOMAC A1 score, WOMAC B stiffness subscale, and WOMAC C physical function subscale through week 24, were analyzed using a mixed model for repeated measures (MMRM). Statistical tests were 2-sided (alpha, P=0.10). Safety assessments included treatment-emergent adverse events (TEAEs).ResultsEfficacy was evaluated in 172 subjects (placebo, n=69; CNTX-4975 0.5 mg, n=33; CNTX-4975 1.0 mg, n=70). Mean WOMAC A1 pain scores at baseline were 7.4 (placebo), 7.2 (CNTX-4975 0.5 mg), and 7.2 (CNTX-4975 1.0 mg). In the primary efficacy analysis, significant improvements vs placebo in WOMAC A1 scores were observed at week 12 with CNTX-4975 0.5 mg (LSMD: −0.8; P=0.07) and CTNX-4975 1.0 mg (LSMD: −1.6; P<0.0001). Significant improvements vs placebo were also observed at week 24 with CNTX-4975 1.0 mg (LSMD: −1.35; P=0.0002). In the MMRM analysis, significant improvements in WOMAC A1 scores vs placebo were demonstrated with CNTX-4975 0.5 mg at week 12 (LSMD: −0.9; P=0.087) but not week 24 (LSMD: −0.5; P=0.41), and with CNTX-4975 1.0 mg at weeks 12 (LSMD: −1.5; P=0.0003) and 24 (LSMD: −0.9; P=0.067). CNTX-4975 1.0 mg significantly improved WOMAC B (LSMD: −2.5; P=0.0013) and WOMAC C scores vs placebo (LSMD: −18.3; P=0.004) at week 12. Numerically greater improvements were observed in WOMAC B and C at week 24, but differences were not significant (WOMAC B LSMD: −1.2; P=0.14; WOMAC C LSMD: −7.2; P=0.28). In the safety population, the incidence of TEAEs was 30% for placebo or CNTX-4975 1.0 mg, and 47% for CNTX-4975 0.5 mg at week 24. Most TEAEs were considered unrelated to study treatment. Arthralgia was the most common TEAE with CNTX-4975 1.0 mg (placebo, 5.7%; CNTX-4975 1.0 mg, 7.0%).ConclusionsA single injection of CNTX-4975 1.0 mg improved pain with walking, knee stiffness, and physical function, and was well tolerated in subjects with moderate to severe osteoarthriti...