Molecular cloning of cDNA encoding a novel platelet-endothelial cell tetra-span antigen, PETA-3

Platelet-endothelial cell tetra-span antigen (PETA-3) was originally identified as a novel human platelet surface glycoprotein, gp27, which was detected by a monoclonal antibody (MoAb), 14A2.H1. Although this glycoprotein is present in low abundance on the platelet surface, MoAb 14A2.H1 stimulates platelet aggregation and mediator release. We now report isolation of a cDNA clone encoding PETA-3 from a library derived from the megakaryoblastic leukemia cell line MO7e. The clone encodes an open reading frame of 253 amino acids that displays 25% to 30% amino acid sequence identity with several members of the newly defined Tetraspan, or Transmembrane 4 superfamily. These proteins consist of four conserved putative transmembrane domains with a large divergent extracellular loop between the third and fourth membrane-spanning regions. PETA-3 has a single consensus sequence for N-linked glycosylation located in this extracellular loop. A single PETA-3 RNA transcript (1.6 kb) was detected in RNA isolated from MO7e cells, bone marrow stromal cells, the C11 endothelial cell line, and several myeloid leukemia cell lines. No transcript was detected in the lymphoblastoid cell lines MOLT-4 and BALM-1. This pattern correlates well with previous protein expression data. Northern blot analysis of RNA from a range of human tissues indicated that the transcript was present in most tissues, the notable exception being brain.Stephen Fitter, Tim J. Tetaz, Michael C. Berndt, and Leonie K. Ashma

Neurology

Contains reports on six research projects.U. S. Public Health Service (B-3055-4, B-3090-4, MH-06175-02)U. S. Air Force (AF49(638)-1313)U.S. Navy. Office of Naval Research (Nonr-1841(70)

Defective removal of ribonucleotides from DNA promotes systemic autoimmunity

Genome integrity is continuously challenged by the DNA damage that arises during normal cell metabolism. Biallelic mutations in the genes encoding the genome surveillance enzyme ribonuclease H2 (RNase H2) cause Aicardi-Goutières syndrome (AGS), a pediatric disorder that shares features with the autoimmune disease systemic lupus erythematosus (SLE). Here we determined that heterozygous parents of AGS patients exhibit an intermediate autoimmune phenotype and demonstrated a genetic association between rare RNASEH2 sequence variants and SLE. Evaluation of patient cells revealed that SLE- and AGS-associated mutations impair RNase H2 function and result in accumulation of ribonucleotides in genomic DNA. The ensuing chronic low level of DNA damage triggered a DNA damage response characterized by constitutive p53 phosphorylation and senescence. Patient fibroblasts exhibited constitutive upregulation of IFN-stimulated genes and an enhanced type I IFN response to the immunostimulatory nucleic acid polyinosinic:polycytidylic acid and UV light irradiation, linking RNase H2 deficiency to potentiation of innate immune signaling. Moreover, UV-induced cyclobutane pyrimidine dimer formation was markedly enhanced in ribonucleotide-containing DNA, providing a mechanism for photosensitivity in RNase H2-associated SLE. Collectively, our findings implicate RNase H2 in the pathogenesis of SLE and suggest a role of DNA damage-associated pathways in the initiation of autoimmunity

The effects of conflict role and intensity on preschoolers’ expectations about peer conflict

Using a puppet procedure depicting hypothetical conflict involving the participant and a peer, 96 preschoolers’ (48 boys and 48 girls; M 1/4 5.14 years, SD 1/4 0.78 years) expectations about peer conflict were assessed as a function of their role in the conflict (i.e., initiator of or responder to initial provocation) and the intensity level of the conflict. Initiators of conflict expected less conflict escalation and subsequent problems with the same peer from the conflict than did responders, particularly following low-intensity conflict. Findings also indicated that, for low-intensity but not high-intensity conflict, girls expected the same peer to provoke them during a subsequent interaction more often than did boys. Results provide further support for assessing preschoolers’ understanding of conflict and are consistent with previous work demonstrating a self-serving bias in young children’s perceptions and reports of their conflicts with other children. Moreover, findings are discussed in terms of their implications for the development of peer relations.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Genetically Determined Height and Risk of Non-hodgkin Lymphoma

Although the evidence is not consistent, epidemiologic studies have suggested that taller adult height may be associated with an increased risk of some non-Hodgkin lymphoma (NHL) subtypes. Height is largely determined by genetic factors, but how these genetic factors may contribute to NHL risk is unknown. We investigated the relationship between genetic determinants of height and NHL risk using data from eight genome-wide association studies (GWAS) comprising 10,629 NHL cases, including 3,857 diffuse large B-cell lymphoma (DLBCL), 2,847 follicular lymphoma (FL), 3,100 chronic lymphocytic leukemia (CLL), and 825 marginal zone lymphoma (MZL) cases, and 9,505 controls of European ancestry. We evaluated genetically predicted height by constructing polygenic risk scores using 833 height-associated SNPs. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for association between genetically determined height and the risk of four NHL subtypes in each GWAS and then used fixed-effect meta-analysis to combine subtype results across studies. We found suggestive evidence between taller genetically determined height and increased CLL risk (OR = 1.08, 95% CI = 1.00\u20131.17, p = 0.049), which was slightly stronger among women (OR = 1.15, 95% CI: 1.01\u20131.31, p = 0.036). No significant associations were observed with DLBCL, FL, or MZL. Our findings suggest that there may be some shared genetic factors between CLL and height, but other endogenous or environmental factors may underlie reported epidemiologic height associations with other subtypes

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe

Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes

Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10−8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10−9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10−8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture