Comprehensive epigenomic profiling reveals the extent of disease-specific chromatin states and informs target discovery in ankylosing spondylitis.

Ankylosing spondylitis (AS) is a common, highly heritable inflammatory arthritis characterized by enthesitis of the spine and sacroiliac joints. Genome-wide association studies (GWASs) have revealed more than 100 genetic associations whose functional effects remain largely unresolved. Here, we present a comprehensive transcriptomic and epigenomic map of disease-relevant blood immune cell subsets from AS patients and healthy controls. We find that, while CD14+ monocytes and CD4+ and CD8+ T cells show disease-specific differences at the RNA level, epigenomic differences are only apparent upon multi-omics integration. The latter reveals enrichment at disease-associated loci in monocytes. We link putative functional SNPs to genes using high-resolution Capture-C at 10 loci, including PTGER4 and ETS1, and show how disease-specific functional genomic data can be integrated with GWASs to enhance therapeutic target discovery. This study combines epigenetic and transcriptional analysis with GWASs to identify disease-relevant cell types and gene regulation of likely pathogenic relevance and prioritize drug targets.

The effect of landscape and human settlement on the genetic differentiation and presence of Paragonimus species in Mesoamerica.

Foodborne diseases are a neglected research area, and despite the existence of many tools for diagnosis and genetic studies, very little is known about the effect of the landscape on the genetic diversity and presence of parasites. One of these foodborne disease is paragonimiasis, caused by trematodes of the genus Paragonimus, which is responsible for a high number of infections in humans and wild animals. The main Paragonimus sp reported in Mesoamerica is Paragonimus mexicanus, yet there are doubts about its correct identification as a unique species throughout the region. This, together with a lack of detailed knowledge about their ecology, evolution and differentiation, may complicate the implementation of control strategies across the Mesoamerican region. We had the goal of delimiting the species of P. mexicanus found throughout Mesoamerica and determining the effect of landscape and geology on the diversity and presence of the parasite. We found support for the delimitation of five genetic groups. The genetic differentiation among these groups was positively affected by elevation and the isolation of river basins, while the parasite's presence was affected negatively only by the presence of human settlements. These results suggest that areas with lower elevation, connected rivers basins, and an absence of human settlements have low genetic differentiation and high P. mexicanus presence, which may increase the risk of Paragonimus infection. These demonstrate the importance of accurate species delimitation and consideration of the effect of landscape on Paragonimus in the proposal of adequate control strategies. However, other landscape variables cannot be discarded, including temperature, rainfall regime, and spatial scale (local, landscape and regional). These additional variables were not explored here, and should be considered in future studies.

A genetics-led approach defines the drug target landscape of 30 immune-related traits.

Most candidate drugs currently fail later-stage clinical trials, largely due to poor prediction of efficacy on early target selection1. Drug targets with genetic support are more likely to be therapeutically valid2,3, but the translational use of genome-scale data such as from genome-wide association studies for drug target discovery in complex diseases remains challenging4-6. Here, we show that integration of functional genomic and immune-related annotations, together with knowledge of network connectivity, maximizes the informativeness of genetics for target validation, defining the target prioritization landscape for 30 immune traits at the gene and pathway level. We demonstrate how our genetics-led drug target prioritization approach (the priority index) successfully identifies current therapeutics, predicts activity in high-throughput cellular screens (including L1000, CRISPR, mutagenesis and patient-derived cell assays), enables prioritization of under-explored targets and allows for determination of target-level trait relationships. The priority index is an open-access, scalable system accelerating early-stage drug target selection for immune-mediated disease.

Translating GWAS in rheumatic disease: approaches to establishing mechanism and function for genetic associations with ankylosing spondylitis.

Ankylosing spondylitis (AS) is a highly heritable chronic inflammatory arthritis characterized by osteoproliferation, fusion of affected joints and systemic manifestations. Many disease associations for AS have been reported through genome-wide association studies; however, identifying modulated genes and functional mechanism remains challenging. This review summarizes current genetic associations involving AS and describes strategic approaches for functional follow-up of disease-associated variants. Fine mapping using methods leveraging Bayesian approaches are outlined. Evidence highlighting the importance of context specificity for regulatory variants is reviewed, noting current evidence in AS for the relevant cell and tissue type to conduct such analyses. Technological advances for understanding the regulatory landscape within which functional variants may act are discussed using exemplars. Approaches include defining regulatory elements based on chromatin accessibility, effects of variants on genes at a distance through evidence of physical interactions (chromatin conformation capture), expression quantitative trait loci mapping and single-cell methodologies. Opportunities for mechanistic studies to investigate the function of specific variants, regulatory elements and genes enabled by genome editing using clustered regularly interspaced short palindromic repeats/Cas9 are also described. Further progress in our understanding of the genetics of AS through functional genomic and epigenomic approaches offers new opportunities to understand mechanism and develop innovative treatments.

A multiplexed transcription activator-like effector system for detecting specific DNA sequences.

Transcription activator-like effectors (TALEs), originating from the Xanthomonas genus of bacteria, bind to specific DNA sequences based on amino acid sequence in the repeat-variable diresidue (RVD) positions of the protein. By altering these RVDs, it has been shown that a TALE protein can be engineered to bind virtually any DNA sequence of interest. The possibility of multiplexing TALEs for the purposes of identifying specific DNA sequences has yet to be explored. Here, we demonstrate a system in which a TALE protein bound to a nitrocellulose strip has been utilized to capture purified DNA, which is then detected using the binding of a second distinct TALE protein conjugated to a protein tag that is then detected by a dot blot. This system provides a signal only when both TALEs bind to their respective sequences, further demonstrating the specificity of the TALE binding.

Rural communities improving quality through collaboration: the MaineHealth story.

Small and rural communities face unique challenges in improving healthcare quality. To address these challenges, MaineHealth, an integrated health system serving small and rural communities, leveraged knowledge, resources, and data through collaboration to help providers improve care and outcomes for asthma, heart failure, diabetes, and depression. The programs emphasized patient self-care, used uniform clinical standards, and supported population-based data collection. This collaborative approach provided an effective way to achieve improved outcomes across a geographically and structurally diverse system, and it can help influence improvement efforts in other small and medium-sized rural communities.