Explaining the genetics of many diseases is challenging because most associations localize to incompletely characterized regulatory regions. We show that transcription factors (TFs) occupy multiple loci of individual complex genetic disorders using novel computational methods. Application to 213 phenotypes and 1,544 TF binding datasets identifies 2,264 relationships between hundreds of TFs and 94 phenotypes, including AR in prostate cancer and GATA3 in breast cancer. Strikingly, nearly half of the systemic lupus erythematosus risk loci are occupied by the Epstein-Barr virus EBNA2 protein and many co-clustering human TFs, revealing gene-environment interaction. Similar EBNA2-anchored associations exist in multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis, and celiac disease. Instances of allele-dependent DNA binding and downstream effects on gene expression at plausibly causal variants support genetic mechanisms dependent upon EBNA2. Our results nominate mechanisms that operate across risk loci within disease phenotypes, suggesting new paradigms for disease origins.

The data presented support the view that follow-up liver biopsies, as recommended by published guidelines, for patients on long-term low-dose methotrexate can be avoided if PIIINP levels are consistently normal. This approach would have reduced the number of patients requiring biopsy in our series by 45%. The PIIINP assay will also be helpful in the management of patients on methotrexate in whom liver biopsy is contraindicated, and in patients with nonalcoholic steatohepatitis.

Biliary atresia is a fibroinflammatory obstruction of the extrahepatic biliary tree in neonates. While intrahepatic bile duct proliferation is universal at diagnosis, bile duct paucity develops later. We hypothesized that polarized T helper lymphocyte responses orchestrate progression of intrahepatic biliary injury in this disease. IL-17A-GFP, CD11c/DTR and IL17RA−/− mice were used to examine T-lymphocyte polarization, inflammatory leukocyte recruitment and biliary injury in rhesus-rotavirus induced biliary atresia. Multiparameter flow cytometry and automated image analysis of immunostaining were applied to liver tissue samples from infants with biliary atresia. In the mouse model, activated CD4+ lymphocytes started to emerge in the liver on day 8 after viral challenge while innate immune responses were waning. Plasma IL-17A levels rose concomitant with hepatic accumulation of Th17 lymphocytes and myeloid dendritic cells. Targeted depletion of CD11c+ dendritic cells diminished hepatic IL-17A production and ameliorated intrahepatic bile duct injury. Recombinant IL17A induced expression of CCL2 in neonatal cholangiocytes in vitro, and blockade of the corresponding chemokine receptor CCR2 reduced recruitment of inflammatory macrophages to the liver in vivo. Genetic disruption of IL-17A signaling was associated with downregulation of hepatic Ccl2/Ccr2 mRNA expression, reduced infiltration of the liver with inflammatory Ly6Chi macrophages and improved survival. In the liver of infants with biliary atresia, cholangiocytes were found to express IL-17 receptor A and the prevalence of IL-17A+ cells was positively correlated with the degree of CD68+ macrophage infiltration at diagnosis. Hepatic CD4+ lymphocytes were chief producers of IL-17A in patients with progressive disease undergoing liver transplantation. Conclusion Our findings identify the dendritic cell-Th17-macrophage axis as target for the development of strategies to block progression of intrahepatic bile duct injury in patients with biliary atresia.

Systemic Lupus Erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly-replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared to the non-risk allele of rs11889341. We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus triggered by immune hypersensitivity to food. Herein, we tested whether genetic risk factors for known, non-allergic, immune-mediated diseases, particularly those involving autoimmunity, were associated with EoE risk. We used the high-density Immunochip platform, encoding 200,000 genetic variants for major auto-immune disease. Accordingly, 1,214 subjects with EoE of European ancestry and 3,734 population controls were genotyped and assessed using data directly generated or imputed from the previously published GWAS. We found lack of association of EoE with the genetic variants in the major histocompatibility complex (MHC) class I, II, and III genes and nearly all other loci using a highly powered study design with dense genotyping throughout the locus. Importantly, we identified an EoE risk locus at 16p13 with genome-wide significance (Pcombined = 2.05 × 10−9, odds ratio = 0.76–0.81). This region is known to encode for the genes CLEC16A, DEXI, and CIITI, which are expressed in immune cells and esophageal epithelial cells. Suggestive EoE risk were also seen 5q23 (intergenic) and 7p15 (JAZF1). Overall, we have identified an additional EoE risk locus at 16p13 and highlight a shared and unique genetic etiology of EoE with a spectrum of immune-associated diseases.

CpG) award. M.T.W. is supported by the NIH (grant no. R01 NS099068), a Cincinnati Children's Research Foundation Endowed Scholar Award, and a CCHMC CpG award. M.E.R.'s work is funded by the NIH (grant nos. R37 AI045898, U19 AI070235, R01 AI057803, R01 HG010730, and R01 AR073228); the Campaign Urging Research for Eosinophilic Disease; and the Sunshine Charitable Foundation and its supporters, Denise and David Bunning. This study was originally funded by the Consortium of Food Allergy Researchers (COFAR, National Institute of Allergy and Infectious Diseases grant no. U19AI066738). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Disclosure of potential conflict of interest: V. Mukkada is a consultant for Shire, a Takeda company. T. Wen is a coinventor of the EoE diagnostic panel, a patent owned by Cincinnati Children's Hospital Medical Center, and serves as a consultant for NanoString Technologies, Inc, and a consultant committee member for GlaxoSmithKline. M. E. Rothenberg is a consultant for Pulm One, Spoon Guru, ClostraBio, Serpin Pharm, Allakos, Celgene, Astra Zeneca, Arena Pharmaceuticals, Guidepoint, and Suvretta Capital Management; has an equity interest in the first 5 listed and royalties from reslizumab (Teva Pharmaceuticals), PEESSv2 (Mapi Research Trust), and UpToDate; and is an inventor of patents owned by Cincinnati Children's Hospital Medical Center. The rest of the authors declare that they have no relevant conflicts of interest.

We report the association of eosinophilic esophagitis (EoE) and hypertrophic cardiomyopathy (HCM) and provide genetic data indicating a linkage between EoE and HCM. The letter begins with an index patient diagnosed with both EoE and HCM and found to have a known genetic mutation for HCM. We then identify an odds ratio of nearly 8 for having both EoE and HCM following review of an electronic medical record with >1,000,000 individuals. Finally, via a candidate gene approach we identify significant association of HCM gene variants in a cohort of EoE patients versus control subjects. Collectively, we have identified a putative interaction between EoE and HCM with clinical and pathogenic implications.

The effect of dose counter on rescue inhalers has not been studied in Medicaid children METHODS: Claims data for Medicaid HMO children were analyzed for effect of dose counters on ER utilization, hospital admissions and health care costs. Outcomes included hospital admissions/1000, ER visits/1000, health care costs. The potential cost savings from having a dose counter were calculated. RESULTS: ER visits without dose counter were 149.36 per 1000 and 101.44 per thousand with. Admissions per 1000 without dose counter were 7.91 per 1000 and with 4.36. Admissions were 81.6% higher without dose counter and ER Visits 47.2% higher without dose counter.