Genome-wide association study and meta-analysis in multiple populations identifies new loci for peanut allergy and establishes C11orf30/EMSY as a genetic risk factor for food allergy.

BACKGROUND: Peanut allergy (PA) is a complex disease with both environmental and genetic risk factors. Previously, PA loci were identified in filaggrin (FLG) and HLA in candidate gene studies, and loci in HLA were identified in a genome-wide association study and meta-analysis. OBJECTIVE: We sought to investigate genetic susceptibility to PA. METHODS: Eight hundred fifty cases and 926 hyper-control subjects and more than 7.8 million genotyped and imputed single nucleotide polymorphisms (SNPs) were analyzed in a genome-wide association study to identify susceptibility variants for PA in the Canadian population. A meta-analysis of 2 phenotypes (PA and food allergy) was conducted by using 7 studies from the Canadian, American (n = 2), Australian, German, and Dutch (n = 2) populations. RESULTS: An SNP near integrin α6 (ITGA6) reached genome-wide significance with PA (P = 1.80 × 10-8), whereas SNPs associated with Src kinase-associated phosphoprotein 1 (SKAP1), matrix metallopeptidase 12 (MMP12)/MMP13, catenin α3 (CTNNA3), rho GTPase-activating protein 24 (ARHGAP24), angiopoietin 4 (ANGPT4), chromosome 11 open reading frame (C11orf30/EMSY), and exocyst complex component 4 (EXOC4) reached a threshold suggestive of association (P ≤ 1.49 × 10-6). In the meta-analysis of PA, loci in or near ITGA6, ANGPT4, MMP12/MMP13, C11orf30, and EXOC4 were significant (P ≤ 1.49 × 10-6). When a phenotype of any food allergy was used for meta-analysis, the C11orf30 locus reached genome-wide significance (P = 7.50 × 10-11), whereas SNPs associated with ITGA6, ANGPT4, MMP12/MMP13, and EXOC4 and additional C11orf30 SNPs were suggestive (P ≤ 1.49 × 10-6). Functional annotation indicated that SKAP1 regulates expression of CBX1, which colocalizes with the EMSY protein coded by C11orf30. CONCLUSION: This study identifies multiple novel loci as risk factors for PA and food allergy and establishes C11orf30 as a risk locus for both PA and food allergy. Multiple genes (C11orf30/EMSY, SKAP1, and CTNNA3) identified by this study are involved in epigenetic regulation of gene expression.

Association of a change in erythropoiesis-stimulating agent dose during hospitalization and subsequent hemoglobin levels and transfusions in hemodialysis patients.

BACKGROUND: Erythropoiesis-stimulating agent (ESA) doses are often increased in hospitalized dialysis patients in response to acute anemia with unknown consequences. We sought to determine whether increases in ESA dose during hospital admission were associated with changes in transfusion requirement and risk of exceeding recommended hemoglobin targets. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Linked administrative, laboratory, and blood transfusion data were used to identify a total of 700 hospitalizations involving 484 long-term hemodialysis patients between 2004 and 2008 in the Calgary Health Region, Canada. PREDICTOR: Change in ESA dose was determined by comparing the average weekly dose over the 6 weeks preceding admission to that administered during the 14 days following admission. OUTCOMES & MEASUREMENTS: Cox proportional hazards models adjusted for baseline patient characteristics were used to model the association between changes in ESA dose and outcomes, including exceeding recommended hemoglobin targets, receipt of blood transfusion, cardiovascular outcomes, and death. RESULTS: There was a significant increase in the risk of exceeding recommended hemoglobin targets as the ESA dose was increased by ≥40 µg/wk (equivalent darbepoetin alfa dose) above baseline (HR, 2.21; 95% CI, 1.19-4.10). However, an increase in ESA dose was not associated with reduced need for blood transfusion, risk of cardiovascular outcomes, or death. LIMITATIONS: Residual confounding by clinical events that may lead to changes in the management of patients and may have influenced the observed relationship between predictor and outcomes. CONCLUSIONS: Increasing the ESA dose at hospitalization in hemodialysis patients is associated with higher risk of exceeding recommended hemoglobin targets, but does not appear to be associated with the need for transfusion, risk of cardiovascular outcomes, or death.

The NLRP3 inflammasome promotes renal inflammation and contributes to CKD.

Inflammation significantly contributes to the progression of chronic kidney disease (CKD). Inflammasome-dependent cytokines, such as IL-1ß and IL-18, play a role in CKD, but their regulation during renal injury is unknown. Here, we analyzed the processing of caspase-1, IL-1ß, and IL-18 after unilateral ureteral obstruction (UUO) in mice, which suggested activation of the Nlrp3 inflammasome during renal injury. Compared with wild-type mice, Nlrp3(-/-) mice had less tubular injury, inflammation, and fibrosis after UUO, associated with a reduction in caspase-1 activation and maturation of IL-1ß and IL-18; these data confirm that the Nlrp3 inflammasome upregulates these cytokines in the kidney during injury. Bone marrow chimeras revealed that Nlrp3 mediates the injurious/inflammatory processes in both hematopoietic and nonhematopoietic cellular compartments. In tissue from human renal biopsies, a wide variety of nondiabetic kidney diseases exhibited increased expression of NLRP3 mRNA, which correlated with renal function. Taken together, these results strongly support a role for NLRP3 in renal injury and identify the inflammasome as a possible therapeutic target in the treatment of patients with progressive CKD.