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.

Validation of a case definition to define chronic dialysis using outpatient administrative data.

BACKGROUND: Administrative health care databases offer an efficient and accessible, though as-yet unvalidated, approach to studying outcomes of patients with chronic kidney disease and end-stage renal disease (ESRD). The objective of this study is to determine the validity of outpatient physician billing derived algorithms for defining chronic dialysis compared to a reference standard ESRD registry. METHODS: A cohort of incident dialysis patients (Jan. 1-Dec. 31, 2008) and prevalent chronic dialysis patients (Jan 1, 2008) was selected from a geographically inclusive ESRD registry and administrative database. Four administrative data definitions were considered: at least 1 outpatient claim, at least 2 outpatient claims, at least 2 outpatient claims at least 90 days apart, and continuous outpatient claims at least 90 days apart with no gap in claims greater than 21 days. Measures of agreement of the four administrative data definitions were compared to a reference standard (ESRD registry). Basic patient characteristics are compared between all 5 patient groups. RESULTS: 1,118,097 individuals formed the overall population and 2,227 chronic dialysis patients were included in the ESRD registry. The three definitions requiring at least 2 outpatient claims resulted in kappa statistics between 0.60-0.80 indicating "substantial" agreement. "At least 1 outpatient claim" resulted in "excellent" agreement with a kappa statistic of 0.81. CONCLUSIONS: Of the four definitions, the simplest (at least 1 outpatient claim) performed comparatively to other definitions. The limitations of this work are the billing codes used are developed in Canada, however, other countries use similar billing practices and thus the codes could easily be mapped to other systems. Our reference standard ESRD registry may not capture all dialysis patients resulting in some misclassification. The registry is linked to on-going care so this is likely to be minimal. The definition utilized will vary with the research objective.

The effect of nocturnal and conventional hemodialysis on markers of nutritional status: results from a randomized trial.

OBJECTIVE: More frequent dialysis may improve nutrition and remove dietary restrictions in hemodialysis (HD) patients. We present results from a trial comparing nutritional parameters between nocturnal hemodialysis (NHD) and conventional HD patients. METHODS: Patients were randomized to conventional thrice weekly HD or NHD for a 6-month study period. Dietary intake was recorded by patients using a 3-day food record at baseline and study exit. RESULTS: Of 51 patients, 23 completed baseline and exit food records and were included in the analysis. Although dietary intake of calcium, potassium, and lipids increased in the NHD group, serum levels of calcium and potassium remained within target limits. The majority of NHD subjects were able to reduce or discontinue their phosphate binders and maintain serum phosphate levels within target limits. Serum albumin improved among the NHD group (0.7 g/L) and declined for the conventional group (-1.6 g/L). None of the between group differences achieved statistical significance. CONCLUSIONS: As compared with conventional dialysis, NHD was associated with a nonstatistically significant increase in dietary intake for some nutrients, with maintenance of serum levels for potassium, calcium, and phosphorus. Whether increased dietary intake translates into improvement in morbidity and mortality remains to be determined.

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.

Association of Metabolic Markers with self-reported osteoarthritis among middle-aged BMI-defined non-obese individuals: a cross-sectional study.

BACKGROUND: Osteoarthritis (OA) is a chronic degenerative joint disease. While it is well-established that obesity affects OA through increased axial loading on the joint cartilage, the indirect effect of obesity through metabolic processes among the body mass index (BMI)-defined non-obese population, i.e., BMI < 30 kg/m2, is less known. Our goal was to evaluate the association of metabolic markers including body fat percentage (BF%), waist circumference, maximum weight gain during adulthood and serum creatinine with self-reported OA to establish if such measures offer additional information over BMI among the non-obese population between 40 and 65 years of age. METHODS: Cross-sectional data from two cycles of the Canadian Health Measures Survey (CHMS) in 2007-2009 and 2009-2011 were analyzed. Sex-specific logistic regression models were developed to evaluate the association of self-reported OA with metabolic markers. Models were separately adjusted for age, BMI categories and serum creatinine, and a stratified analysis across BM categories was performed. In a secondary analysis, we evaluated the association of self-reported OA, cardiovascular diseases and hypertension across BF% categories. RESULTS: Of 2462 individuals, 217 (8.8%) self-reported OA. After adjusting for age and BMI, those within BF%-defined overweight/obese category had 2.67 (95% CI: 1.32-3.51) and 2.11(95% CI: 1.38-3.21) times higher odds of reporting self-reported OA compared to those within BF%-defined athletic/acceptable category for females and males, respectively. BF% was also significantly associated with self-reported OA after adjusting for age and serum creatinine only among females (OR: 1.47, 95%CI: 1.12-1.84). Furthermore, among the BMI-defined overweight group, the age-adjusted odds of self-reported OA was significantly higher for overweight/obese BF% compared to athletic/acceptable BF% in both females and males. In a secondary analysis, we showed that the association of self-reported OA and hypertension/cardiovascular diseases is significantly higher among BF% overweight/obese (OR: 1.37, 95%CI: 1.19-3.09) compared to BF% athletic/acceptable (OR: 1.13, 95%CI: 0.87-2.82). CONCLUSION: Our results provide corroborating evidence for a relationship between body fat and OA in a population-based study, while no significant independent correlates were found between other metabolic markers and OA prevalence. Future investigation on the longitudinal relationship between BF and OA among this sub-population may inform targeted prevention opportunities.

Association of body mass index (BMI) and percent body fat among BMI-defined non-obese middle-aged individuals: Insights from a population-based Canadian sample.

OBJECTIVES: To evaluate the association between percent body fat (%BF) and body mass index (BMI) among BMI-defined non-obese individuals between 40 and 69 years of age using a population-based Canadian sample. DATA AND METHODS: Cross-sectional data from the Canadian Health Measures Survey (2007 and 2009) was used to select all middle-aged individuals with BMI < 30 kg/m2 (n = 2,656). %BF was determined from anthropometric skinfolds and categorized according to sex-specific equations. Association of other anthropometry measures and metabolic markers were evaluated across different %BF categories. Significance of proportions was evaluated using chi-squared and Bonferroni-adjusted Wald test. Diagnostic performance measures of BMI-defined overweight categories compared to those defined by %BF were reported. RESULTS: The majority (69%) of the sample was %BF-defined overweight/obese, while 55% were BMI-defined overweight. BMI category was not concordant with %BF classification for 30% of the population. The greatest discordance between %BF and BMI was observed among %BF-defined overweight/obese women (32%). Sensitivity and specificity of BMI-defined overweight compared to %BF-defined overweight/obese were (58%, 94%) among females and (82%, 59%) among males respectively. According to the estimated negative predictive value, if an individual is categorized as BMI-defined non-obese, he/she has a 52% chance of being in the %BF-defined overweight/obese category. CONCLUSION: Middle-aged individuals classified as normal by BMI may be overweight/obese based on measures of %BF. These individuals may be at risk for chronic diseases, but would not be identified as such based on their BMI classification. Quantifying %BF in this group could inform targeted strategies for disease prevention.

A cluster randomized trial of an enhanced eGFR prompt in chronic kidney disease.

BACKGROUND AND OBJECTIVES: Despite reporting estimated GFR (eGFR), use of evidence-based interventions in CKD remains suboptimal. This study sought to determine the effect of an enhanced eGFR laboratory prompt containing specific management recommendations, compared with standard eGFR reporting in CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A cluster randomized trial of a standard or enhanced eGFR laboratory prompt was performed in 93 primary care practices in Alberta, Canada. Although all adult patients with CKD (eGFR <60 ml/min per 1.73 m(2)) were included, medication data were only available for elderly patients (aged ≥66 years). The primary outcome, the proportion of patients with diabetes or proteinuria receiving an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB), was assessed in elderly CKD patients. RESULTS: There were 5444 elderly CKD patients with diabetes or proteinuria who were eligible for primary outcome assessment, irrespective of baseline ACEi/ARB use. ACEi/ARB use in the subsequent year was 77.1% and 76.9% in the standard and enhanced prompt groups, respectively. In the subgroup of elderly patients with an eGFR <30 ml/min per 1.73 m(2), ACEi/ARB use was higher in the enhanced prompt group. Among 22,092 CKD patients, there was no difference in the likelihood of a composite clinical outcome (death, ESRD, doubling of serum creatinine, or hospitalization for myocardial infarction, heart failure, or stroke) over a median of 2.1 years. CONCLUSIONS: In elderly patients with CKD and an indication for ACEi/ARB, an enhanced laboratory prompt did not increase use of these medications.

Nocturnal hypoxia and loss of kidney function.

BACKGROUND: Although obstructive sleep apnea (OSA) is more common in patients with kidney disease, whether nocturnal hypoxia affects kidney function is unknown. METHODS: We studied all adult subjects referred for diagnostic testing of sleep apnea between July 2005 and December 31 2007 who had serial measurement of their kidney function. Nocturnal hypoxia was defined as oxygen saturation (SaO2) below 90% for ≥12% of the nocturnal monitoring time. The primary outcome, accelerated loss of kidney function, was defined as a decline in estimated glomerular filtration rate (eGFR) ≥4 ml/min/1.73 m(2) per year. RESULTS: 858 participants were included and followed for a mean study period of 2.1 years. Overall 374 (44%) had nocturnal hypoxia, and 49 (5.7%) had accelerated loss of kidney function. Compared to controls without hypoxia, patients with nocturnal hypoxia had a significant increase in the adjusted risk of accelerated kidney function loss (odds ratio (OR) 2.89, 95% confidence interval [CI] 1.25, 6.67). CONCLUSION: Nocturnal hypoxia was independently associated with an increased risk of accelerated kidney function loss. Further studies are required to determine whether treatment and correction of nocturnal hypoxia reduces loss of kidney function.