Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma

Background: Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor. Methods We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry). Results We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively;P-value < 5x10(-8)) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84x10(-8)). Conclusions: These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk. Impact Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci

<i>Campylobacter</i> Colonization and Diversity in Young Turkeys in the Context of Gastrointestinal Distress and Antimicrobial Treatment

Young turkeys are vulnerable to undifferentiated gastrointestinal distress, including “irritable and crabby syndrome” (ICS), which compromises flock performance and is typically treated with a combination of penicillin and gentamicin (P/G). However, the effects of ICS and P/G treatment on Campylobacter remain poorly understood. We investigated the impact of ICS and P/G treatment on Campylobacter levels and diversity in four flocks from three turkey farms. Cecum and jejunum samples were analyzed weekly from day of hatch to week 4–5. All four flocks became colonized with multidrug resistant (MDR) Campylobacter jejuni and C. coli by week 2–3, and two developed ICS. ICS and P/G treatment did not significantly impact total Campylobacter levels or strain genotypes but impacted species and antimicrobial resistance (AMR) profiles. One flock was raised under antibiotic-free (ABF) conditions while another flock at the same farm was raised conventionally. The ABF flock did not develop ICS while its counterpart did. However, Campylobacter strains, AMR profiles and sequence types were generally shared between these two flocks. Our findings suggest that ICS and P/G treatment impacted Campylobacter population dynamics in commercial young turkey flocks, and that ABF flocks may become readily colonized by MDR strains from non-ABF flocks at the same farm

Campylobacter Colonization and Diversity in Young Turkeys in the Context of Gastrointestinal Distress and Antimicrobial Treatment

Young turkeys are vulnerable to undifferentiated gastrointestinal distress, including &ldquo;irritable and crabby syndrome&rdquo; (ICS), which compromises flock performance and is typically treated with a combination of penicillin and gentamicin (P/G). However, the effects of ICS and P/G treatment on Campylobacter remain poorly understood. We investigated the impact of ICS and P/G treatment on Campylobacter levels and diversity in four flocks from three turkey farms. Cecum and jejunum samples were analyzed weekly from day of hatch to week 4&ndash;5. All four flocks became colonized with multidrug resistant (MDR) Campylobacter jejuni and C. coli by week 2&ndash;3, and two developed ICS. ICS and P/G treatment did not significantly impact total Campylobacter levels or strain genotypes but impacted species and antimicrobial resistance (AMR) profiles. One flock was raised under antibiotic-free (ABF) conditions while another flock at the same farm was raised conventionally. The ABF flock did not develop ICS while its counterpart did. However, Campylobacter strains, AMR profiles and sequence types were generally shared between these two flocks. Our findings suggest that ICS and P/G treatment impacted Campylobacter population dynamics in commercial young turkey flocks, and that ABF flocks may become readily colonized by MDR strains from non-ABF flocks at the same farm

Metabolomic data presents challenges for epidemiological meta-analysis: a case study of childhood body mass index from the ECHO consortium

IntroductionMeta-analyses across diverse independent studies provide improved confidence in results. However, within the context of metabolomic epidemiology, meta-analysis investigations are complicated by differences in study design, data acquisition, and other factors that may impact reproducibility.ObjectiveThe objective of this study was to identify maternal blood metabolites during pregnancy (&gt; 24 gestational weeks) related to offspring body mass index (BMI) at age two years through a meta-analysis framework.MethodsWe used adjusted linear regression summary statistics from three cohorts (total N = 1012 mother-child pairs) participating in the NIH Environmental influences on Child Health Outcomes (ECHO) Program. We applied a random-effects meta-analysis framework to regression results and adjusted by false discovery rate (FDR) using the Benjamini-Hochberg procedure.ResultsOnly 20 metabolites were detected in all three cohorts, with an additional 127 metabolites detected in two of three cohorts. Of these 147, 6 maternal metabolites were nominally associated (P &lt; 0.05) with offspring BMI z-scores at age 2&nbsp;years in a meta-analytic framework including at least two studies: arabinose (Coefmeta = 0.40 [95% CI 0.10,0.70], Pmeta = 9.7 × 10-3), guanidinoacetate (Coefmeta = -&nbsp;0.28 [-&nbsp;0.54, -&nbsp;0.02], Pmeta = 0.033), 3-ureidopropionate (Coefmeta = 0.22 [0.017,0.41], Pmeta = 0.033), 1-methylhistidine (Coefmeta = -&nbsp;0.18 [-&nbsp;0.33, -&nbsp;0.04], Pmeta = 0.011), serine (Coefmeta = -&nbsp;0.18 [-&nbsp;0.36, -&nbsp;0.01], Pmeta = 0.034), and lysine (Coefmeta = -&nbsp;0.16 [-&nbsp;0.32, -&nbsp;0.01], Pmeta = 0.044). No associations were robust to multiple testing correction.ConclusionsDespite including three cohorts with large sample sizes (N &gt; 100), we failed to identify significant metabolite associations after FDR correction. Our investigation demonstrates difficulties in applying epidemiological meta-analysis to clinical metabolomics, emphasizes challenges to reproducibility, and highlights the need for standardized best practices in metabolomic epidemiology