An Analysis of Growth, Differentiation and Apoptosis Genes with Risk of Renal Cancer

We conducted a case-control study of renal cancer (987 cases and 1298 controls) in Central and Eastern Europe and analyzed genomic DNA for 319 tagging single-nucleotide polymorphisms (SNPs) in 21 genes involved in cellular growth, differentiation and apoptosis using an Illumina Oligo Pool All (OPA). A haplotype-based method (sliding window analysis of consecutive SNPs) was used to identify chromosome regions of interest that remained significant at a false discovery rate of 10%. Subsequently, risk estimates were generated for regions with a high level of signal and individual SNPs by unconditional logistic regression adjusting for age, gender and study center. Three regions containing genes associated with renal cancer were identified: caspase 1/5/4/12(CASP 1/5/4/12), epidermal growth factor receptor (EGFR), and insulin-like growth factor binding protein-3 (IGFBP3). We observed that individuals with CASP1/5/4/12 haplotype (spanning area upstream of CASP1 through exon 2 of CASP5) GGGCTCAGT were at higher risk of renal cancer compared to individuals with the most common haplotype (OR:1.40, 95% CI:1.10–1.78, p-value = 0.007). Analysis of EGFR revealed three strong signals within intron 1, particularly a region centered around rs759158 with a global p = 0.006 (GGG: OR:1.26, 95% CI:1.04–1.53 and ATG: OR:1.55, 95% CI:1.14–2.11). A region in IGFBP3 was also associated with increased risk (global p = 0.04). In addition, the number of statistically significant (p-value<0.05) SNP associations observed within these three genes was higher than would be expected by chance on a gene level. To our knowledge, this is the first study to evaluate these genes in relation to renal cancer and there is need to replicate and extend our findings. The specific regions associated with risk may have particular relevance for gene function and/or carcinogenesis. In conclusion, our evaluation has identified common genetic variants in CASP1, CASP5, EGFR, and IGFBP3 that could be associated with renal cancer risk

Building a Clinical Research Network in Trauma Orthopaedics: The Major Extremity Trauma Research Consortium (METRC)

OBJECTIVESLessons learned from battle have been fundamental to advancing the care of injuries that occur in civilian life. Equally important is the need to further refine these advances in civilian practice, so they are available during future conflicts. The Major Extremity Trauma Research Consortium (METRC) was established to address these needs.METHODSMETRC is a network of 22 core level I civilian trauma centers and 4 core military treatment centers-with the ability to expand patient recruitment to more than 30 additional satellite trauma centers for the purpose of conducting multicenter research studies relevant to the treatment and outcomes of orthopaedic trauma sustained in the military. Early measures of success of the Consortium pertain to building of an infrastructure to support the network, managing the regulatory process, and enrolling and following patients in multiple studies.RESULTSMETRC has been successful in maintaining the engagement of several leading, high volume, level I trauma centers that form the core of METRC; together they operatively manage 15,432 major fractures annually. METRC is currently funded to conduct 18 prospective studies that address 6 priority areas. The design and implementation of these studies are managed through a single coordinating center. As of December 1, 2015, a total of 4560 participants have been enrolled.CONCLUSIONSSuccess of METRC to date confirms the potential for civilian and military trauma centers to collaborate on critical research issues and leverage the strength that comes from engaging patients and providers from across multiple centers

Atlas of tissue- and developmental stage specific gene expression for the bovine insulin-like growth factor (IGF) system

The insulin-like growth factor (IGF) axis is fundamental for mammalian growth and development. However, no comprehensive reference data on gene expression across tissues and pre- and postnatal developmental stages are available for any given species. Here we provide systematic promoter- and splice variant specific information on expression of IGF system components in embryonic (Day 48), fetal (Day 153), term (Day 277, placenta) and juvenile (Day 365–396) tissues of domestic cow, a major agricultural species and biomedical model. Analysis of spatiotemporal changes in expression of IGF1, IGF2, IGF1R, IGF2R, IGFBP1-8 and IR genes, as well as lncRNAs H19 and AIRN, by qPCR, indicated an overall increase in expression from embryo to fetal stage, and decrease in expression from fetal to juvenile stage. The stronger decrease in expression of lncRNAs (average ―16-fold) and ligands (average ―12.1-fold) compared to receptors (average ―5.7-fold) and binding proteins (average ―4.3-fold) is consistent with known functions of IGF peptides and supports important roles of lncRNAs in prenatal development. Pronounced overall reduction in postnatal expression of IGF system components in lung (―12.9-fold) and kidney (―13.2-fold) are signatures of major changes in organ function while more similar hepatic expression levels (―2.2-fold) are evidence of the endocrine rather than autocrine/paracrine role of IGFs in postnatal growth regulation. Despite its rapid growth, placenta displayed a more stable expression pattern than other organs during prenatal development. Quantitative analyses of contributions of promoters P0-P4 to global IGF2 transcript in fetal tissues revealed that P4 accounted for the bulk of transcript in all tissues but skeletal muscle. Demonstration of IGF2 expression in fetal muscle and postnatal liver from a promoter orthologous to mouse and human promoter P0 provides further evidence for an evolutionary and developmental shift from placenta-specific P0-expression in rodents and suggests that some aspects of bovine IGF expression may be closer to human than mouse

Time to Peak Glucose and Peak C-Peptide During the Progression to Type 1 Diabetes in the Diabetes Prevention Trial and TrialNet Cohorts

OBJECTIVE To assess the progression of type 1 diabetes using time to peak glucose or C-peptide during oral glucose tolerance tests (OGTTs) in autoantibody-positive relatives of people with type 1 diabetes. RESEARCH DESIGN AND METHODS We examined 2-h OGTTs of participants in the Diabetes Prevention Trial Type 1 (DPT-1) and TrialNet Pathway to Prevention (PTP) studies. We included 706 DPT-1 participants (mean ± SD age, 13.84 ± 9.53 years; BMI Z-score, 0.33 ± 1.07; 56.1% male) and 3,720 PTP participants (age, 16.01 ± 12.33 years; BMI Z-score, 0.66 ± 1.3; 49.7% male). Log-rank testing and Cox regression analyses with adjustments (age, sex, race, BMI Z-score, HOMA-insulin resistance, and peak glucose/C-peptide levels, respectively) were performed. RESULTS In each of DPT-1 and PTP, higher 5-year diabetes progression risk was seen in those with time to peak glucose >30 min and time to peak C-peptide >60 min (P < 0.001 for all groups), before and after adjustments. In models examining strength of association with diabetes development, associations were greater for time to peak C-peptide versus peak C-peptide value (DPT-1: χ2 = 25.76 vs. χ2 = 8.62; PTP: χ2 = 149.19 vs. χ2 = 79.98; all P < 0.001). Changes in the percentage of individuals with delayed glucose and/or C-peptide peaks were noted over time. CONCLUSIONS In two independent at-risk populations, we show that those with delayed OGTT peak times for glucose or C-peptide are at higher risk of diabetes development within 5 years, independent of peak levels. Moreover, time to peak C-peptide appears more predictive than the peak level, suggesting its potential use as a specific biomarker for diabetes progression