The Canadian Partnership for Tomorrow Project: a pan-Canadian platform for research on chronic disease prevention.

BACKGROUND: Understanding the complex interaction of risk factors that increase the likelihood of developing common diseases is challenging. The Canadian Partnership for Tomorrow Project (CPTP) is a prospective cohort study created as a population-health research platform for assessing the effect of genetics, behaviour, family health history and environment (among other factors) on chronic diseases. METHODS: Volunteer participants were recruited from the general Canadian population for a confederation of 5 regional cohorts. Participants were enrolled in the study and core information obtained using 2 approaches: attendance at a study assessment centre for all study measures (questionnaire, venous blood sample and physical measurements) or completion of the core questionnaire (online or paper), with later collection of other study measures where possible. Physical measurements included height, weight, percentage body fat and blood pressure. Participants consented to passive follow-up through linkage with administrative health databases and active follow-up through recontact. All participant data across the 5 regional cohorts were harmonized. RESULTS: A total of 307 017 participants aged 30-74 from 8 provinces were recruited. More than half provided a venous blood sample and/or other biological sample, and 33% completed physical measurements. A total of 709 harmonized variables were created; almost 25% are available for all participants and 60% for at least 220 000 participants. INTERPRETATION: Primary recruitment for the CPTP is complete, and data and biosamples are available to Canadian and international researchers through a data-access process. The CPTP will support research into how modifiable risk factors, genetics and the environment interact to affect the development of cancer and other chronic diseases, ultimately contributing evidence to reduce the global burden of chronic disease.

Metabolites Associated with Polygenic Risk of Breast Cancer.

While hundreds of germline genetic variants have been associated with breast cancer risk, the mechanisms underlying the impacts of most of these variants on breast cancer remain uncertain. Metabolomics may offer valuable insights into the mechanisms underlying genetic risks of breast cancer. Among 143 cancer-free female participants, we used linear regression analyses to explore associations between the genetic risk of breast cancer, as determined by a previously developed polygenic risk score (PRS) that included 266 single-nucleotide polymorphisms (SNPs), and 223 measures of metabolites obtained from blood samples using nuclear magnetic resonance (NMR). A false discovery rate of 10% was applied to account for multiple comparisons. PRS was statistically significantly associated with 45 metabolite measures. These were primarily measures of very low-density lipoproteins (VLDLs) and high-density lipoproteins (HDLs), including triglycerides, cholesterol, and phospholipids. For example, the strongest effect was observed with the percent ratio of medium VLDL triglycerides to total lipids (0.53 unit increase in mean-standardized ln-transformed percent ratio per unit increase in PRS; q = 0.1). While larger-scale studies are needed to confirm these results, this exploratory study presents biologically plausible findings that are consistent with previously reported associations between lipids and breast cancer risk. If confirmed, these lipids could be targeted for lifestyle and pharmaceutical interventions among women at increased genetic risk of breast cancer.

Analyses of associations with asthma in four asthma population samples from Canada and Australia.

Asthma, atopy, and related phenotypes are heterogeneous complex traits, with both genetic and environmental risk factors. Extensive research has been conducted and over hundred genes have been associated with asthma and atopy phenotypes, but many of these findings have failed to replicate in subsequent studies. To separate true associations from false positives, candidate genes need to be examined in large well-characterized samples, using standardized designs (genotyping, phenotyping and analysis). In an attempt to replicate previous associations we amalgamated the power and resources of four studies and genotyped 5,565 individuals to conduct a genetic association study of 93 previously associated candidate genes for asthma and related phenotypes using the same set of 861 single-nucleotide polymorphisms (SNPs), a common genotyping platform, and relatively harmonized phenotypes. We tested for association between SNPs and the dichotomous outcomes of asthma, atopy, atopic asthma, and airway hyperresponsiveness using a general allelic likelihood ratio test. No SNP in any gene reached significance levels that survived correction for all tested SNPs, phenotypes, and genes. Even after relaxing the usual stringent multiple testing corrections by performing a gene-based analysis (one gene at a time as if no other genes were typed) and by stratifying SNPs based on their prior evidence of association, no genes gave strong evidence of replication. There was weak evidence to implicate the following: IL13, IFNGR2, EDN1, and VDR in asthma; IL18, TBXA2R, IFNGR2, and VDR in atopy; TLR9, TBXA2R, VDR, NOD2, and STAT6 in airway hyperresponsiveness; TLR10, IFNGR2, STAT6, VDR, and NPSR1 in atopic asthma. Additionally we found an excess of SNPs with small effect sizes (OR < 1.4). The low rate of replication may be due to small effect size, differences in phenotypic definition, differential environmental effects, and/or genetic heterogeneity. To aid in future replication studies of asthma genes a comprehensive database was compiled and is available to the scientific community at http://genapha.icapture.ubc.ca/.

Metabolic profiling of adherence to diet, physical activity and body size recommendations for cancer prevention.

Maintaining a healthy body weight, eating well and being physically active lowers cancer risk by 30%. However, the biology underlying these relationships is not well understood. We examined cross-sectional associations between metabolites and cancer preventive behaviors as well as the relevance to cancer-related pathways among 120 participants (50% men, mean BMI 26.6 kg/m2, mean age 54 years) with no history of smoking or cancer. Participants completed questionnaires, physical measurements and provided blood samples. Non-targeted nuclear magnetic resonance captured 223 metabolite measures. Factor analysis was performed separately for amino acid, fatty acid and lipoprotein groups. Multivariable-adjusted linear regression was used to evaluate associations between cancer preventive recommendations and metabolite-containing factors (p-value < 0.05, false discovery rate <0.20). An inflammation-related metabolite (glycoprotein acetylation) loaded strongly on a factor that was associated with excess adiposity (body fat ≥25% (men) or ≥30% (women) ß (SE) = 0.74 (0.18)) and not meeting physical activity recommendations (ß (SE) = 0.40 (0.20)). Insulin sensitivity-related metabolites including monounsaturated and polyunsaturated fats were lower among participants not meeting recommendations for adiposity, fruits and vegetables and physical activity while branched chain amino acids were higher. Cancer preventive behaviors were associated with complex metabolic signatures, including alterations in pathways known to be involved in cancer pathogenesis.

Albumin resuscitation increases cardiomyocyte contractility and decreases nitric oxide synthase II expression in rat endotoxemia.

OBJECTIVE: Hypotension and hypoperfusion during septic shock may contribute to tissue hypoxia and the intramyocardial inflammatory response that results in myocardial dysfunction. Therefore, we hypothesized that crystalloid or colloid resuscitation may alter myocardial dysfunction. DESIGN: Randomized, controlled, prospective animal study. SETTING: University animal laboratory. SUBJECTS: Sprague-Dawley rats (250-300 g, n = 6/group). INTERVENTIONS: Rats received an intraperitoneal injection of 10 mg/kg lipopolysaccharide or control. One hour later, rats were randomized to intravenous resuscitation and received either 30 mL/kg normal saline, 10 mL/kg 10% pentastarch, 10 mL/kg 5% rat albumin, or no volume. MEASUREMENTS AND MAIN RESULTS: We measured fractional shortening of cardiomyocytes isolated 5 hrs after lipopolysaccharide or control injection. In separate identical experiments, we measured myocardial interleukin-6, macrophage inhibitory protein-2, and nitric oxide synthase II protein and messenger RNA expression. Control fractional shortening of 24.1 +/- 2.2% was decreased by lipopolysaccharide to 18.8 +/- 1.2% (p <.001). Volume resuscitation after lipopolysaccharide significantly improved fractional shortening (p <.001). In particular, albumin resuscitation increased fractional shortening to 23.5 +/- 0.9%, which was more than either saline (fractional shortening 20.1 +/- 1.7%,p <.01) or pentastarch (fractional shortening 21.4 +/- 0.9%,p <.01). Myocardial macrophage inhibitory protein-2 protein and interleukin-6 and macrophage inhibitory protein-2 messenger RNA expression and neutrophil content were elevated following lipopolysaccharide (p <.05) but were not altered by volume resuscitation. Myocardial nitric oxide synthase II protein and messenger RNA expression increased following lipopolysaccharide (p <.01) and decreased with albumin resuscitation. CONCLUSIONS: We conclude that following lipopolysaccharide injection, volume resuscitation improves cardiomyocyte fractional shortening. Albumin resuscitation is particularly beneficial in preventing reduced cardiomyocyte contractility, and this benefit may be related to an albumin-induced reduction in nitric oxide synthase II protein and messenger RNA expression following endotoxin injection.