Jessica Dennis

The effects of provincial bicycle helmet legislation on helmet use and bicycle ridership in Canada

Background Bicycle helmet legislation has been variably implemented in six of 10 Canadian provinces. The objectives of this study were to determine the association between the comprehensiveness of helmet legislation and both helmet use and bicycle ridership. Methods Analysis of helmet use was based on data from the 2005 Canadian Community Health Survey (CCHS) and included respondents from three Canadian provinces (Saskatchewan, Ontario, and Nova Scotia). Analysis of bicycle use was based on data from the 2000–01, 2003, 2005, and 2007 cycles of the CCHS and included respondents from all provinces. In the time between the 2000–01 and 2007 cycles, two provinces (Prince Edward Island (PEI) and Alberta) implemented helmet legislation. Results Helmets were reportedly worn by 73.2% (95% CI 69.3% to 77.0%) of respondents in Nova Scotia, where legislation applies to all ages, by 40.6% (95% CI 39.2% to 42.0%) of respondents in Ontario, where legislation applies to those less than 18 years of age, and by 26.9% (95% CI 23.9% to 29.9%) of respondents in Saskatchewan, where no legislation exists. Though legislation applied to youth in both Ontario and Nova Scotia, helmet use was lower among youth in Ontario than among youth in Nova Scotia (46.7% (95% CI 44.1% to 49.4%) vs 77.5% (95% CI 70.9% to 84.1%)). Following the implementation of legislation in PEI and Alberta, recreational and commuting bicycle use remained unchanged among youth and adults. Conclusions Canadian youth and adults are significantly more likely to wear helmets as the comprehensiveness of helmet legislation increases. Helmet legislation is not associated with changes in ridership.

Helmet legislation and admissions to hospital for cycling related head injuries in Canadian provinces and territories: interrupted time series analysis

Objective To investigate the association between helmet legislation and admissions to hospital for cycling related head injuries among young people and adults in Canada. Design Interrupted time series analysis using data from the National Trauma Registry Minimum Data Set. Setting Canadian provinces and territories; between 1994 and 2003, six of 10 provinces implemented helmet legislation. Participants All admissions (n=66 716) to acute care hospitals in Canada owing to cycling related injury between 1994 and 2008. Main outcome measure Rate of admissions to hospital for cycling related head injuries before and after the implementation of provincial helmet legislation. Results Between 1994 and 2008, 66 716 hospital admissions were for cycling related injuries in Canada. Between 1994 and 2003, the rate of head injuries among young people decreased by 54.0% (95% confidence interval 48.2% to 59.8%) in provinces with helmet legislation compared with 33.1% (23.3% to 42.9%) in provinces and territories without legislation. Among adults, the rate of head injuries decreased by 26.0% (16.0% to 36.3%) in provinces with legislation but remained constant in provinces and territories without legislation. After taking baseline trends into consideration, however, we were unable to detect an independent effect of legislation on the rate of hospital admissions for cycling related head injuries. Conclusions Reductions in the rates of admissions to hospital for cycling related head injuries were greater in provinces with helmet legislation, but injury rates were already decreasing before the implementation of legislation and the rate of decline was not appreciably altered on introduction of legislation. While helmets reduce the risk of head injuries and we encourage their use, in the Canadian context of existing safety campaigns, improvements to the cycling infrastructure, and the passive uptake of helmets, the incremental contribution of provincial helmet legislation to reduce hospital admissions for head injuries seems to have been minimal.

The endothelial protein C receptor (PROCR) Ser219Gly variant and risk of common thrombotic disorders: a HuGE review and meta-analysis of evidence from observational studies

The endothelial protein C receptor (EPCR) limits thrombus formation by enhancing activation of the protein C anticoagulant pathway, and therefore may play a role in the etiology of thrombotic disorders. The rs867186 single-nucleotide polymorphism in the PROCR gene (g.6936A > G, c.4600A > G), resulting in a serine-to-glycine substitution at codon 219, has been associated with reduced activation of the protein C pathway, although its association with thrombosis risk remains unclear. The present study is a highly comprehensive systematic review and meta-analysis, including unpublished genome-wide association study results, conducted to evaluate the evidence for an association between rs867186 and 2 common thrombotic outcomes, venous thromboembolism (VTE) and myocardial infarction (MI), which are hypothesized to share some etiologic pathways. MEDLINE, EMBASE, and HuGE Navigator were searched through July 2011 to identify relevant epidemiologic studies, and data were summarized using random-effects meta-analysis. Twelve candidate genes and 13 genome-wide association studies were analyzed (11 VTE and 14 MI, including 37,415 cases and 84,406 noncases). Under the additive genetic model, the odds of VTE increased by a factor of 1.22 (95% confidence interval, 1.11-1.33, P < .001) for every additional copy of the G allele. No evidence for association with MI was observed.

Bias in the case-only design applied to studies of gene–environment and gene–gene interaction: a systematic review and meta-analysis

BACKGROUND The case-only study, proposed as a design specifically for assessing departure from multiplicative gene-environment and gene-gene interactions, is of considerable potential value but there are concerns about its validity. The objective of this study was to evaluate the extent and sources of bias in the case-only design by means of a systematic review and meta-regression analysis. METHODS The MEDLINE, CINAHL, EMBASE and PUBMED databases were searched through to 7 October 2009. Studies that assessed bias in the case-only design applied to the study of gene-environment and gene-gene interaction were identified. Qualitative comments on the sources and extent of bias were extracted. A meta-regression analysis of the ratio (IOR(CC)/IOR(CO)) of the case-control (IOR(CC)) and case-only (IOR(CO)) interaction odds ratios was conducted based on studies in which both methods were applied to the same data set. RESULTS The search yielded 365 unique articles of which 38 met the inclusion criteria. Potential sources of bias in the case-only design included non-independence of genotype and exposure in the source population. Meta-regression analysis, based on 24 evaluations, produced a mean IOR(CC)/IOR(CO) of 1.06 [95% confidence interval (95% CI) 0.93-1.22], suggesting that bias in case-only designs is not common in practice. The I(2) statistic indicated that 23.9% (95% uncertainty interval 0-53.9%) of the observed variation was due to heterogeneity between studies, which was not explained by any methodological characteristics of the included studies. CONCLUSION As understanding of the relationships between genes and environmental exposures in the population improves, the case-only design may prove to be of considerable value.

RFC1 80G>A Is a Genetic Determinant of Methotrexate Efficacy in Rheumatoid Arthritis: A Human Genome Epidemiologic Review and Meta‐Analysis of Observational Studies

Associations have been reported between candidate genes and the response to methotrexate (MTX) in rheumatoid arthritis (RA) patients, but most of the studies have been small and have yielded conflicting results. This study was undertaken to provide a systematic review of all genetic variant associations with MTX efficacy and toxicity, and to conduct a meta‐analysis evaluating the most commonly studied single‐nucleotide polymorphism for which prior cumulative analysis has been lacking.

Alcohol consumption and the risk of breast cancer among BRCA1 and BRCA2 mutation carriers

Alcohol consumption increases the risk of breast cancer among women in the general population, but its effect on women who carry a BRCA gene mutation is unclear. We conducted a case-control study of 1925 matched pairs of predominantly premenopausal women who carry a BRCA1 or a BRCA2 mutation. Information on current alcohol consumption was obtained from a questionnaire administered during the course of genetic counselling or at the time of enrollment. A modest inverse association between breast cancer and reported current alcohol consumption was observed among women with a BRCA1 mutation (OR = 0.82, 95% CI 0.70-0.96), but not among women with a BRCA2 mutation (OR = 1.00; 95% CI 0.71-1.41). Compared to non-drinkers, exclusive consumption of wine was associated with a significant reduction in the risk of breast cancer among BRCA1 carriers (p-trend = 0.01). Alcohol consumption does not appear to increase breast cancer risk in women carrying a BRCA gene mutation.

Breast Cancer Risk in Relation to Alcohol Consumption and BRCA Gene Mutations – A Case‐Only Study of Gene‐Environment Interaction

Abstract:  The variable penetrance of the BRCA1 and BRCA2 genes suggests that other genetic or environmental factors may interact with these mutations to modify breast cancer risk. The objective of this study was to measure departures from multiplicative effects of alcohol consumption and BRCA gene mutations. A cohort of French‐Canadian breast cancer patients was tested for BRCA gene mutations and completed a food frequency questionnaire. The case‐only odds ratio (COR) was calculated. A total of 857 women, including 10 BRCA1 and 33 BRCA2 mutation carriers, participated in the study. No significant interaction between alcohol consumption and BRCA1 mutations was detected, although the interaction with wine consumption suggested a sub‐multiplicative effect (COR = 0.38, 95% CI: 0.08–1.81). Consumption of alcohol other than wine interacted significantly with BRCA2 mutations (COR = 2.15, 95% CI: 1.03–4.49). Consumption of wine may protect against BRCA1‐associated tumors, while women with BRCA2 mutations may be at greater risk of alcohol‐induced breast cancer.

Bicycling injury hospitalisation rates in Canadian jurisdictions: analyses examining associations with helmet legislation and mode share

Objectives The purpose of this study was to calculate exposure-based bicycling hospitalisation rates in Canadian jurisdictions with different helmet legislation and bicycling mode shares, and to examine whether the rates were related to these differences. Methods Administrative data on hospital stays for bicycling injuries to 10 body region groups and national survey data on bicycling trips were used to calculate hospitalisation rates. Rates were calculated for 44 sex, age and jurisdiction strata for all injury causes and 22 age and jurisdiction strata for traffic-related injury causes. Inferential analyses examined associations between hospitalisation rates and sex, age group, helmet legislation and bicycling mode share. Results In Canada, over the study period 2006–2011, there was an average of 3690 hospitalisations per year and an estimated 593 million annual trips by bicycle among people 12 years of age and older, for a cycling hospitalisation rate of 622 per 100 million trips (95% CI 611 to 633). Hospitalisation rates varied substantially across the jurisdiction, age and sex strata, but only two characteristics explained this variability. For all injury causes, sex was associated with hospitalisation rates; females had rates consistently lower than males. For traffic-related injury causes, higher cycling mode share was consistently associated with lower hospitalisation rates. Helmet legislation was not associated with hospitalisation rates for brain, head, scalp, skull, face or neck injuries. Conclusions These results suggest that transportation and health policymakers who aim to reduce bicycling injury rates in the population should focus on factors related to increased cycling mode share and female cycling choices. Bicycling routes designed to be physically separated from traffic or along quiet streets fit both these criteria and are associated with lower relative risks of injury.

Genome-Wide Investigation of DNA Methylation Marks Associated with FV Leiden Mutation

In order to investigate whether DNA methylation marks could contribute to the incomplete penetrance of the FV Leiden mutation, a major genetic risk factor for venous thrombosis (VT), we measured genome-wide DNA methylation levels in peripheral blood samples of 98 VT patients carrying the mutation and 251 VT patients without the mutation using the dedicated Illumina HumanMethylation450 array. The genome-wide analysis of 388,120 CpG probes identified three sites mapping to the SLC19A2 locus whose DNA methylation levels differed significantly (p<3 10−8) between carriers and non-carriers. The three sites replicated (p<2 10−7) in an independent sample of 214 individuals from five large families ascertained on VT and FV Leiden mutation among which 53 were carriers and 161 were non-carriers of the mutation. In both studies, these three CpG sites were also associated (2.33 10−11<p<3.02 10−4) with biomarkers of the Protein C pathway known to be influenced by the FV Leiden mutation. A comprehensive linkage disequilibrium (LD) analysis of the whole locus revealed that the original associations were due to LD between the FV Leiden mutation and a block of single nucleotide polymorphisms (SNP) located in SLC19A2. After adjusting for this block of SNPs, the FV Leiden mutation was no longer associated with any CpG site (p>0.05). In conclusion, our work clearly illustrates some promises and pitfalls of DNA methylation investigations on peripheral blood DNA in large epidemiological cohorts. DNA methylation levels at SLC19A2 are influenced by SNPs in LD with FV Leiden, but these DNA methylation marks do not explain the incomplete penetrance of the FV Leiden mutation.

Blood triglyceride levels are associated with DNA methylation at the serine metabolism gene PHGDH.

Efficient interventions to reduce blood triglycerides are few; newer and more tolerable intervention targets are needed. Understanding the molecular mechanisms underlying blood triglyceride levels variation is key to identifying new therapies. To explore the role of epigenetic mechanisms on triglyceride levels, a blood methylome scan was conducted in 199 individuals from 5 French-Canadian families ascertained on venous thromboembolism, and findings were replicated in 324 French unrelated patients with venous thromboembolism. Genetic context and functional relevance were investigated. Two DNA methylation sites associated with triglyceride levels were identified. The first one, located in the ABCG1 gene, was recently reported, whereas the second one, located in the promoter of the PHGDH gene, is novel. The PHGDH methylation site, cg14476101, was found to be associated with variation in triglyceride levels in a threshold manner: cg14476101 was inversely associated with triglyceride levels only when triglyceride levels were above 1.12 mmol/L (discovery P-value = 8.4 × 10−6; replication P-value = 0.0091). Public databases findings supported a functional role of cg14476101 on PHGDH expression. PHGDH catalyses the first step in the serine biosynthesis pathway. These findings highlight the role of epigenetic regulation of the PHGDH gene in triglyceride metabolism, providing novel insights on putative intervention targets.