Genome-wide association study with additional genetic and post-transcriptional analyses reveals novel regulators of plasma factor XI levels.

Coagulation factor XI (FXI) has become increasingly interesting for its role in pathogenesis of thrombosis. While elevated plasma levels of FXI have been associated with venous thromboembolism and ischemic stroke, its deficiency is associated with mild bleeding. We aimed to determine novel genetic and post-transcriptional plasma FXI regulators.We performed a genome-wide association study (GWAS) for plasma FXI levels, using novel data imputed to the 1000 Genomes reference panel. Individual GWAS analyses, including a total of 16,169 European individuals from the ARIC, GHS, MARTHA and PROCARDIS studies, were meta-analysed and further replicated in 2,045 individuals from the F5L family, GAIT2 and MEGA studies. Additional association with activated partial thromboplastin time (aPTT) was tested for the top SNPs. In addition, a study on the effect of miRNA on FXI regulation was performed using in silico prediction tools and in vitro luciferase assays.Three loci showed robust, replicating association with circulating FXI levels: KNG1 (rs710446, P-value = 2.07 × 10-302), F11 (rs4253417, P-value = 2.86 × 10-193), and a novel association in GCKR (rs780094, P-value = 3.56 ×10-09), here for the first time implicated in FXI regulation. The two first SNPs (rs710446 and rs4253417) also associated with aPTT. Conditional and haplotype analyses demonstrated a complex association signal, with additional novel SNPs modulating plasma FXI levels in both the F11 and KNG1 loci. Finally, eight miRNAs were predicted to bind F11 mRNA. Over-expression of either miR-145 or miR-181 significantly reduced the luciferase activity in cells transfected with a plasmid containing FXI-3'UTR.These results should open the door to new therapeutic targets for thrombosis prevention.

Long-range epigenetic regulation is conferred by genetic variation located at thousands of independent loci.

The interplay between genetic and epigenetic variation is only partially understood. One form of epigenetic variation is methylation at CpG sites, which can be measured as methylation quantitative trait loci (meQTL). Here we report that in a panel of lymphocytes from 1,748 individuals, methylation levels at 1,919 CpG sites are correlated with at least one distal (trans) single-nucleotide polymorphism (SNP) (P<3.2 × 10(-13); FDR<5%). These trans-meQTLs include 1,657 SNP-CpG pairs from different chromosomes and 262 pairs from the same chromosome that are >1 Mb apart. Over 90% of these pairs are replicated (FDR<5%) in at least one of two independent data sets. Genomic loci harbouring trans-meQTLs are significantly enriched (P<0.001) for long non-coding transcripts (2.2-fold), known epigenetic regulators (2.3-fold), piwi-interacting RNA clusters (3.6-fold) and curated transcription factors (4.1-fold), including zinc-finger proteins (8.75-fold). Long-range epigenetic networks uncovered by this approach may be relevant to normal and disease states.

Cautious enthusiasm about GWAS findings.

In this issue of Blood, Ma and colleagues report the first agnostic investigation by a genome-wide association study (GWAS) in search of genetic determinants of a variation in plasma plasminogen levels.

Health promotion research and practice require sound policy analysis models: the case of Quebec's Tobacco Act.

In this paper we illustrate how policy analysis models can deepen our understanding of the challenges facing health promoters advocating for policy change. Specifically we describe the factors underpinning the adoption of Québec's Tobacco Act (1998) and the role played by actors from governmental public health agencies (GPHAs). Data were collected through interviews (n=39), newspapers articles (n=569) and documents (n > 200) from GPHAs, NGOs, the Québec National Assembly, and opponents to the legislative measures. Data collection and analysis were based on Sabatier and Jenkins-Smith's Advocacy Coalition Framework (1999) and Lemieux's theorization of coalition structuring (1998). We explain the adoption of the Act by: (1) the broad recognition within the policy elite of the main parameters of tobacco use (i.e. lethality, addictive properties, and legitimacy of governmental intervention), (2) the impacts of a series of events (e.g. cigarette contraband crisis) that enabled tobacco control advocates to influence public debates, and the governmental agenda, (3) the critical contribution of a coalition of GPHAs pooling resources to address both the sanitary and economic aspects of the legislation while countering the opposition's strategy, and (4) the failure of the opponents to present an unified voice on the definition of the tobacco policy. This study illustrates the merits of applying a policy-change model to grasp the complexity of the process. Our findings call for the development of permanent policy analysis capabilities within public health agencies and for a broader scrutiny of the non-health-related dimensions of policy debates.

Healthy public policy A conceptual cognitive framework.

More than three decades ago, the report A New Perspective on the Health of Canadians (1974) highlighted the significance of other determinants than the healthcare system. The adoption of healthy public policy was identified in the Ottawa Charter (1986) as one of five strategies aiming to promote health. It must now be acknowledged that even if we have a better understanding of health determinants, the latter are not necessarily taken into consideration when developing public policies. The purpose of this paper is to help foster a better understanding of the healthy public policies by presenting a conceptual framework that is inspired by the Advocacy Coalition Framework developed by Sabatier and Jenkins-Smith (1999). On the one hand, this paper intends to show the relevance of the notion of subsystem of public policies in healthy public policy process. On the other, it aims to convince that it is necessary to channel the analysis around the decision-making process, the prospective evaluation of public policies and the knowledge transfer and appropriation process. Finally, the purpose of this paper is to contribute to the ongoing debate about the role of knowledge, values or beliefs in the formulation and adoption of public policies. After briefly summarizing the theoretical developments in studies on public policies, the logic and components of the ACF are introduced. The main criticisms regarding the ACF are then examined, followed by an introduction of the conceptual framework that is adapted to the reality of healthy public policies. The notions of the subsystem of public policy(ies), of process and of learning process are central to this framework.

Fighting a tobacco-tax rollback: a political analysis of the 1994 cigarette contraband crisis in Canada.

We identify factors that led a regional government (Quebec, Canada) to opt for a reduction of its tobacco tax to combat tobacco smuggling. Then we explore the fallout of Quebec's tobacco-tax rollback on its tobacco control policy. We conducted qualitative research using a case-study design and multiple sources of data. We applied the Advocacy Coalition Framework in respect of data collection and analysis. Advocates of the tobacco-tax rollback framed the contraband problem in a way that won the support of an array of actors. However, anti-tobacco activists succeeded in convincing the government to invest more in tobacco control. The new resources were instrumental in enhancing the activists' ability to promote legislative measures. Our approach sheds light on the tobacco industry's strategy to have governments reducing their tobacco tax. Quebec offers an example of how tobacco control activists can transform defeat into the cornerstone of a comprehensive tobacco control policy.

Multiple genome-wide analyses of smoking behavior in the Framingham Heart Study.

BACKGROUND: Cigarette smoking behavior may have a genetic basis. We assessed evidence for quantitative trait loci (QTLs) affecting the maximum number of cigarettes smoked per day, a trait meant to quantify this behavior, using data collected over 40 years as part of the Framingham Heart Study's original and offspring cohorts. RESULTS: Heritability was estimated to be approximately 21% using variance components (VC) methods (SOLAR), while oligogenic linkage and segregation analysis based on Bayesian Markov chain Monte Carlo (MCMC) methods (LOKI) estimated a mean of two large QTLs contributing approximately 28% and 20%, respectively, to the trait's variance. Genome-wide parametric (FASTLINK) and VC linkage analyses (SOLAR) revealed several LOD scores greater than 1.0, with peak LOD scores using both methods on chromosomes 2, 17, and 20; multi-point MCMC methods followed up on these chromosomes. The most robust linkage results were for a QTL between 65 and 84 cM on chromosome 20 with signals from multiple sex- and age-adjusted analyses including two-point LOD scores of 1.30 (parametric) and 1.07 (heritability = 0.17, VC) at 70.51 cM, a multi-point LOD score of 1.50 (heritability = 0.20, VC) at 84 cM, and an intensity ratio of 12.0 (MCMC) at 65 cM. CONCLUSION: Familial aggregation of the maximum number of cigarettes smoked per day was consistent with a genetic component to this behavior, and oligogenic segregation analyses using MCMC suggested two important QTLs. Linkage signals on chromosome 20 between 65 and 84 cM were seen using multiple analytical methods. No linkage result, however, met genome-wide statistical significance criteria, and the true relationship between these regions and smoking behavior remains unclear.