Inequalities in cardiovascular disease mortality : the role of behavioural, physiological and social risk factors

Background: While the relationship between socioeconomic disadvantage and cardiovascular disease (CVD) is well established, the role that traditional cardiovascular risk factors play in this association remains unclear. We examined the association between education attainment and CVD mortality and the extent to which behavioural, social and physiological factors explained this relationship. Methods: Adults (n=38 355) aged 40-69 years living in Melbourne, Australia were recruited in 1990-1994. Subjects with baseline CVD risk factor data ascertained through questionnaire and physical measurement were followed for an average of 9.4 years with CVD deaths verified by review of medical records and autopsy reports. Results: CVD mortality was higher for those with primary education only compared to those who had completed tertiary education, with a hazard ratio (HR) of 1.66 (95% confidence interval [CI] 1.11-2.49) after adjustment for age, country of birth and gender. Those from the lowest educated group had a more adverse cardiovascular risk factor profile compared to the highest educated group, and adjustment for these risk factors reduced the HR to 1.18 (95% CI 0.78-1.77). In analysis of individual risk factors, smoking and waist circumference explained most of the difference in CVD mortality between the highest and lowest education groups. Conclusions: Most of the excess CVD mortality in lower socioeconomic groups can be explained by known risk factors, particularly smoking and overweight. While targeting cardiovascular risk factors should not divert efforts from addressing the underlying determinants of health inequalities, it is essential that known risk factors are addressed effectively among lower socioeconomic groups.

HABITAT : a longitudinal multilevel study of physical acitvity change in mid-aged adults

Purpose. To explore the role of the neighborhood environment in supporting walking Design. Cross sectional study of 10,286 residents of 200 neighborhoods. Participants were selected using a stratified two-stage cluster design. Data were collected by mail survey (68.5% response rate). Setting. The Brisbane City Local Government Area, Australia, 2007. Subjects. Brisbane residents aged 40 to 65 years. Measures. Environmental: street connectivity, residential density, hilliness, tree coverage, bikeways, and street lights within a one kilometer circular buffer from each resident’s home; and network distance to nearest river or coast, public transport, shop, and park. Walking: minutes in the previous week categorized as < 30 minutes, ≥ 30 < 90 minutes, ≥ 90 < 150 minutes, ≥ 150 < 300 minutes, and ≥ 300 minutes. Analysis. The association between each neighborhood characteristic and walking was examined using multilevel multinomial logistic regression and the model parameters were estimated using Markov chain Monte Carlo simulation. Results. After adjustment for individual factors, the likelihood of walking for more than 300 minutes (relative to <30 minutes) was highest in areas with the most connectivity (OR=1.93, 99% CI 1.32-2.80), the greatest residential density (OR=1.47, 99% CI 1.02-2.12), the least tree coverage (OR=1.69, 99% CI 1.13-2.51), the most bikeways (OR=1.60, 99% CI 1.16-2.21), and the most street lights (OR=1.50, 99% CI 1.07-2.11). The likelihood of walking for more than 300 minutes was also higher among those who lived closest to a river or the coast (OR=2.06, 99% CI 1.41-3.02). Conclusion. The likelihood of meeting (and exceeding) physical activity recommendations on the basis of walking was higher in neighborhoods with greater street connectivity and residential density, more street lights and bikeways, closer proximity to waterways, and less tree coverage. Interventions targeting these neighborhood characteristics may lead to improved environmental quality as well as lower rates of overweight and obesity and associated chromic disease.

A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease

Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03-1.21), P = 1.4 × 10(-8)]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis.

Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping

Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10−8). More than 70 prostate cancer susceptibility loci, explaining ~30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.

Fine-mapping identifies multiple prostate cancer risk loci on 5p15 some associating with TERT expression

Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease.

EUELC project : a multi-centre, multipurpose study to investigate early stage NSCLC, and to establish a biobank for ongoing collaboration

The European Early Lung Cancer (EUELC) project aims to determine if specific genetic alterations occurring in lung carcinogenesis are detectable in the respiratory epithelium. In order to pursue this objective, nonsmall cell lung cancer (NSCLC) patients with a very high risk of developing progressive lung cancer were recruited from 12 centres in eight European countries: France, Germany, southern Ireland, Italy, the Netherlands, Poland, Spain and the UK. In addition, NSCLC patients were followed up every 6 months for 36 months. A European Bronchial Tissue Bank was set up at the University of Liverpool (Liverpool, UK) to optimise the use of biological specimens. The molecular - pathological investigations were subdivided into specific work packages that were delivered by EUELC Partners. The work packages encompassed mutational analysis, genetic instability, methylation profiling, expression profiling utilising immunohistochemistry and chip-based technologies, as well as in-depth analysis of FHIT and RARβ genes, the telomerase catalytic subunit hTERT and genotyping of susceptibility genes in specific pathways. The EUELC project engendered a tremendous collaborative effort, and it enabled the EUELC Partners to establish protocols for assessing molecular biomarkers in early lung cancer with the view to using such biomarkers for early diagnosis and as intermediate end-points in future chemopreventive programmes. Copyright©ERS Journals Ltd 2009.

InterLACE : a new international collaboration for a Life course approach to women's reproductive health and chronic disease events.

Evidence from population-based studies of women increasingly points to the inter-related nature of reproductive health, lifestyle, and chronic disease risk. This paper describes the recently established International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease. InterLACE aims to advance the evidence base for women's health policy beyond associations from disparate studies by means of systematic and culturally sensitive synthesis of longitudinal data. Currently InterLACE draws on individual level data for reproductive health and chronic disease among 200,000 women from over thirteen studies of women's health in seven countries. The rationale for this multi-study research programme is set out in terms of a life course perspective to reproductive health. The research programme will build a comprehensive picture of reproductive health through life in relation to chronic disease risk. Although combining multiple international studies poses methodological challenges, InterLACE represents an invaluable opportunity to strength evidence to guide the development of timely and tailored preventive health strategies.

Hypoxia-inducible factor-1α in non small cell lung cancer: Relation to growth factor, protease and apoptosis pathways

Hypoxia-inducible factor (HIF)-1α is the regulatory subunit of HIF-1 that is stabilized under hypoxic conditions. Under different circumstances, HIF-1α may promote both tumorigenesis and apoptosis. There is conflicting data on the importance of HIF-1α as a prognostic factor. This study evaluated HIF-1α expression in 172 consecutive patients with stage I-IIIA non small cell lung cancer (NSCLC) using standard immunohistochemical techniques. The extent of HIF-1α nuclear immunostaining was determined using light microscopy and the results were analyzed using the median (5%) as a low cut-point and 60% as a high positive cut-point. Using the low cut-point, positive associations were found with epidermal growth factor receptor (EGFR; p = 0.01), matrix metalloproteinase (MMP)-9 (p = 0.003), membranous (p < 0.001) and perinuclear (p = 0.004) carbonic anhydrase (CA) IX, pS3 (p = 0.008), T-stage (p = 0.042), tumor necrosis (TN; p < 0.001) and squamous histology (p < 0.001). No significant association was found with Bcl-2 or either N- or overall TMN stage or prognosis. When the high positive cut-point was used, HIF-1α was associated with a poor prognosis (p = 0.034). In conclusion, the associations with EGFR, MMP-9, p53 and CA IX suggest that these factors may either regulate or be regulated by HIF-1α. The association with TN and squamous-type histology, which is relatively more necrotic than other NSCLC types, reflects the role of hypoxia in the regulation of HIF-1α. The prognostic data may reflect a change in the behavior of HIF-1α in increasingly hypoxic environments. © 2004 Wiley-Liss, Inc.

Tumour necrosis is an independent prognostic marker in non-small cell lung cancer : correlation with biological variables

Background Tumour necrosis (TN) is recognized to be a consequence of chronic cellular hypoxia. TN and hypoxia correlate with poor prognosis in solid tumours. Methods In a retrospective study the prognostic implications of the extent of TN was evaluated in non-small cell lung cancer (NSCLC) and correlated with clinicopathological variables and expression of epidermal growth factor receptor, Bcl-2, p53 and matrix metalloproteinase-9 (MMP-9). Tissue specimens from 178 surgically resected cases of stage I-IIIA NSCLC with curative intent were studied. The specimens were routinely processed, formalin-fixed and paraffin-embedded. TN was graded as extensive or either limited or absent by two independent observers; disagreements were resolved using a double-headed microscope. The degree of reproducibility was estimated by re-interpreting 40 randomly selected cases after a 4 month interval. Results Reproducibility was attained in 36/40 cases, Kappa score=0.8 P<0.001. TN correlated with T-stage (P=0.001), platelet count (P=0.004) and p53 expression (P=0.031). Near significant associations of TN with N-stage (P=0.063) and MMP-9 expression (P=0.058) were seen. No association was found with angiogenesis (P=0.98). On univariate (P=0.0016) and multivariate analysis (P=0.023) TN was prognostic. Conclusion These results indicate that extensive TN reflects an aggressive tumour phenotype in NSCLC and may improve the predictive power of the TMN staging system. The lack of association between TN and angiogenesis may be important although these variables were not evaluated on serial sections. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

The baby boomers and beyond report : physical activity levels of older Western Australians 2006

Participation in sufficient levels of physical activity provides significant health benefits, particularly in older adults. The monitoring of physical activity levels in the Western Australian population is therefore necessary for developing and implementing strategies and programs for increasing participation. The Premier’s Physical Activity Taskforce (PATF) conducted a survey in 2006 to measure physical activity levels among Western Australian adults to follow-up the 1999 and 2002 state physical activity surveys. There is now widespread agreement that many health problems of older life – including the onset of frailty and disability – can be postponed or delayed by adopting health-enhancing habits such as physical activity. Adults over 65 years are the most rapidly growing age group and will continue to rise as more persons turn 65. If older adults could be encouraged to be more active as they age, frailty and disability associated with falls would be reduced, and function and physical and mental health in older people would be improved thereby reducing the burden of disease and injury. Given that physical inactivity is one of the most important and modifiable risk factors contributing to ill health, particularly for people as they age, the overall aim of this study was to examine patterns of physical activity in those aged 45 years and over – referred to hereafter as baby boomers+ – in more detail.

The 10 Australian ecosystems most vulnerable to tipping points

We identify the 10 major terrestrial and marine ecosystems in Australia most vulnerable to tipping points, in which modest environmental changes can cause disproportionately large changes in ecosystem properties. To accomplish this we independently surveyed the coauthors of this paper to produce a list of candidate ecosystems, and then refined this list during a 2-day workshop. The list includes (1) elevationally restricted mountain ecosystems, (2) tropical savannas, (3) coastal floodplains and wetlands, (4) coral reefs, (5) drier rainforests, (6) wetlands and floodplains in the Murray-Darling Basin, (7) the Mediterranean ecosystems of southwestern Australia, (8) offshore islands, (9) temperate eucalypt forests, and (10) salt marshes and mangroves. Some of these ecosystems are vulnerable to widespread phase-changes that could fundamentally alter ecosystem properties such as habitat structure, species composition, fire regimes, or carbon storage. Others appear susceptible to major changes across only part of their geographic range, whereas yet others are susceptible to a large-scale decline of key biotic components, such as small mammals or stream-dwelling amphibians. For each ecosystem we consider the intrinsic features and external drivers that render it susceptible to tipping points, and identify subtypes of the ecosystem that we deem to be especially vulnerable. © 2011 Elsevier Ltd.

Fine-mapping the HOXB region detects common variants tagging a rare coding allele : evidence for synthetic association in prostate cancer

The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.

Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10−14, odds ratio = 0.86, 95% confidence interval = 0.82–0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.

A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer

Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.