Pablo Fernández-Navarro

Common Breast Cancer Susceptibility Variants in LSP1 and RAD51L1 Are Associated with Mammographic Density Measures that Predict Breast Cancer Risk

Background: Mammographic density adjusted for age and body mass index (BMI) is a heritable marker of breast cancer susceptibility. Little is known about the biologic mechanisms underlying the association between mammographic density and breast cancer risk. We examined whether common low-penetrance breast cancer susceptibility variants contribute to interindividual differences in mammographic density measures. Methods: We established an international consortium (DENSNP) of 19 studies from 10 countries, comprising 16,895 Caucasian women, to conduct a pooled cross-sectional analysis of common breast cancer susceptibility variants in 14 independent loci and mammographic density measures. Dense and nondense areas, and percent density, were measured using interactive-thresholding techniques. Mixed linear models were used to assess the association between genetic variants and the square roots of mammographic density measures adjusted for study, age, case status, BMI, and menopausal status. Results: Consistent with their breast cancer associations, the C-allele of rs3817198 in LSP1 was positively associated with both adjusted dense area (P = 0.00005) and adjusted percent density (P = 0.001), whereas the A-allele of rs10483813 in RAD51L1 was inversely associated with adjusted percent density (P = 0.003), but not with adjusted dense area (P = 0.07). Conclusion: We identified two common breast cancer susceptibility variants associated with mammographic measures of radiodense tissue in the breast gland. Impact: We examined the association of 14 established breast cancer susceptibility loci with mammographic density phenotypes within a large genetic consortium and identified two breast cancer susceptibility variants, LSP1-rs3817198 and RAD51L1-rs10483813, associated with mammographic measures and in the same direction as the breast cancer association. Cancer Epidemiol Biomarkers Prev; 21(7); 1156–. ©2012 AACR.

Health impact assessment of a reduction in ambient PM2.5 levels in Spain

BACKGROUND Health effects linked to exposure to high air pollutant levels have been described in depth, and many recent epidemiologic studies have also consistently reported positive associations between exposure to air pollutants at low concentrations (particularly PM(2.5)) and adverse health outcomes. OBJECTIVE To estimate the number of avoidable deaths associated with reducing PM(2.5) levels in Spain. MATERIALS AND METHODS For exposure assessment, we used the US Environmental Protection Agencys Community Multiscale Air Quality model to simulate air pollution levels with a spatial resolution of 18×18 km(2). Two different scenarios were compared, namely, a baseline 2004 scenario based on Spains National Emissions Inventory and a projected 2011 scenario in which a reduction in PM(2.5) was estimated on the basis of the benefits that might be attained if specific air quality policies were implemented. Using an 18×18 km(2) grid, air pollution data were estimated for the entire Iberian Peninsula, the Balearic Islands, Ceuta and Melilla. For these strata, crude all-cause mortality rates (ICD-10: A00-Y98) were then calculated for the over-30 and 25-74 age groups, taking into account the 2004 population figures corresponding to these same age groups, selected in accordance with the concentration-response functions (Pope CA 3rd, Burnett RT, Thun MJ, Calle EE, Krewski D, Ito K et al. Lung cancer, cardiopulmonary mortality, and long-term exposure to fine particulate air pollution. JAMA 2002; 287:1132-41; Laden F, Schwartz J, Speizer FE, Dockery DW. Reduction in fine particulate air pollution and mortality: extended follow-up of the Harvard Six Cities study. Am J Respir Crit Care Med 2006; 173:667-72.). Health impacts were assessed using the Environmental Benefits Mapping and Analysis Program (BenMAP). RESULTS Air quality improvement was defined as an average annual reduction of 0.7 μg/m(3) in PM(2.5) levels. Using long-term health impact assessment analysis, we estimated that 1720 (673-2760) all-cause deaths (6 per 100,000 population) in the over-30 age group and 1450 (780-2108) all-cause deaths (5 per 100,000 population) in the 25-74 age group could be prevented annually. CONCLUSIONS The results showed the potential benefits in general mortality which could be expected if pollution control policies were successfully implemented by 2011. A specifically adapted BenMAP could be used as a tool for estimating health impacts associated with changes in air pollution in Spain.

Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk

Mammographic density reflects the amount of stromal and epithelial tissues in relation to adipose tissue in the breast and is a strong risk factor for breast cancer. Here we report the results from meta-analysis of genome-wide association studies (GWAS) of three mammographic density phenotypes: dense area, non-dense area and percent density in up to 7,916 women in stage 1 and an additional 10,379 women in stage 2. We identify genome-wide significant (P<5×10−8) loci for dense area (AREG, ESR1, ZNF365, LSP1/TNNT3, IGF1, TMEM184B, SGSM3/MKL1), non-dense area (8p11.23) and percent density (PRDM6, 8p11.23, TMEM184B). Four of these regions are known breast cancer susceptibility loci, and four additional regions were found to be associated with breast cancer (P<0.05) in a large meta-analysis. These results provide further evidence of a shared genetic basis between mammographic density and breast cancer and illustrate the power of studying intermediate quantitative phenotypes to identify putative disease susceptibility loci.

Proximity to mining industry and cancer mortality

Mining installations are releasing toxic substances into the environment which could pose a health problem to populations in their vicinity. We sought to investigate whether there might be excess cancer-related mortality in populations residing in towns lying in the vicinity of Spanish mining industries governed by the Integrated Pollution Prevention and Control Directive, and the European Pollutant Release and Transfer Register Regulation, according to the type of extraction method used. An ecologic study was designed to examine municipal mortality due to 32 types of cancer, across the period 1997 through 2006. Population exposure to pollution was estimated on the basis of distance from town of residence to pollution source. Poisson regression models, using the Bayesian conditional autoregressive model proposed by Besag, York and Molliè and Integrated Nested Laplace Approximations for Bayesian inference, were used: to analyze risk of dying from cancer in a 5-kilometer zone around mining installations; effect of type of industrial activity; and to conduct individual analyses within a 50-kilometer radius of each installation. Excess mortality (relative risk, 95% credible interval) of colorectal cancer (1.097, 1.041-1.157), lung cancer (1.066, 1.009-1.126) specifically related with proximity to opencast coal mining, bladder cancer (1.106, 1.016-1.203) and leukemia (1.093, 1.003-1.191) related with other opencast mining installations, was detected among the overall population in the vicinity of mining installations. Other tumors also associated in the stratified analysis by type of mine, were: thyroid, gallbladder and liver cancers (underground coal installations); brain cancer (opencast coal mining); stomach cancer (coal and other opencast mining installations); and myeloma (underground mining installations). The results suggested an association between risk of dying due to digestive, respiratory, hematologic and thyroid cancers and proximity to Spanish mining industries. These associations were dependent on the type of mine.

Worldwide impact of economic cycles on suicide trends over 3 decades: Differences according to level of development. A mixed effect model study

Objectives To investigate the trends and correlations of gross domestic product (GDP) adjusted for purchasing power parity (PPP) per capita on suicide rates in 10 WHO regions during the past 30 years. Design Analyses of databases of PPP-adjusted GDP per capita and suicide rates. Countries were grouped according to the Global Burden of Disease regional classification system. Data sources World Banks official website and WHOs mortality database. Statistical analyses After graphically displaying PPP-adjusted GDP per capita and suicide rates, mixed effect models were used for representing and analysing clustered data. Results Three different groups of countries, based on the correlation between the PPP-adjusted GDP per capita and suicide rates, are reported: (1) positive correlation: developing (lower middle and upper middle income) Latin-American and Caribbean countries, developing countries in the South East Asian Region including India, some countries in the Western Pacific Region (such as China and South Korea) and high-income Asian countries, including Japan; (2) negative correlation: high-income and developing European countries, Canada, Australia and New Zealand and (3) no correlation was found in an African country. Conclusions PPP-adjusted GDP per capita may offer a simple measure for designing the type of preventive interventions aimed at lowering suicide rates that can be used across countries. Public health interventions might be more suitable for developing countries. In high-income countries, however, preventive measures based on the medical model might prove more useful.

Cancer mortality in towns in the vicinity of incinerators and installations for the recovery or disposal of hazardous waste

BACKGROUND Waste treatment plants release toxic emissions into the environment which affect neighboring towns. OBJECTIVES To investigate whether there might be excess cancer mortality in towns situated in the vicinity of Spanish-based incinerators and installations for the recovery or disposal of hazardous waste, according to the different categories of industrial activity. METHODS An ecologic study was designed to examine municipal mortality due to 33 types of cancer, across the period 1997-2006. Population exposure to pollution was estimated on the basis of distance from town of residence to pollution source. Using Besag-York-Mollié (BYM) regression models with Integrated Nested Laplace approximations for Bayesian inference, and Mixed Poisson regression models, we assessed the risk of dying from cancer in a 5-kilometer zone around installations, analyzed the effect of category of industrial activity, and conducted individual analyses within a 50-kilometer radius of each installation. RESULTS Excess cancer mortality (BYM model: relative risk, 95% credible interval) was detected in the total population residing in the vicinity of these installations as a whole (1.06, 1.04-1.09), and, principally, in the vicinity of incinerators (1.09, 1.01-1.18) and scrap metal/end-of-life vehicle handling facilities, in particular (1.04, 1.00-1.09). Special mention should be made of the results for tumors of the pleura (1.71, 1.34-2.14), stomach (1.18, 1.10-1.27), liver (1.18, 1.06-1.30), kidney (1.14, 1.04-1.23), ovary (1.14, 1.05-1.23), lung (1.10, 1.05-1.15), leukemia (1.10, 1.03-1.17), colon-rectum (1.08, 1.03-1.13) and bladder (1.08, 1.01-1.16) in the vicinity of all such installations. CONCLUSIONS Our results support the hypothesis of a statistically significant increase in the risk of dying from cancer in towns near incinerators and installations for the recovery or disposal of hazardous waste.

Differences in maternal and paternal age between Schizophrenia and other psychiatric disorders

Advanced parental age has been shown to increase offspring risk for a number of neuropsychiatric disorders including schizophrenia and Downs syndrome. Other psychiatric disorders have been less studied with respect to the effect of parental age on offspring risk. In this study we examine if advanced parental age increased risk for ICD-10 diagnoses. We hypothesized that advanced parental age would increase risk for offspring psychotic disorders and mental retardation but not other ICD-10 diagnoses. We examined follow-up data for 30,965 subjects treated in outpatient psychiatric facilities between 1980 and 2007. Subjects were younger than 18 years of age at their first outpatient visit. A comparison group was obtained from data on registered births in Spain from 1975. We compared parental age (maternal, paternal, combined) across diagnostic categories using ANOVA and logistic regression was used to estimate the risk of psychopathology in the offspring with advanced parental age (maternal, paternal, combined). Maternal and paternal ages were higher for subjects diagnosed with mental retardation. Risk for psychotic disorders showed a significant linear increase only with advancing maternal age, and not paternal age as is more often reported.

Time trends in municipal distribution patterns of cancer mortality in Spain

BackgroundNew disease mapping techniques widely used in small-area studies enable disease distribution patterns to be identified and have become extremely popular in the field of public health. This paper reports on trends in the geographical mortality patterns of the most frequent cancers in Spain, over a period of 20 years.MethodsWe studied the municipal spatial pattern of stomach, colorectal, lung, breast, prostate and urinary bladder cancer mortality in Spain across four quinquennia, spanning the period 1989-2008. Case data were broken down by town (8073 municipalities), period and sex. Expected cases for each town were calculated using reference rates for each five-year period. For map plotting purposes, smoothed municipal relative risks were calculated using the conditional autoregressive model proposed by Besag, York and Mollié, with independent data for each quinquennium. We evaluated the presence of spatial patterns in maps on the basis of models, calculating the variance in relative risk corresponding to the structured spatial component and the unstructured component, as well as the proportion of variance explained by the structured spatial component.ResultsThe mortality patterns observed for stomach, colorectal and lung cancer were maintained over the 20 years covered by the study. Prostate cancer and the tumours studied in women showed no defined spatial pattern, with the single exception of stomach cancer. The trend in spatial fractional variance indicated the possibility of a change in the spatial pattern in breast, bladder and colorectal cancer in women during the last five-year period. The paper goes on to discuss ways in which spatio-temporal data are depicted in the case of cancer, and review the risk factors that may possibly influence the respective tumours’ spatial patterns.ConclusionIn men, the marked geographical patterns of stomach, colorectal, lung and bladder cancer remained stable over time. Breast, colorectal and bladder cancer in women show signs of the possible appearance of a spatial pattern in Spain and should therefore be monitored.

Gastric cancer mortality trends in Spain, 1976-2005, differences by autonomous region and sex

BackgroundGastric cancer is the second leading cause of oncologic death worldwide. One of the most noteworthy characteristics of this tumors epidemiology is the marked decline reported in its incidence and mortality in almost every part of the globe in recent decades. This study sought to describe gastric cancer mortality time trends in Spains regions for both sexes.MethodsMortality data for the period 1976 through 2005 were obtained from the Spanish National Statistics Institute. Cases were identified using the International Classification of Diseases 9th and 10th revision (codes 151 and C16, respectively). Crude and standardized mortality rates were calculated by geographic area, sex, and five-year period. Joinpoint regression analyses were performed to ascertain whether changes in gastric cancer mortality trends had occurred, and to estimate the annual percent change by sex and geographic area.ResultsGastric cancer mortality decreased across the study period, with the downward trend being most pronounced in women and in certain regions situated in the interior and north of mainland Spain. Across the study period, there was an overall decrease of 2.90% per annum among men and 3.65% per annum among women. Generally, regions in which the rate of decline was sharpest were those that had initially registered the highest rates. However, the rate of decline was not constant throughout the study period: joinpoint analysis detected a shift in trend for both sexes in the early 1980s.ConclusionGastric cancer mortality displayed in both sexes a downward trend during the study period, both nationally and regionally. The different trend in rates in the respective geographic areas translated as greater regional homogeneity in gastric cancer mortality by the end of the study period. In contrast, rates in women fell more than did those in men. The increasing differences between the sexes could indicate that some risk factors may be modifying the sex-specific pattern of this tumor.

Leukemia-related mortality in towns lying in the vicinity of metal production and processing installations.

BACKGROUND Releases to the environment of toxic substances stemming from industrial metal production and processing installations can pose a health problem to populations in their vicinity. OBJECTIVES To investigate whether there might be excess leukemia-related mortality in populations residing in towns in the vicinity of Spanish metal industries included in the European Pollutant Emission Register. METHODS Ecologic study designed to examine mortality due to leukemia at a municipal level, during the period 1994-2003. Population exposure to pollution was estimated on the basis of distance from town of residence to pollution source. Using Poisson regression models, we analyzed: risk of dying from leukemia in a 5-kilometer zone around installations which had become operational prior to 1990; effect of pollution discharge route and type of industrial activity; and risk gradient within a 50-kilometer radius of such installations. RESULTS Excess mortality (relative risk, 95% confidence interval) was detected in the vicinity of pre-1990 installations (1.07, 1.02-1.13 in men; 1.05, 1.00-1.11 in women), with this being more elevated in the case of installations that released pollution to air versus water. On stratifying by type of industrial activity, statistically significant associations were also observed among women residing in the vicinity of galvanizing installations (1.58, 1.09-2.29) and surface-treatment installations using an electrolytic or chemical process (1.34, 1.10-1.62), which released pollution to air. There was an effect whereby risk increased with proximity to certain installations. CONCLUSIONS The results suggest an association between risk of dying due to leukemia and proximity to Spanish metal industries.