A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus.

BACKGROUND: Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk. AIM: To identify CNVs associated with osteoporotic bone fracture risk. METHOD: We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies. RESULTS: A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p = 8.69 × 10(-5)). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p = 0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk. CONCLUSIONS: These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.

Social inequalities and mortality in Europe--results from a large multi-national cohort.

BACKGROUND: Socio-economic inequalities in mortality are observed at the country level in both North America and Europe. The purpose of this work is to investigate the contribution of specific risk factors to social inequalities in cause-specific mortality using a large multi-country cohort of Europeans. METHODS: A total of 3,456,689 person/years follow-up of the European Prospective Investigation into Cancer and Nutrition (EPIC) was analysed. Educational level of subjects coming from 9 European countries was recorded as proxy for socio-economic status (SES). Cox proportional hazard model's with a step-wise inclusion of explanatory variables were used to explore the association between SES and mortality; a Relative Index of Inequality (RII) was calculated as measure of relative inequality. RESULTS: Total mortality among men with the highest education level is reduced by 43% compared to men with the lowest (HR 0.57, 95% C.I. 0.52-0.61); among women by 29% (HR 0.71, 95% C.I. 0.64-0.78). The risk reduction was attenuated by 7% in men and 3% in women by the introduction of smoking and to a lesser extent (2% in men and 3% in women) by introducing body mass index and additional explanatory variables (alcohol consumption, leisure physical activity, fruit and vegetable intake) (3% in men and 5% in women). Social inequalities were highly statistically significant for all causes of death examined in men. In women, social inequalities were less strong, but statistically significant for all causes of death except for cancer-related mortality and injuries. DISCUSSION: In this European study, substantial social inequalities in mortality among European men and women which cannot be fully explained away by accounting for known common risk factors for chronic diseases are reported.

Educational level and risk of colorectal cancer in EPIC with specific reference to tumor location.

Existing evidence is inconclusive on whether socioeconomic status (SES) and educational inequalities influence colorectal cancer (CRC) risk, and whether low or high SES/educational level is associated with developing CRC. The aim of our study was to investigate the relationship between educational level and CRC. We studied data from 400,510 participants in the EPIC (European Prospective Investigation into Cancer and Nutrition) study, of whom 2,447 developed CRC (colon: 1,551, rectum: 896, mean follow-up 8.3 years). Cox proportional hazard regression analysis stratified by age, gender and center, and adjusted for potential confounders were used to estimate hazard ratios (HR) and 95% confidence intervals (95%CI). Relative indices of inequality (RII) for education were estimated using Cox regression models. We conducted separate analyses for tumor location, gender and geographical region. Compared with participants with college/university education, participants with vocational secondary education or less had a nonsignificantly lower risk of developing CRC. When further stratified for tumor location, adjusted risk estimates for the proximal colon were statistically significant for primary education or less (HR 0.73, 95%CI 0.57-0.94) and for vocational secondary education (HR 0.76, 95%CI 0.58-0.98). The inverse association between low education and CRC risk was particularly found in women and Southern Europe. These associations were statistically significant for CRC, for colon cancer and for proximal colon cancer. In conclusion, CRC risk, especially in the proximal colon, is lower in subjects with a lower educational level compared to those with a higher educational level. This association is most pronounced in women and Southern Europe.

Hepatocellular carcinoma risk factors and disease burden in a European cohort: a nested case-control study.

BACKGROUND: To date, no attempt has been made to systematically determine the apportionment of the hepatocellular carcinoma burden in Europe or North America among established risk factors. METHODS: Using data collected from 1992 to 2006, which included 4,409,809 person-years in the European Prospective Investigation into Cancer and nutrition (EPIC), we identified 125 case patients with hepatocellular carcinoma, of whom 115 were matched to 229 control subjects. We calculated odds ratios (ORs) for the association of documented risk factors for hepatocellular carcinoma with incidence of this disease and estimated their importance in this European cohort. RESULTS: Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (OR = 9.10, 95% confidence interval [CI] = 2.10 to 39.50 and OR = 13.36, 95% CI = 4.11 to 43.45, respectively), obesity (OR = 2.13, 95% CI = 1.06 to 4.29), former or current smoking (OR = 1.98, 95% CI = 0.90 to 4.39 and OR = 4.55, 95% CI = 1.90 to 10.91, respectively), and heavy alcohol intake (OR = 1.77, 95% CI = 0.73 to 4.27) were associated with hepatocellular carcinoma. Smoking contributed to almost half of all hepatocellular carcinomas (47.6%), whereas 13.2% and 20.9% were attributable to chronic HBV and HCV infection, respectively. Obesity and heavy alcohol intake contributed 16.1% and 10.2%, respectively. Almost two-thirds (65.7%, 95% CI = 50.6% to 79.3%) of hepatocellular carcinomas can be accounted for by exposure to at least one of these documented risk factors. CONCLUSIONS: Smoking contributed to more hepatocellular carcinomas in this Europe-wide cohort than chronic HBV and HCV infections. Heavy alcohol consumption and obesity also contributed to sizeable fractions of this disease burden. These contributions may be underestimates because EPIC volunteers are likely to be more health conscious than the general population.

Intake of whole grains in Scandinavia is associated with healthy lifestyle, socio-economic and dietary factors.

OBJECTIVE: To identify the dietary, lifestyle and socio-economic factors associated with the intake of whole grains (WG) in Norway, Sweden and Denmark. DESIGN: A cross-sectional study. SETTING: Subsample of the Scandinavian cohort 'HELGA' consisting of three prospective cohorts: The Norwegian Women and Cancer Study; The Northern Sweden Health and Disease Study; and the Danish Diet, Cancer and Health Study. SUBJECTS: A total of 8702 men and women aged 30-65 years. Dietary data are from one 24 h dietary recall and data on socio-economic status and lifestyle factors including anthropometric values are from the baseline collection of data. RESULTS: Vegetables, fruits, dairy products, fish and shellfish, coffee, tea and margarine were directly associated with the intake of WG, whereas red meat, white bread, alcohol and cakes and biscuits were inversely associated. Smoking and BMI were consistently inversely associated with the intake of WG. Furthermore, length of education was directly associated with the intake of WG among women. CONCLUSIONS: The intake of WG was found to be directly associated with healthy diet, lifestyle and socio-economic factors and inversely associated with less healthy factors, suggesting that these factors are important for consideration as potential confounders when studying WG intake and disease associations.

The role of smoking and diet in explaining educational inequalities in lung cancer incidence.

BACKGROUND: Studies in many countries have reported higher lung cancer incidence and mortality in individuals with lower socioeconomic status. METHODS: To investigate the role of smoking in these inequalities, we used data from 391,251 participants in the European Prospective Investigation into Cancer and Nutrition study, a cohort of individuals in 10 European countries. We collected information on smoking (history and quantity), fruit and vegetable consumption, and education through questionnaires at study entry and gathered data on lung cancer incidence for a mean of 8.4 years. Socioeconomic status was defined as the highest attained level of education, and participants were grouped by sex and region of residence (Northern Europe, Germany, or Southern Europe). Relative indices of inequality (RIIs) of lung cancer risk unadjusted and adjusted for smoking were estimated using Cox regression models. Additional analyses were performed by histological type. RESULTS: During the study period, 939 men and 692 women developed lung cancer. Inequalities in lung cancer risk (RII(men) = 3.62, 95% confidence interval [CI] = 2.77 to 4.73, 117 vs 52 per 100,000 person-years for lowest vs highest education level; RII(women) = 2.39, 95% CI = 1.77 to 3.21, 46 vs 25 per 100,000 person-years) decreased after adjustment for smoking but remained statistically significant (RII(men) = 2.29, 95% CI = 1.75 to 3.01; RII(women) = 1.59, 95% CI = 1.18 to 2.13). Large RIIs were observed among men and women in Northern European countries and among men in Germany, but inequalities in lung cancer risk were reverse (RIIs < 1) among women in Southern European countries. Inequalities differed by histological type. Adjustment for smoking reduced inequalities similarly for all histological types and among men and women in all regions. In all analysis, further adjustment for fruit and vegetable consumption did not change the estimates. CONCLUSION: Self-reported smoking consistently explains approximately 50% of the inequalities in lung cancer risk due to differences in education.

Population-wide changes in reported lifestyle are associated with redistribution of adipose tissue.

AIMS: The Northern Sweden MONICA project 1986-2004 demonstrated a marked increase in average body mass, an unchanged prevalence of diabetes, and a decrease in myocardial infarctions and lately also in stroke. This study estimates the relative importance of time-trends in lifestyle on average waist and hip circumference on a population level. METHODS: From a series of independent cross-sectional surveys, a study population of 2,831 men and 2,976 women was formed. Associations between lifestyle factors and waist and hip circumference were estimated. Partial regression coefficients for every level of the lifestyle factors were multiplied by the differences in the proportion of the population reporting the corresponding levels of the respective lifestyle factors in 1986 and 2004. The sum of the product terms for each item represents the respective estimated impact of change in waist and hip circumference. RESULTS: Lifestyle trends associated with changes in hip circumference were (women/men): higher education level (+4.0 mm/+2.4 mm), fewer smokers (+0.4 mm/+0.9 mm), a slight increase in alcohol consumption (+0.4 mm/+0.3 mm), and more saturated fat from meat in women (-0.9 mm) and more fibre from grains in men (+0.6 mm). Average waist circumference was influenced by increased levels of physical activity (-2.2 mm/-4.6 mm), fewer female smokers (-0.3 mm), and a higher intake of saturated fatty acids from meat among men (+1.8 mm). CONCLUSIONS: We identified physical activity and the intake of meat and whole-grain products as prime candidates for lifestyle interventions in northern Sweden.

Trends in lifestyle 1986-99 in a 25- to 64-year-old population of the Northern Sweden MONICA project.

AIMS: The authors explore the time trends in lifestyle factors in the Northern Sweden MONICA population, including physical activity, intake of certain foods, coffee and alcohol consumption, smoking, and the use of smokeless tobacco. METHODS: Four health surveys during a 14-year time span were compared (1986, 1990, 1994, and 1999). The participation rate in all surveys was high. A questionnaire with similar or comparable questions about lifestyle factors was used across all health surveys. RESULTS: A large variation was demonstrated in the consumption of saturated fat in dairy products across the surveys. The use of butter on bread and of 3% fat milk clearly declined in favour of using low-fat margarine and 1-1.5% fat milk. A decline in the intake of boiled or baked potatoes together with an increase in the intake of pasta and rice was demonstrated. There were no changes in leisure-time physical activity. The proportion of the population using tobacco was unaltered. In men, smoking declined during the period but simultaneously there was an increase in the use of smokeless tobacco. The use of "boiled" or Scandinavian coffee diminished and more frequent use of alcohol was seen, especially in men. CONCLUSION: Pronounced changes were seen in food consumption with a decrease in saturated fat intake, boiled coffee, and potatoes and an increase in alcohol, rice, and pasta consumption. No clear time trends were found in physical activity or in the use of tobacco.