Two truncating variants in FANCC and breast cancer risk

Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95% CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.Peer reviewe

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape : A Large-Scale Genome-Wide Interaction Study

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, women 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.Peer reviewe

Ballistic-Limit Velocities for 7.62 mm APM2 Bullets and Aluminum Alloy Armor Plates

In a previous paper, we presented a scaling law for the ballistic-limit velocity for the 7.62 mm APM2 bullet and aluminum armor plates. This scaling law predicts that the ballistic-limit velocity is proportional to the square root of the product of plate thickness and a material strength term. In this note, we present additional ballistic data from the US Army Research Laboratory (ARL) and the Norwegian University of Science and Technology (NTNU) to show that this scaling law is accurate for eight aluminum alloys, plate thicknesses from 10 to 60 mm, and yield strengths from 51 to 414 MPa

Sedentary behaviour and risk of mortality from all-causes and cardiometabolic diseases in adults: evidence from the HUNT3 population cohort

Background: Sedentary behaviour is a potential risk factor for chronic-ill health and mortality, that is, independent of health-enhancing physical activity. Few studies have investigated the risk of mortality associated with multiple contexts of sedentary behaviour. Objective: To examine the prospective associations of total sitting time, TV-viewing time and occupational sitting with mortality from all causes and cardiometabolic diseases. Methods: Data from 50 817 adults aged ≥20 years from the Nord-Trøndelag Health Study 3 (HUNT3) in 2006-2008 were linked to the Norwegian Cause of Death Registry up to 31 December 2010. Cox proportional hazards models examined all-cause and cardiometabolic disease-related mortality associated with total sitting time, TV-viewing and occupational sitting, adjusting for multiple potential confounders including physical activity. Results: After mean follow-up of 3.3 years (137 315.8 person-years), 1068 deaths were recorded of which 388 were related to cardiometabolic diseases. HRs for all-cause mortality associated with total sitting time were 1.12 (95% CI 0.89 to 1.42), 1.18 (95% CI 0.90 to 1.57) and 1.65 (95% CI 1.24 to 2.21) for total sitting time 4-<7, 7-<10 and ≥10 h/day, respectively, relative to <4 h/day after adjusting for confounders ( p-trend=0.001). A similar pattern of associations was observed between total sitting time and mortality from cardiometabolic diseases, but TV-viewing time and occupational sitting showed no or borderline significant associations with all-cause or cardiometabolic disease-related mortality over the same follow-up period. Conclusions: Total sitting time is associated with all-cause and cardiometabolic disease-related mortality in the short term. However, prolonged sitting in specific contexts (ie, watching TV, at work) do not adversely impact health in the same timeframe. These findings suggest that adults should be encouraged to sit less throughout the day to reduce their daily total sitting time

Cross-sectional associations of total sitting and leisure screen time with cardiometabolic risk in adults. Results from the HUNT Study, Norway

Objectives: To examine associations of total sitting time, TV-viewing and leisure-time computer use with cardiometabolic risk biomarkers in adults. Design: Population based cross-sectional study. Methods: Waist circumference, BMI, total cholesterol, HDL cholesterol, blood pressure, non-fasting glucose, gamma glutamyltransferase (GGT) and triglycerides were measured in 48,882 adults aged 20 years or older from the Nord-Trøndelag Health Study 2006-2008 (HUNT3). Adjusted multiple regression models were used to test for associations between these biomarkers and self-reported total sitting time, TV-viewing and leisure-time computer use in the whole sample and by cardiometabolic disease status sub-groups. Results: In the whole sample, reporting total sitting time ≥10. h/day was associated with poorer BMI, waist circumference, total cholesterol, HDL cholesterol, diastolic blood pressure, systolic blood pressure, non-fasting glucose, GGT and triglyceride levels compared to those reporting total sitting time <4. h/day (all p<. 0.05). TV-viewing ≥4. h/day was associated with poorer BMI, waist circumference, total cholesterol, HDL cholesterol, systolic blood pressure, GGT and triglycerides compared to TV-viewing <. 1. h/day (all p<. 0.05). Leisure-time computer use ≥1. h/day was associated with poorer BMI, total cholesterol, diastolic blood pressure, GGT and triglycerides compared with those reporting no leisure-time computing. Sub-group analyses by cardiometabolic disease status showed similar patterns in participants free of cardiometabolic disease, while similar albeit non-significant patterns were observed in those with cardiometabolic disease. Conclusions: Total sitting time, TV-viewing and leisure-time computer use are associated with poorer cardiometabolic risk profiles in adults. Reducing sedentary behaviour throughout the day and limiting TV-viewing and leisure-time computer use may have health benefits. © 2013 Sports Medicine Australia

Exercício físico, desporto e função pulmonar em adolescentes fumadores versus não fumadores

RESUMO: A actividade física reduzida está, inequivocamente, associada a um aumento das taxas de morbilidade e mortalidade na idade adulta.Os autores estudaram a relação existente entre o tabagismo na adolescência e o exercício físico, assim como o papel da actividade desportiva na função pulmonar.Foram avaliados 8305 estudantes (idades 13-18 anos) do município de Nord-Trondelag, Noruega, submetidos a um inquérito pessoal abrangendo os hábitos tabágicos e a actividade física. Esta última foi classificada em três níveis: exercício eâ 4 dias//semana; exercício 2-3 dias/semana; exercício dâ 1 dia/semana; Os desportos individuais englobavam desportos de elevada endurance, como sejam o esqui, o ciclismo e a corrida, e de reduzida endurance de que são exemplo a equitação, a ginástica, a musculação, o boxe, o wrestling, o judo e o taekwondo. Constituem desportos de equipa o futebol, o andebol e o voleibol. Foram incluídos no grupo de fumadores os adolescentes com hábitos tabágicos diários ou ocasionais e considerados como fumadores passivos os estudantes expostos ao fumo do tabaco no núcleo familiar (progenitores, irmãos).Um mês após completarem o inquérito foram submetidos a um exame clínico que incluiu a determinação da altura e peso e a realização de espirometrias segundo os requisitos da American Thoracic Society. Foram avaliadas a CVF, VEMS, DEM50 e Ãndice de Tiffeneau. Todos os estudantes com Asma Brônquica (1005) foram excluídos.Cerca de 2993 adolescentes (41,0%) nunca fumaram e 1342 (18,4%) eram fumadores regulares (10% diários). Nos fumadores diários, a idade de início foi de 13,9 anos, tendo os hábitos tabágicos aumentado com a idade.A maioria dos estudantes (88%) exercia uma actividade desportiva, pelo menos, 2 dias por semana, fora da escola, sendo esta mais frequente no sexo masculino (p<0,001), com particular relevância para o desporto de competição.A prática de exercício físico estava inversamente relacionada com o tabagismo, sendo os desportos de reduzida endurance os preferidos pelos fumadores.O abandono da actividade desportiva ocorreu com maior incidência nos fumadores diários (53%) e ocasionais (43%) quando comparados com os não fumadores (26%), sendo a idade média desses indivíduos de 15 anos. Cerca de 35% iniciaram os hábitos tabágicos antes de cessarem a prática desportiva e 30% começaram a fumar no mesmo ano em que a abandonaram.Os adolescentes não fumadores (independentemente do sexo) que efectuavam desportos de competição apresentavam valores mais elevados de CVF, VEMS e DEM50 do que os jovens não praticantes (parâmetros ajustados tendo em atenção a frequência de exercício físico). Diferenças médias observadas no sexo masculino: CVF 95 ml (p=0,01), VEMS 11,3 ml (p<0,00 l), DEM50 155 ml (p=0,03); e no feminino: CVF 65 ml (p=0,04), VEMS 10 ml (p=0,03), DEM50 156 ml (p=0,02). Não se verificou, no entanto, uma correlação significativa equivalente nos fumadores. COMENTÃRIO: O tabagismo constitui um grave problema de saúde pública na actualidade. Assim, torna-se prioritário diminuir o número de novos fumadores entre a população adolescente. Quando os jovens entre os 13-14 anos experimentam o 1º cigarro, a maioria desconhece os malefícios a que se expõe. Entre as consequências a curto prazo encontram-se a adição à nicotina, a associação com outras toxicodependências e diversas patologias pulmonares e não pulmonares. As consequências a longo prazo são reforçadas pelo facto de os jovens fumadores regulares manterem os hábitos tabágicos na vida adulta.Os adolescentes representam um dos grupos populacionais mais permissivos à iniciação tabágica. Múltiplas variáveis contribuem para este facto: aceitabilidade social do tabagismo; fácil acesso aos cigarros; exposição e vulnerabilidade para o marketing e publicidade ao tabaco; importância do modelo dos progenitores e outros adultos; símbolo de autonomia e maturidade; pressão do grupo em que o jovem se insere.Holmen e colaboradores verificaram que a actividade física estava inversamente relacionada com os hábitos tabágicos e que existia uma correlação positiva entre o exercício e a função pulmonar. Estudos efectuados anteriormente nos EUA tinham evidenciado os mesmos resultados: adolescentes que praticavam, pelo menos, um desporto, tinham uma menor probabilidade de se tornarem fumadores regulares (inferior em 40%).Os baixos níveis de tabagismo entre os estudantes atletas devem-se a diversos factores: elevada auto-estima alcançada pela prática desportiva; redução do papel das influências externas; percepção da diminuição da performance física relacionada com os hábitos tabágicos, atenção redobrada sobre os efeitos nefastos do tabaco; aconselhamento por parte do treinador ou responsáveis desportivos.Os adolescentes fumadores apresentam uma diminuição da resistência e desempenho físico e uma maior frequência de patologia respiratória, problemas emocionais e comportamentos âde riscoâ (alcoolismo, sexo não protegido, uso de drogas ilícitas).Torna-se, assim, claro que a promoção do desporto desempenha um importante papel na prevenção e cessação do tabagismo. A comprovação cientifica de que a idade de iniciação tabágica precede ou coincide com a fase de abandono da actividade desportiva vem reforçar este facto. O contributo do desporto na desabituação tabágica resulta da redução dos sintomas de abstinência, melhoria da qualidade de vida (englobando as suas vertentes física e psicológica) e diminuição do ganho ponderal observado após a cessação. Este papel da actividade desportiva poderá assumir particular relevância nos países de baixo poder económico, nos quais se torna incomportável o custo da terapêutica de substituição nicotínica ou de antidepressivos como a bupropiona. à de salientar, também, que as técnicas de desabituação não farmacológicas se revelam mais atractivas no caso dos jovens fumadores.Os autores verificaram, simultaneamente, que adolescentes não fumadores com maior actividade física revelavam uma capacidade pulmonar superior. Este facto sugere que a prática desportiva deverá começar antes da idade usual de iniciação tabágica, podendo ter um efeito potenciador sobre a função pulmonar. No entanto, é indispensável a realização de novos estudos científicos para validar esta teoria. Palavras-chave: Tabagismo, adolescência, exercício físico, função pulmonar, Key-words: Adolescent smoking habits, Physical exercise, lung functio

Gender differences in asthma prevalence may depend on how asthma is defined

BACKGROUND: Asthma may be defined either as wheeze within the previous 12 months (current wheeze) doctor-diagnosed asthma (DDA), or current wheeze plus confirmed airway hyperresponsiveness (AHR). AIMS: We wanted to estimate asthma prevalence in randomly selected adolescents based on different criteria for asthma diagnosis, study gender differences in reported asthma-like symptoms vs DDA, and relate our findings to measurements of AHR, levels of exhaled nitric oxide (ENO) and total IgE. METHODS: As part of the health survey of North-Trondelag (HUNT), 8571 adolescents aged 13-19 years were investigated with an interview on allergic and respiratory symptoms (phase I study). Of these, 401 subjects who reported wheeze within the previous 12 months (current wheeze) and 213 non-symptomatic controls were randomly selected and investigated with allergy screening, methacholine bronchoprovocation test and measurements of ENO (phase II study). RESULTS: In the phase I study prevalence of current wheeze was 26% (30% in girls and 23% in boys, P < 0.01). Prevalence of DDA was 10.8% (10.5% in girls and 11% in boys). Among subjects with current wheeze, the likelihood of having DDA was reduced in girls compared to boys, odds ratio (95% CI) 0.82 (0.68-0.98) which was partly explained by a longer history of wheeze among boys. In the phase II study, although more girls than boys with current wheeze had AHR (62% versus 50%, P < 0.02) more boys than girls reported DDA (44% vs. 32%, P < 0.02). Of the objective parameters, increased levels of ENO most strongly increased the risk of having DDA. CONCLUSIONS: When asthma is defined as DDA, there is a risk of underestimating the prevalence of asthma, especially among girls