BACKGROUNDGenetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking. METHODSWe used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity. RESULTSProtein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants. CONCLUSIONSThe results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.

Our findings suggest that a western dietary pattern is associated with a substantially increased risk for type 2 diabetes in men.

In this Dutch population, food consumption patterns were independently associated with blood pressure and plasma glucose and cholesterol concentrations.

Moderately higher adiposity at age 18 years is associated with increased premature death in younger and middle-aged U.S. women.

Polygenic risk scores (PRS) have been shown to predict breast cancer risk in European women, but their utility in Asian women is unclear. Here we evaluate the best performing PRSs for European-ancestry women using data from 17,262 breast cancer cases and 17,695 controls of Asian ancestry from 13 case-control studies, and 10,255 Chinese women from a prospective cohort (413 incident breast cancers). Compared to women in the middle quintile of the risk distribution, women in the highest 1% of PRS distribution have a~2.7-fold risk and women in the lowest 1% of PRS distribution has~0.4-fold risk of developing breast cancer. There is no evidence of heterogeneity in PRS performance in Chinese, Malay and Indian women. A PRS developed for European-ancestry women is also predictive of breast cancer risk in Asian women and can help in developing risk-stratified screening programmes in Asia.

Genetic factors underlying leukocyte telomere length (LTL) may provide insights into telomere homeostasis, with direct links to disease susceptibility. Genetic evaluation of 23,096 Singaporean Chinese samples identifies 10 genome-wide loci ( P < 5 × 10 −8 ). Several of these contain candidate genes ( TINF2 , PARP1 , TERF1 , ATM and POT1 ) with potential roles in telomere biology and DNA repair mechanisms. Meta-analyses with additional 37,505 European individuals reveals six more genome-wide loci, including associations at MPHOSPH6 , NKX2-3 and TYMS . We demonstrate that longer LTL associates with protection against respiratory disease mortality [HR = 0.854(0.804–0.906), P = 1.88 × 10 −7 ] in the Singaporean Chinese samples. We further show that the LTL reducing SNP rs7253490 associates with respiratory infections ( P = 7.44 × 10 −4 ) although this effect may not be strongly mediated through LTL. Our data expands on the genetic basis of LTL and may indicate on a potential role of LTL in immune competence.

Repositioning of the global epicentre of non-optimal cholesterol NCD Risk Factor Collaboration (NCD-RisC)* High blood cholesterol is typically considered a feature of wealthy western countries 1,2. However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world 3 and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health 4,5. However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low-and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol-which is a marker of cardiovascular riskchanged from those in western Europe such as Belgium,

ObjectiveThis study aimed to investigate total and device-specific screen viewing (SV) and its determinants in children aged 2 years and below.DesignCross-sectional study conducted in February 2014.SettingWell-child clinics in Singapore national polyclinics.ParticipantsParents of children (Singapore citizens or permanent residents) aged 2 years and below were enrolled during routine clinic visits. Out of 794 eligible parent–child dyads, 725 (91.3%) provided informed consent and were included in the analysis.Main outcome measuresDevice-specific information on SV and determinants was ascertained using interviewer-administered survey questionnaires. The prevalence and duration of aggregate and device-specific SV were reported. Associations with potential determinants were investigated using multiple logistic regression analysis. A p value less than 0.05 was considered statistically significant.ResultsThe prevalence of daily SV and SV ≥2 h/day constituted 53.5% and 16.3%, respectively. The majority of children aged 18–24 months (88.2%) engaged in daily SV. TVs and mobile devices were the most commonly used screen devices, followed by computers and video consoles. In multivariable analysis, younger child age, Chinese ethnicity and setting rules on time of SV were strongly and consistently associated with lower levels of any SV and SV ≥2 h/day. Parental knowledge of SV recommendations and less parental SV were additionally associated with lower levels of SV ≥2 h/day. The number of screen devices was not associated with children's SV.ConclusionsIn contrast to recommendations, SV prevalence in children aged less than 2 years is high and appears to increase steadily across age groups. TVs and mobile devices are most frequently used. Improving parental knowledge of SV recommendations, reducing parental SV and especially the implementation of strict rules on SV time could be successful strategies to reduce SV in young children.