Contrasting male and female trends in tobacco-attributed mortality in China:evidence from successive nationwide prospective cohort studies

SummaryBackgroundChinese men now smoke more than a third of the world's cigarettes, following a large increase in urban then rural usage. Conversely, Chinese women now smoke far less than in previous generations. We assess the oppositely changing effects of tobacco on male and female mortality.MethodsTwo nationwide prospective studies 15 years apart recruited 220 000 men in about 1991 at ages 40–79 years (first study) and 210 000 men and 300 000 women in about 2006 at ages 35–74 years (second study), with follow-up during 1991–99 (mid-year 1995) and 2006–14 (mid-year 2010), respectively. Cox regression yielded sex-specific adjusted mortality rate ratios (RRs) comparing smokers (including any who had stopped because of illness, but not the other ex-smokers, who are described as having stopped by choice) versus never-smokers.FindingsTwo-thirds of the men smoked; there was little dependence of male smoking prevalence on age, but many smokers had not smoked cigarettes throughout adult life. Comparing men born before and since 1950, in the older generation, the age at which smoking had started was later and, particularly in rural areas, lifelong exclusive cigarette use was less common than in the younger generation. Comparing male mortality RRs in the first study (mid-year 1995) versus those in the second study (mid-year 2010), the proportional excess risk among smokers (RR-1) approximately doubled over this 15-year period (urban: RR 1·32 [95% CI 1·24–1·41] vs 1·65 [1·53–1·79]; rural: RR 1·13 [1·09–1·17] vs 1·22 [1·16–1·29]), as did the smoking-attributed fraction of deaths at ages 40–79 years (urban: 17% vs 26%; rural: 9% vs 14%). In the second study, urban male smokers who had started before age 20 years (which is now typical among both urban and rural young men) had twice the never-smoker mortality rate (RR 1·98, 1·79–2·19, approaching Western RRs), with substantial excess mortality from chronic obstructive pulmonary disease (COPD RR 9·09, 5·11–16·15), lung cancer (RR 3·78, 2·78–5·14), and ischaemic stroke or ischaemic heart disease (combined RR 2·03, 1·66–2·47). Ex-smokers who had stopped by choice (only 3% of ever-smokers in 1991, but 9% in 2006) had little smoking-attributed risk more than 10 years after stopping. Among Chinese women, however, there has been a tenfold intergenerational reduction in smoking uptake rates. In the second study, among women born in the 1930s, 1940s, 1950s, and since 1960 the proportions who had smoked were, respectively, 10%, 5%, 2%, and 1% (3097/30 943, 3265/62 246, 2339/97 344, and 1068/111 933). The smoker versus non-smoker RR of 1·51 (1·40–1·63) for all female mortality at ages 40–79 years accounted for 5%, 3%, 1%, and <1%, respectively, of all the female deaths in these four successive birth cohorts. In 2010, smoking caused about 1 million (840 000 male, 130 000 female) deaths in China.InterpretationSmoking will cause about 20% of all adult male deaths in China during the 2010s. The tobacco-attributed proportion is increasing in men, but low, and decreasing, in women. Although overall adult mortality rates are falling, as the adult population of China grows and the proportion of male deaths due to smoking increases, the annual number of deaths in China that are caused by tobacco will rise from about 1 million in 2010 to 2 million in 2030 and 3 million in 2050, unless there is widespread cessation.FundingWellcome Trust, MRC, BHF, CR-UK, Kadoorie Charitable Foundation, Chinese MoST and NSF

Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants

The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR-Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD. 2022, The Author(s).T. Kessler is supported by the Corona-Foundation (Junior Research Group Translational Cardiovascular Genomics) and the German Research Foundation (DFG) as part of the Sonderforschungsbereich SFB 1123 (B02). T.J. was supported by a Medical Research Council DTP studentship (MR/S502443/1). J.D. is a British Heart Foundation Professor, European Research Council Senior Investigator, and National Institute for Health and Care Research (NIHR) Senior Investigator. J.C.H. acknowledges personal funding from the British Heart Foundation (FS/14/55/30806) and is a member of the Oxford BHF Centre of Research Excellence (RE/13/1/30181). R.C. has received funding from the British Heart Foundation and British Heart Foundation Centre of Research Excellence. O.G. has received funding from the British Heart Foundation (BHF) (FS/14/66/3129). P.S.d.V. was supported by American Heart Association grant number 18CDA34110116 and National Heart, Lung, and Blood Institute grant R01HL146860. The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I), R01HL087641, R01HL059367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. We thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by grant UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The Trøndelag Health Study (The HUNT Study) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority and the Norwegian Institute of Public Health. The K.G. Jebsen Center for Genetic Epidemiology is financed by Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology; and Central Norway Regional Health Authority. Whole genome sequencing for the HUNT study was funded by HL109946. The GerMIFs gratefully acknowledge the support of the Bavarian State Ministry of Health and Care, furthermore founded this work within its framework of DigiMed Bayern (grant DMB-1805-0001), the German Federal Ministry of Education and Research (BMBF) within the framework of ERA-NET on Cardiovascular Disease (Druggable-MI-genes, 01KL1802), within the scheme of target validation (BlockCAD, 16GW0198K), within the framework of the e:Med research and funding concept (AbCD-Net, 01ZX1706C), the British Heart Foundation (BHF)/German Centre of Cardiovascular Research (DZHK)-collaboration (VIAgenomics) and the German Research Foundation (DFG) as part of the Sonderforschungsbereich SFB 1123 (B02), the Sonderforschungsbereich SFB TRR 267 (B05), and EXC2167 (PMI). This work was supported by the British Heart Foundation (BHF) under grant RG/14/5/30893 (P.D.) and forms part of the research themes contributing to the translational research portfolios of the Barts Biomedical Research Centre funded by the UK National Institute for Health Research (NIHR). I.S. is supported by a Precision Health Scholars Award from the University of Michigan Medical School. This work was supported by the European Commission (HEALTH-F2–2013-601456) and the TriPartite Immunometabolism Consortium (TrIC)-NovoNordisk Foundation (NNF15CC0018486), VIAgenomics (SP/19/2/344612), the British Heart Foundation, a Wellcome Trust core award (203141/Z/16/Z to M.F. and H.W.) and the NIHR Oxford Biomedical Research Centre. M.F. and H.W. are members of the Oxford BHF Centre of Research Excellence (RE/13/1/30181). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. C.P.N. and T.R.W. received funding from the British Heart Foundation (SP/16/4/32697). C.J.W. is funded by NIH grant R35-HL135824. B.N.W. is supported by the National Science Foundation Graduate Research Program (DGE, 1256260). This research was supported by BHF (SP/13/2/30111) and conducted using the UK Biobank Resource (application 9922). O.M. was funded by the Swedish Heart and Lung Foundation, the Swedish Research Council, the European Research Council ERC-AdG-2019-885003 and Lund University Infrastructure grant ‘Malmö population-based cohorts’ (STYR 2019/2046). T.R.W. is funded by the British Heart Foundation. I.K., S. Koyama, and K. Ito are funded by the Japan Agency for Medical Research and Development, AMED, under grants JP16ek0109070h0003, JP18kk0205008h0003, JP18kk0205001s0703, JP20km0405209 and JP20ek0109487. The Biobank Japan is supported by AMED under grant JP20km0605001. J.L.M.B. acknowledges research support from NIH R01HL125863, American Heart Association (A14SFRN20840000), the Swedish Research Council (2018-02529) and Heart Lung Foundation (20170265) and the Foundation Leducq (PlaqueOmics: New Roles of Smooth Muscle and Other Matrix Producing Cells in Atherosclerotic Plaque Stability and Rupture, 18CVD02. A.V.K. has been funded by grant 1K08HG010155 from the National Human Genome Research Institute. K.G.A. has received support from the American Heart Association Institute for Precision Cardiovascular Medicine (17IFUNP3384001), a KL2/Catalyst Medical Research Investigator Training (CMeRIT) award from the Harvard Catalyst (KL2 TR002542) and the NIH (1K08HL153937). A.S.B. has been supported by funding from the National Health and Medical Research Council (NHMRC) of Australia (APP2002375). D.S.A. has received support from a training grant from the NIH (T32HL007604). N.P.B., M.C.C., J.F. and D.-K.J. have been funded by the National Institute of Diabetes and Digestive and Kidney Diseases (2UM1DK105554). EPIC-CVD was funded by the European Research Council (268834) and the European Commission Framework Programme 7 (HEALTH-F2-2012-279233). The coordinating center was supported by core funding from the UK Medical Research Council (G0800270; MR/L003120/1), British Heart Foundation (SP/09/002, RG/13/13/30194, RG/18/13/33946) and NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome. Support for title page creation and format was provided by AuthorArranger, a tool developed at the National Cancer Institute.Scopu

Global heterogeneity in folic acid fortification policies and implications for prevention of neural tube defects and stroke: a systematic reviewResearch in context

Summary: Background: Folic acid (pteroylmonoglutamic acid) supplements are highly effective for prevention of neural tube defects (NTD) prompting implementation of mandatory or voluntary folic acid fortification for prevention of NTDs. We used plasma folate levels in population studies by country and year to compare effects of folic acid fortification types (mandatory or voluntary folic acid fortification policies) on plasma folate levels, NTD prevalence and stroke mortality rates. Methods: We conducted systematic reviews of (i) implementation of folic acid fortification in 193 countries that were member states of the World Health Organization by country and year, and (ii) estimated population mean plasma folate levels by year and type of folic acid fortification. We identified relevant English language reports published between Jan 1, 1990 and July 31, 2023 using Google Scholar, Medline, Embase and Global Health. Eligibility criteria were observational or interventional studies with >1000 participants. Studies of pregnant women or children 25 nmol/L were 100%, 15% and 7%, respectively). Among 75 countries with NTD prevalence, mean (95% CI) prevalence per 10,000 population were 4.19 (4.11–4.28), 7.61 (7.47–7.75) and 9.66 (9.52–9.81) with mandatory, voluntary and no folic acid fortification, respectively. However, age-standardised trends in stroke mortality rates were unaltered by the introduction of folic acid fortification. Interpretation: There is substantial heterogeneity in folic acid fortification policies worldwide where folic acid fortification are associated with 50–100% higher population mean plasma folate levels and 25–50% lower NTD prevalence compared with no fortification. Many thousand NTD pregnancies could be prevented yearly if all countries implemented mandatory folic acid fortification. Further trials of folic acid for stroke prevention are required in countries without effective folic acid fortification policies. Funding: Medical Research Council (UK) and British Heart Foundation

Body-mass index, blood pressure, and cause-specific mortality in India: a prospective cohort study of 500 810 adults

Summary: Background: The association between cause-specific mortality and body-mass index (BMI) has been studied mainly in high-income countries. We investigated the relations between BMI, systolic blood pressure, and mortality in India. Methods: Men and women aged 35 years or older were recruited into a prospective study from the general population in Chennai, India between Jan 1, 1998, and Dec 31, 2001. Participants were interviewed (data collected included age, sex, education, socioeconomic status, medical history, tobacco smoking, and alcohol intake) and measured (height, weight, and blood pressure). Deaths were identified by linkage to Chennai city mortality records and through active surveillance by household visits from trained graduate non-medical fieldworkers. After the baseline survey, households were visited once in 2002–05, then biennially until 2015. During these repeat visits, structured narratives of any deaths that took place before March 31, 2015, were recorded for physician coding. During 2013–14, a random sample of participants was also resurveyed as per baseline to assess long-term variability in systolic blood pressure and BMI. Cox regression (standardised for tobacco, alcohol, and social factors) was used to relate mortality rate ratios (RRs) at ages 35–69 years to systolic blood pressure, BMI, or BMI adjusted for usual systolic blood pressure. Findings: 500 810 participants were recruited. After exclusion of those with chronic disease or incomplete data, 414 746 participants aged 35–69 years (mean 46 [SD 9]; 45% women) remained. At recruitment, mean systolic blood pressure was 127 mm Hg (SD 15), and mean BMI was 23·2 kg/m2 (SD 3·8). Correlations of resurvey and baseline measurements were 0·50 for systolic blood pressure and 0·88 for BMI. Low BMI was strongly associated with poverty, tobacco, and alcohol. Of the 29 519 deaths at ages 35–69 years, the cause was vascular for 14 935 deaths (12 504 cardiac, 1881 stroke, and 550 other). Vascular mortality was strongly associated with systolic blood pressure: RRs per 20 mm Hg increase in usual systolic blood pressure were 2·45 (95% CI 2·16–2·78) for stroke mortality, 1·74 (1·64–1·84) for cardiac mortality, and 1·84 (1·75–1·94) for all vascular mortality. Although BMI strongly affected systolic blood pressure (an increase of about 1 mm Hg per kg/m2) and diabetes prevalence, BMI was little related to cardiac or stroke mortality, with only small excesses even for grade 1 obesity (ie, BMIs of 30·0–35·0 kg/m2). After additional adjustment for usual systolic blood pressure, BMI was inversely related to cardiac and stroke mortality throughout the range 15·0–30·0 kg/m2: when underweight participants (ie, BMI 15·0–18·5 kg/m2) were compared with overweight participants (ie, BMI 25·0–30·0 kg/m2), the blood-pressure-adjusted RR was 1·28 (95% CI 1·20–1·38) for cardiac mortality and 1·46 (1·22–1·73) for stroke mortality. Interpretation: In this South Asian population, BMI was little associated with vascular mortality, even though increased BMI is associated with increased systolic blood pressure, which in turn is associated with increased vascular mortality. Hence, some close correlates of below-average BMI must have important adverse effects, which could be of relevance in all populations. Funding: UK Medical Research Council, British Heart Foundation, Cancer Research UK

Experimental study of optical transitions in be-doped GaAs/AlAs multiple quantum wells

We present a photoluminescence study of optical transitions in Be acceptor-doped GaAs/AlAs multiple quantum wells at room and liquid nitrogen temperatures. We investigate excitonic spectra and reveal acceptor-impurity induced effects in multiple quantum wells having different width