{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T07:14:20Z","timestamp":1793862860334,"version":"4.6.1"},"reference-count":50,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,2,24]],"date-time":"2021-02-24T00:00:00Z","timestamp":1614124800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,2,24]],"date-time":"2021-02-24T00:00:00Z","timestamp":1614124800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Med"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Males experience higher rates of coronary heart disease (CHD) than females, but the circulating traits underpinning this difference are poorly understood. We examined sex differences in systemic metabolites measured at four life stages, spanning childhood to middle adulthood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Data were from the Avon Longitudinal Study of Parents and Children (7727 offspring, 49% male; and 6500 parents, 29% male). Proton nuclear magnetic resonance (\n                      <jats:sup>1<\/jats:sup>\n                      H-NMR) spectroscopy from a targeted metabolomics platform was performed on EDTA-plasma or serum samples to quantify 229 systemic metabolites (including lipoprotein-subclass-specific lipids, pre-glycaemic factors, and inflammatory glycoprotein acetyls). Metabolites were measured in the same offspring once in childhood (mean age 8\u00a0years), twice in adolescence (16\u00a0years and 18\u00a0years) and once in early adulthood (25\u00a0years), and in their parents once in middle adulthood (50\u00a0years). Linear regression models estimated differences in metabolites for males versus females on each occasion (serial cross-sectional associations).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>At 8\u00a0years, total lipids in very-low-density lipoproteins (VLDL) were lower in males; levels were higher in males at 16\u00a0years and higher still by 18\u00a0years and 50\u00a0years (among parents) for medium-or-larger subclasses. Larger sex differences at older ages were most pronounced for VLDL triglycerides\u2014males had 0.19 standard deviations (SD) (95% CI\u2009=\u20090.12, 0.26) higher at 18\u00a0years, 0.50 SD (95% CI\u2009=\u20090.42, 0.57) higher at 25\u00a0years, and 0.62 SD (95% CI\u2009=\u20090.55, 0.68) higher at 50\u00a0years. Low-density lipoprotein (LDL) cholesterol, apolipoprotein-B, and glycoprotein acetyls were generally lower in males across ages. The direction and magnitude of effects were largely unchanged when adjusting for body mass index measured at the time of metabolite assessment on each occasion.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our results suggest that males begin to have higher VLDL triglyceride levels in adolescence, with larger sex differences at older ages. Sex differences in other CHD-relevant metabolites, including LDL cholesterol, show the opposite pattern with age, with higher levels among females. Such life course trends may inform causal analyses with clinical endpoints in specifying traits which underpin higher age-adjusted CHD rates commonly seen among males.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12916-021-01929-2","type":"journal-article","created":{"date-parts":[[2021,2,23]],"date-time":"2021-02-23T21:02:37Z","timestamp":1614114157000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Sex differences in systemic metabolites at four life stages: cohort study with repeated metabolomics"],"prefix":"10.1186","volume":"19","author":[{"given":"Joshua A.","family":"Bell","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana L.","family":"Santos Ferreira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail","family":"Fraser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Luiza G.","family":"Soares","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura D.","family":"Howe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah A.","family":"Lawlor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Carslake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Davey Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda M.","family":"O\u2019Keeffe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,24]]},"reference":[{"issue":"10100","key":"1929_CR1","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.1016\/S0140-6736(17)32152-9","volume":"390","author":"M Naghavi","year":"2017","unstructured":"Naghavi M, Abajobir AA, Abbafati C, Abbas KM, Abd-Allah F, Abera SF, et al. Global, regional, and national age-sex specific mortality for 264 causes of death, 1980\u20132016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390(10100):1151\u2013210.","journal-title":"Lancet."},{"issue":"1","key":"1929_CR2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jacc.2017.04.052","volume":"70","author":"GA Roth","year":"2017","unstructured":"Roth GA, Johnson C, Abajobir A, Abd-Allah F, Abera SF, Abyu G, et al. Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. J Am Coll Cardiol. 2017;70(1):1\u201325.","journal-title":"J Am Coll Cardiol"},{"issue":"9","key":"1929_CR3","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1161\/01.CIR.0000118498.35499.B2","volume":"109","author":"B Unal","year":"2004","unstructured":"Unal B, Critchley JA, Capewell S. Explaining the decline in coronary heart disease mortality in England and Wales between 1981 and 2000. Circulation. 2004;109(9):1101\u20137.","journal-title":"Circulation."},{"issue":"11","key":"1929_CR4","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1161\/CIRCULATIONAHA.115.015293","volume":"132","author":"KA Wilmot","year":"2015","unstructured":"Wilmot KA, O\u2019flaherty M, Capewell S, Ford ES, Vaccarino V. Coronary heart disease mortality declines in the United States from 1979 through 2011: evidence for stagnation in young adults, especially women. Circulation. 2015;132(11):997\u20131002.","journal-title":"Circulation."},{"issue":"5","key":"1929_CR5","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1001\/jamacardio.2016.1326","volume":"1","author":"S Sidney","year":"2016","unstructured":"Sidney S, Quesenberry CP, Jaffe MG, Sorel M, Nguyen-Huynh MN, Kushi LH, et al. Recent trends in cardiovascular mortality in the United States and public health goals. JAMA Cardiol. 2016;1(5):594\u20139.","journal-title":"JAMA Cardiol"},{"issue":"14","key":"1929_CR6","doi-asserted-by":"publisher","first-page":"1333","DOI":"10.1056\/NEJMoa1406656","volume":"372","author":"GA Roth","year":"2015","unstructured":"Roth GA, Forouzanfar MH, Moran AE, Barber R, Nguyen G, Feigin VL, et al. Demographic and epidemiologic drivers of global cardiovascular mortality. N Engl J Med. 2015;372(14):1333\u201341.","journal-title":"N Engl J Med"},{"issue":"19","key":"1929_CR7","doi-asserted-by":"publisher","first-page":"2145","DOI":"10.1161\/CIRCULATIONAHA.110.968792","volume":"124","author":"L Mosca","year":"2011","unstructured":"Mosca L, Barrett-Connor E, Kass WN. Sex\/gender differences in cardiovascular disease prevention: what a difference a decade makes. Circulation. 2011;124(19):2145\u201354.","journal-title":"Circulation."},{"issue":"7121","key":"1929_CR8","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1038\/nature05482","volume":"444","author":"SE Kahn","year":"2006","unstructured":"Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature. 2006;444(7121):840\u20136.","journal-title":"Nature."},{"issue":"1","key":"1929_CR9","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.cell.2013.12.012","volume":"156","author":"ED Rosen","year":"2014","unstructured":"Rosen ED, Spiegelman BM. What we talk about when we talk about fat. Cell. 2014;156(1):20\u201344.","journal-title":"Cell."},{"issue":"3","key":"1929_CR10","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1210\/er.2015-1137","volume":"37","author":"A Kautzky-Willer","year":"2016","unstructured":"Kautzky-Willer A, Harreiter J, Pacini G. Sex and gender differences in risk, pathophysiology and complications of type 2 diabetes mellitus. Endocrine Rev. 2016;37(3):278\u2013316.","journal-title":"Endocrine Rev"},{"issue":"6","key":"1929_CR11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1000440","volume":"8","author":"AK Wills","year":"2011","unstructured":"Wills AK, Lawlor DA, Matthews FE, Sayer AA, Bakra E, Ben-Shlomo Y, et al. Life course trajectories of systolic blood pressure using longitudinal data from eight UK cohorts. PLoS Med. 2011;8(6):e1000440.","journal-title":"PLoS Med"},{"key":"1929_CR12","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1016\/j.atherosclerosis.2018.09.030","volume":"278","author":"LM O\u2019Keeffe","year":"2018","unstructured":"O\u2019Keeffe LM, Simpkin AJ, Tilling K, Anderson EL, Hughes AD, Lawlor DA, et al. Sex-specific trajectories of measures of cardiovascular health during childhood and adolescence: a prospective cohort study. Atherosclerosis. 2018;278:190\u20136.","journal-title":"Atherosclerosis."},{"key":"1929_CR13","doi-asserted-by":"publisher","first-page":"103687","DOI":"10.1016\/j.dib.2019.01.035","volume":"23","author":"LM O\u2019Keeffe","year":"2019","unstructured":"O\u2019Keeffe LM, Simpkin AJ, Tilling K, Anderson EL, Hughes AD, Lawlor DA, et al. Data on trajectories of measures of cardiovascular health in the Avon Longitudinal Study of Parents and Children (ALSPAC). Data in Brief. 2019;23:103687.","journal-title":"Data in Brief"},{"key":"1929_CR14","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1146\/annurev-nutr-071816-064827","volume":"37","author":"JC Link","year":"2017","unstructured":"Link JC, Reue K. Genetic basis for sex differences in obesity and lipid metabolism. Ann Rev Nutr. 2017;37:225\u201345.","journal-title":"Ann Rev Nutr"},{"key":"1929_CR15","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.molmet.2018.05.008","volume":"15","author":"BT Palmisano","year":"2018","unstructured":"Palmisano BT, Zhu L, Eckel RH, Stafford JM. Sex differences in lipid and lipoprotein metabolism. Mol Metab. 2018;15:45.","journal-title":"Mol Metab"},{"issue":"18","key":"1929_CR16","doi-asserted-by":"publisher","first-page":"2361","DOI":"10.1161\/CIRCULATIONAHA.107.704569","volume":"117","author":"A Moran","year":"2008","unstructured":"Moran A, Jacobs DR Jr, Steinberger J, Steffen LM, Pankow JS, Hong C-P, et al. Changes in insulin resistance and cardiovascular risk during adolescence. Establishment of differential risk in males and females. Circulation. 2008;117(18):2361\u20138.","journal-title":"Circulation."},{"key":"1929_CR17","doi-asserted-by":"publisher","unstructured":"W\u00fcrtz P, Kangas AJ, Soininen P, Lawlor DA, Davey Smith G, Ala-Korpela M. Quantitative serum NMR metabolomics in large-scale epidemiology: a primer on-omic technology. Am J Epidemiol. 2017;186(9):1084\u201396. https:\/\/doi.org\/10.1093\/aje\/kwx016.","DOI":"10.1093\/aje\/kwx016"},{"issue":"1","key":"1929_CR18","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1186\/s12916-018-1008-8","volume":"16","author":"Q Wang","year":"2018","unstructured":"Wang Q, Ferreira DLS, Nelson SM, Sattar N, Ala-Korpela M, Lawlor DA. Metabolic characterization of menopause: cross-sectional and longitudinal evidence. BMC Med. 2018;16(1):17.","journal-title":"BMC Med"},{"issue":"1","key":"1929_CR19","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1186\/s12916-016-0733-0","volume":"14","author":"Q Wang","year":"2016","unstructured":"Wang Q, W\u00fcrtz P, Auro K, M\u00e4kinen V-P, Kangas AJ, Soininen P, et al. Metabolic profiling of pregnancy: cross-sectional and longitudinal evidence. BMC Med. 2016;14(1):205.","journal-title":"BMC Med"},{"key":"1929_CR20","first-page":"111","volume":"1","author":"A Boyd","year":"2012","unstructured":"Boyd A, Golding J, Macleod J, Lawlor DA, Fraser A, Henderson J, et al. Cohort profile: the \u2018children of the 90s\u2019\u2014the index offspring of the Avon Longitudinal Study of Parents and Children. Int J Epidemiol. 2012;1:111\u201327.","journal-title":"Int J Epidemiol"},{"key":"1929_CR21","doi-asserted-by":"publisher","unstructured":"Northstone K, Lewcock M, Groom A, Boyd A, Macleod J, Timpson N, et al. The Avon Longitudinal Study of Parents and Children (ALSPAC): an update on the enrolled sample of index children in 2019. Wellcome Open Res. 2019;4:51. https:\/\/doi.org\/10.12688\/wellcomeopenres.15132.1.","DOI":"10.12688\/wellcomeopenres.15132.1"},{"issue":"1","key":"1929_CR22","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1093\/ije\/dys066","volume":"42","author":"A Fraser","year":"2013","unstructured":"Fraser A, Macdonald-Wallis C, Tilling K, Boyd A, Golding J, Davey Smith G, et al. Cohort profile: the Avon Longitudinal Study of Parents and Children: ALSPAC mothers cohort. Int J Epidemiol. 2013;42(1):97\u2013110.","journal-title":"Int J Epidemiol"},{"issue":"1","key":"1929_CR23","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1161\/CIRCGENETICS.114.000216","volume":"8","author":"P Soininen","year":"2015","unstructured":"Soininen P, Kangas AJ, W\u00fcrtz P, Suna T, Ala-Korpela M. Quantitative serum nuclear magnetic resonance metabolomics in cardiovascular epidemiology and genetics. Circ Cardiovasc Genet. 2015;8(1):192\u2013206.","journal-title":"Circ Cardiovasc Genet"},{"issue":"22","key":"1929_CR24","doi-asserted-by":"publisher","first-page":"1707","DOI":"10.1001\/archinternmed.2012.3708","volume":"172","author":"D Sidhu","year":"2012","unstructured":"Sidhu D, Naugler C. Fasting time and lipid levels in a community-based population: a cross-sectional study. Arch Intern Med. 2012;172(22):1707\u201310.","journal-title":"Arch Intern Med"},{"issue":"6","key":"1929_CR25","doi-asserted-by":"publisher","first-page":"1558","DOI":"10.1093\/ije\/dyq115","volume":"39","author":"TJ Cole","year":"2010","unstructured":"Cole TJ, Donaldson MD, Ben-Shlomo Y. SITAR\u2014a useful instrument for growth curve analysis. Int J Epidemiol. 2010;39(6):1558\u201366.","journal-title":"Int J Epidemiol"},{"key":"1929_CR26","doi-asserted-by":"publisher","unstructured":"Frysz M, Howe LD, Tobias JH, Paternoster L. Using SITAR (SuperImposition by Translation and Rotation) to estimate age at peak height velocity in Avon Longitudinal Study of Parents and Children. Wellcome Open Res. 2018;3:90. https:\/\/doi.org\/10.12688\/wellcomeopenres.14708.2.","DOI":"10.12688\/wellcomeopenres.14708.2"},{"issue":"1","key":"1929_CR27","doi-asserted-by":"publisher","first-page":"76","DOI":"10.3109\/03014460.2013.856472","volume":"41","author":"T Cole","year":"2014","unstructured":"Cole T, Pan H, Butler G. A mixed effects model to estimate timing and intensity of pubertal growth from height and secondary sexual characteristics. Ann Hum Biol. 2014;41(1):76\u201383.","journal-title":"Ann Hum Biol"},{"issue":"4","key":"1929_CR28","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1210\/jc.2011-3362","volume":"97","author":"SD Harlow","year":"2012","unstructured":"Harlow SD, Gass M, Hall JE, Lobo R, Maki P, Rebar RW, et al. Executive summary of the Stages of Reproductive Aging Workshop+ 10: addressing the unfinished agenda of staging reproductive aging. J Clin Endocrinol Metab. 2012;97(4):1159\u201368.","journal-title":"J Clin Endocrinol Metab"},{"issue":"24","key":"1929_CR29","doi-asserted-by":"publisher","first-page":"3142","DOI":"10.1016\/j.jacc.2018.09.066","volume":"72","author":"JA Bell","year":"2018","unstructured":"Bell JA, Carslake D, O\u2019Keeffe LM, Frysz M, Howe LD, Hamer M, et al. Associations of body mass and fat indexes with cardiometabolic traits. J Am Coll Cardiol. 2018;72(24):3142\u201354.","journal-title":"J Am Coll Cardiol"},{"issue":"12","key":"1929_CR30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001765","volume":"11","author":"P W\u00fcrtz","year":"2014","unstructured":"W\u00fcrtz P, Wang Q, Kangas AJ, Richmond RC, Skarp J, Tiainen M, et al. Metabolic signatures of adiposity in young adults: Mendelian randomization analysis and effects of weight change. PLoS Med. 2014;11(12):e1001765.","journal-title":"PLoS Med"},{"key":"1929_CR31","doi-asserted-by":"publisher","unstructured":"Bull CJ, Bell JA, Murphy N, Sanderson E, Smith GD, Timpson NJ, et al. Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study. medRxiv. 2020. https:\/\/doi.org\/10.1101\/2020.03.19.20031138.","DOI":"10.1101\/2020.03.19.20031138"},{"key":"1929_CR32","doi-asserted-by":"publisher","unstructured":"Richardson TG, Mykkanen J, Pahkala K, Ala-Korpela M, Bell JA, Taylor K, et al. Evaluating the direct effects of childhood adiposity on adult systemic metabolism: a multivariable Mendelian randomization analysis. medRxiv. 2020. https:\/\/doi.org\/10.1101\/2020.08.25.20181412.","DOI":"10.1101\/2020.08.25.20181412"},{"issue":"7280","key":"1929_CR33","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1136\/bmj.322.7280.226","volume":"322","author":"JA Sterne","year":"2001","unstructured":"Sterne JA, Davey SG. Sifting the evidence\u2014what\u2019s wrong with significance tests? BMJ. 2001;322(7280):226\u201331.","journal-title":"BMJ."},{"issue":"2","key":"1929_CR34","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1080\/00031305.2016.1154108","volume":"70","author":"RL Wasserstein","year":"2016","unstructured":"Wasserstein RL, Lazar NA. The ASA\u2019s statement on p-values: context, process, and purpose. Am Statistician. 2016;70(2):129\u201333.","journal-title":"Am Statistician"},{"issue":"9","key":"1929_CR35","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1093\/eurheartj\/eht571","volume":"36","author":"MV Holmes","year":"2014","unstructured":"Holmes MV, Asselbergs FW, Palmer TM, Drenos F, Lanktree MB, Nelson CP, et al. Mendelian randomization of blood lipids for coronary heart disease. Eur Heart J. 2014;36(9):539\u201350.","journal-title":"Eur Heart J"},{"issue":"15","key":"1929_CR36","doi-asserted-by":"publisher","first-page":"1552","DOI":"10.1016\/j.jacc.2015.02.020","volume":"65","author":"BA Ference","year":"2015","unstructured":"Ference BA, Majeed F, Penumetcha R, Flack JM, Brook RD. Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both: a 2\u00d7 2 factorial Mendelian randomization study. J Am Coll Cardiol. 2015;65(15):1552\u201361.","journal-title":"J Am Coll Cardiol"},{"issue":"18","key":"1929_CR37","doi-asserted-by":"publisher","first-page":"1713","DOI":"10.1056\/NEJMoa1615664","volume":"376","author":"MS Sabatine","year":"2017","unstructured":"Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713\u201322.","journal-title":"N Engl J Med"},{"issue":"25","key":"1929_CR38","doi-asserted-by":"publisher","first-page":"2387","DOI":"10.1056\/NEJMoa1410489","volume":"372","author":"CP Cannon","year":"2015","unstructured":"Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387\u201397.","journal-title":"N Engl J Med"},{"issue":"10","key":"1929_CR39","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1001\/jama.2017.11467","volume":"318","author":"BA Ference","year":"2017","unstructured":"Ference BA, Kastelein JJ, Ginsberg HN, Chapman MJ, Nicholls SJ, Ray KK, et al. Association of genetic variants related to CETP inhibitors and statins with lipoprotein levels and cardiovascular risk. JAMA. 2017;318(10):947\u201356.","journal-title":"JAMA."},{"issue":"4","key":"1929_CR40","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1001\/jama.2018.20045","volume":"321","author":"BA Ference","year":"2019","unstructured":"Ference BA, Kastelein JJ, Ray KK, Ginsberg HN, Chapman MJ, Packard CJ, et al. Association of triglyceride-lowering LPL variants and LDL-C\u2013lowering LDLR variants with risk of coronary heart disease. JAMA. 2019;321(4):364\u201373.","journal-title":"JAMA."},{"key":"1929_CR41","doi-asserted-by":"publisher","unstructured":"Sniderman AD. Type III hyperlipoproteinemia: the forgotten, disregarded, neglected, overlooked, ignored but highly atherogenic, and highly treatable dyslipoproteinemia. Clin Chem. 2019;65(2):225\u201327. https:\/\/doi.org\/10.1373\/clinchem.2018.298026.","DOI":"10.1373\/clinchem.2018.298026"},{"issue":"6","key":"1929_CR42","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1038\/nrendo.2010.50","volume":"6","author":"A Sniderman","year":"2010","unstructured":"Sniderman A, Couture P, De Graaf J. Diagnosis and treatment of apolipoprotein B dyslipoproteinemias. Nat Rev Endocrinol. 2010;6(6):335.","journal-title":"Nat Rev Endocrinol"},{"issue":"11","key":"1929_CR43","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1038\/ng.2795","volume":"45","author":"R Do","year":"2013","unstructured":"Do R, Willer CJ, Schmidt EM, Sengupta S, Gao C, Peloso GM, et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet. 2013;45(11):1345.","journal-title":"Nat Genet"},{"issue":"9602","key":"1929_CR44","doi-asserted-by":"publisher","first-page":"1829","DOI":"10.1016\/S0140-6736(07)61778-4","volume":"370","author":"Collaboration PS","year":"2007","unstructured":"Collaboration PS. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55 000 vascular deaths. Lancet. 2007;370(9602):1829\u201339.","journal-title":"Lancet."},{"issue":"9841","key":"1929_CR45","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1016\/S0140-6736(12)60312-2","volume":"380","author":"BF Voight","year":"2012","unstructured":"Voight BF, Peloso GM, Orho-Melander M, Frikke-Schmidt R, Barbalic M, Jensen MK, et al. Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study. Lancet. 2012;380(9841):572\u201380.","journal-title":"Lancet."},{"issue":"22","key":"1929_CR46","doi-asserted-by":"publisher","first-page":"2089","DOI":"10.1056\/NEJMoa1206797","volume":"367","author":"GG Schwartz","year":"2012","unstructured":"Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367(22):2089\u201399.","journal-title":"N Engl J Med"},{"issue":"6","key":"1929_CR47","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1038\/nrg.2016.160","volume":"18","author":"AV Khera","year":"2017","unstructured":"Khera AV, Kathiresan S. Genetics of coronary artery disease: discovery, biology and clinical translation. Nat Rev Genet. 2017;18(6):331.","journal-title":"Nat Rev Genet"},{"key":"1929_CR48","doi-asserted-by":"publisher","unstructured":"Wang Q, Holmes MV, Davey Smith G, Ala-Korpela M. Genetic support for a causal role of insulin resistance on circulating branched-chain amino acids and inflammation. Diab Care. 2017;40(12):1779\u201386. https:\/\/doi.org\/10.2337\/dc17-1642.","DOI":"10.2337\/dc17-1642"},{"key":"1929_CR49","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1038\/nrendo.2015.167","volume":"11","author":"JR Perry","year":"2015","unstructured":"Perry JR, Murray A, Day FR, Ong KK. Molecular insights into the aetiology of female reproductive ageing. Nat Rev Endocrinol. 2015;11:725\u201334.","journal-title":"Nat Rev Endocrinol."},{"issue":"6","key":"1929_CR50","doi-asserted-by":"publisher","first-page":"2560","DOI":"10.1210\/jc.2009-2575","volume":"95","author":"MM Fern\u00e1ndez-Balsells","year":"2010","unstructured":"Fern\u00e1ndez-Balsells MM, Murad MH, Lane M, Lampropulos JF, Albuquerque F, Mullan RJ, et al. Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2010;95(6):2560\u201375.","journal-title":"J Clin Endocrinol Metab"}],"container-title":["BMC Medicine"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12916-021-01929-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s12916-021-01929-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12916-021-01929-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,23]],"date-time":"2021-02-23T21:02:44Z","timestamp":1614114164000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcmedicine.biomedcentral.com\/articles\/10.1186\/s12916-021-01929-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,24]]},"references-count":50,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["1929"],"URL":"https:\/\/doi.org\/10.1186\/s12916-021-01929-2","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.01.15.19015206","asserted-by":"object"}]},"ISSN":["1741-7015"],"issn-type":[{"value":"1741-7015","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,24]]},"assertion":[{"value":"24 August 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 January 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 February 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Written informed consent was provided and ethical approval was obtained from the ALSPAC Law and Ethics Committee and the local research ethics committee. Consent for biological samples has been collected in accordance with the Human Tissue Act (2004). Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"58"}}