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• W4211048696 abstract "HomeHypertensionVol. 79, No. 3Great Chinese Famine and the Effects on Cardiometabolic Health for Future Generations Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBGreat Chinese Famine and the Effects on Cardiometabolic Health for Future Generations Korbua Srichaikul, Robert A. Hegele and David J.A. Jenkins Korbua SrichaikulKorbua Srichaikul Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Ontario, Canada (K.S., D.J.A.J.). Clinical Nutrition Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, Ontario, Canada (K.S., D.J.A.J.). Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada (K.S., D.J.A.J.). Search for more papers by this author , Robert A. HegeleRobert A. Hegele https://orcid.org/0000-0003-2861-5325 Department of Medicine, Western University, London, Ontario, Canada (R.A.H.). Search for more papers by this author and David J.A. JenkinsDavid J.A. Jenkins Correspondence to: David J.A. Jenkins, Departments of Nutritional Sciences, Medical Sciences Bldg, 5th Floor, Room 5336B, 1 King’s College Cir, Toronto, ON, M5S 1A8. Email E-mail Address: [email protected] Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Ontario, Canada (K.S., D.J.A.J.). Clinical Nutrition Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, Ontario, Canada (K.S., D.J.A.J.). Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada (K.S., D.J.A.J.). Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Ontario, Canada (D.J.A.J.). Li Ka Shing Knowledge Institute (D.J.A.J.), St. Michael’s Hospital, Toronto, Ontario, Canada. Division of Endocrinology and Metabolism (D.J.A.J.), St. Michael’s Hospital, Toronto, Ontario, Canada. Search for more papers by this author Originally published9 Feb 2022https://doi.org/10.1161/HYPERTENSIONAHA.121.18546Hypertension. 2022;79:532–535This article is a commentary on the followingHypertension-Mediated Organ Damage: Prevalence, Correlates, and Prognosis in the CommunityIs there a possibility that epigenetic changes that affect cardiovascular disease risk factors may influence outcomes over two generations or more? Although it may be challenging to determine at the molecular level the epigenetic changes that may be responsible for the transfer of risk factors from environmental insults in one generation to another, the findings of Li et al1 provide strongly suggestive evidence that phenotypic traits that are risk factors for cardiovascular disease can be passed from one generation to another after intrauterine deprivation. Remarkably, the generation that originally suffered that intra utero deprivation may even pass these traits on to a second generation. These are the conclusions of Li et al1 who studied those conceived and born at the height of the great Chinese famine of 1959 to 1962 that affected almost the whole of the Chinese mainland and in which it is estimated that approximately 30 million people died of starvation.See related article, pp 518–531The authors studied the participants born at the height of the famine, 1959 to 1961, and compared them with those born both before and after the great famine so that the mean ages between the famine and the no famine study participants could be matched. Their finding that there was a higher prevalence of obesity and raised blood pressure among those born in the famine compared with those born on either side of the famine was not a major surprise, based on the literature and the increased future risk of cardiometabolic disease.2 They demonstrated obesity rates of 11.3% and 8.5% respectively. Similar figures were seen for abdominal obesity at 12.5% versus 11.4% and hypertension at 21% and 20.6%, respectively. However, what was surprising was that, despite the younger age, the second generation showed a similar pattern with obesity at 8.2% versus 4.4%, abdominal obesity at 4.7% versus 3.4%, and hypertension as high as 34.8% versus 31.3%, respectively. Some of the hypertension in both generations could be explained by obesity, but the second-generation outcomes are impressive considering that the average age was only 25 years old. The effects of these increases in cardiovascular disease risk factors remain to be seen but are of concern especially since those second-generation members of the population will be exposed to potentially more westernized lifestyle and diet than the parents, increasing their overall risk for cardiometabolic diseases. Furthermore, the effect on blood pressure is likely to be compounded by age as has been shown by data from the siege of Leningrad, where hypertension was not seen after early life famine exposure by those entering their 50s but was significant by age 70 years.3 The findings for the first generation are in line with the Barker hypothesis, suggesting that low birth weight infants are more prone to cardiometabolic disease in later life,1 based on the concept of in utero development of a thrifty phenotype that is mismatched if the later environment becomes plentiful.4 The broad implications of the hypothesis reflected in the increased risk of cardiometabolic diseases has been observed internationally.5The major contribution of the study by Li et al1 is that the effect was seen not only by the generation that experienced the in utero deprivation but also by the subsequent generation that had no direct connection to the famine. Although the deprivation suffered by the fetus was in no way a reflection of the parents’ choice, one is reminded of the intergenerational nature of misfortune recorded in the King James Version of the Bible, Book of Numbers 14, verse 18: “The Lord is long-suffering and a great mercy,…… visiting the iniquity (ill health) of the fathers upon the children unto the third and fourth generation.” We do not know for how many generations these epigenetic changes will last, but their magnitude, shown in the present study in the second generation, is both simultaneously concerning and hypothesis-generating.What could be the molecular basis of such transgenerational effects? In contrast to genetic variants or mutations, epigenetic changes do not alter the DNA sequence. Instead, epigenetic change refers to a diverse range of extrinsic chemical modifications imposed on key regulatory regions within the genome that alter gene expression, for example, by interfering with binding of transcription factors to silence production of the protein product.6 Direct molecular evidence of inheritance of epigenetic effects is sparse in humans but has been shown in plants and animals (see Figure).6,7 In the mouse, for example, an environmental exposure like starvation might induce chemical changes, such as methylation or histone modification, upon genomic DNA.8 Alternatively, the stress might unleash an abnormal noncoding RNA species that adheres to a critical region within a target gene. These epigenetic forces then hijack the transcription of the gene product. If the gene encodes a protein with beneficial physiological effects, for example, relaxation of vascular tone9 or control of energy expenditure, the aberrant epigenetic mechanism could become detrimental, for example, causing hypertension, obesity, or diabetes, especially if lifestyle is poor.Download figureDownload PowerPointFigure. Inheritance of epigenetic effects in a mouse model. The symbols F0, F1, F2, and F3 refer to the filial generation. In this putative model6 external stress, such as caloric deprivation, causes chemical changes, for example, DNA methylation or histone modification, or enables noncoding RNA (ncRNA) to influence the genome of cells of individual F0. Epigenetic changes do not alter the DNA sequence but instead modulate gene expression, for example, silencing the gene product. Epigenetic modifications affect both somatic cells, with putative health implications that are not transmitted to the next generation, and germ cells (ova or sperm), which can potentially be transmitted intergenerationally. If the F0 female is pregnant, epigenetic modifications also affect both fetal somatic and germ cells. If the cells of the F1 female were directly impacted in utero by her mother’s stress exposure, an abnormal phenotype such as hypertension might be expressed later. In addition, because F1’s germ cells were affected by the same intrauterine stress, epigenetic changes could be transmitted to her daughter F2, also by intergenerational inheritance. Transgenerational inheritance is said to occur when conserved epigenetic changes are passed to F3 and subsequent generations, whose cells never experienced direct exposure to the original stress event. In males, inheritance of epigenetic changes from F0 to F1 is intergenerational, whereas their transmission from F1 to F2 and subsequent generations would be transgenerational. Some reprogramming or resetting of epigenetic changes occurs at each meiosis. The relevance of these putative mechanisms to humans is not definitively established.6Epigenetic modifications acquired in utero might affect fetal somatic cells, with putative health implications that are not transmitted to subsequent generations. However, they might theoretically also affect fetal germ cells (ie, ova or sperm); this could possibly explain transgenerational inheritance.6 For instance, if an exposed female is pregnant, epigenetic modifications can affect both maternal and fetal cells. If the daughter’s somatic cells were impacted by maternal stress while she was in utero, an abnormal phenotype such as hypertension might arise in the daughter later in life, exacerbated by imprudent lifestyle choices. In addition, because the daughter’s germ cells were affected in utero by the original stress to her mother, fixed imprinted epigenetic changes could be transmitted to subsequent generations, by so-called transgenerational inheritance.Persistence of imprinted epigenetic changes might in theory explain how an environmental exposure (eg, starvation) leads to an abnormal phenotype (eg, hypertension) in subsequent generations that were never exposed. Of course, although epigenetic effects would be expressed across the genome, deleterious clinical outcomes would depend on the particular genes that are affected.10 Presently, there is minimal direct molecular evidence of inheritance of epigenetic abnormalities across multiple generations in humans. Epigenetic changes might be inherited over a single generation, but their persistence in subsequent generations assumes that the epigenome can withstand reprogramming at subsequent meioses,6 which has not been shown to our knowledge. Nonetheless, this putative mechanism has potentially far-reaching consequences for human health.8 The observations of Li et al1 should motivate molecular biologists to seek definitive mechanistic proof of transgenerational epigenetic inheritance in humans.In support of the current findings, the Dutch famine (1944–1945) also resulted in evidence of increased heart disease in later life (odds ratio adjusted for sex 3.0 [95% CI, 1.1–8.1]) assessed as angina, Q waves on ECG or revascularization, compared with the nonexposed born on either side of the famine. Interestingly, only those exposed during the first trimester were affected, not those in the second and third trimesters. As expected, the exposed tended to have smaller body weights and head circumference, but the cardiovascular disease risk persisted after her adjustment for birthweight (odds ratio, 3.2 [95% CI, 1.2–8.8).11 Nor was cardiovascular disease the only adverse outcome of the famine, but the first trimester exposed fetus demonstrated in later life reduced size or impaired function of many organs, including lungs and kidney.12 Evidence from the Dutch famine for effects on the grandchildren (F2 generation) is not as clear, possibly because of the younger age at observation. However, the adult offspring (F2) of prenatally exposed fathers (F1), but not of mothers (F1), were heavier, but, as of yet, displayed no health differences from the offspring of the nonexposed. The much smaller numbers (n=360) in the Dutch cohort compared with the present Chinese study may be part of the explanation for this difference in findings.13Many lessons have been learned from famine and food deprivation, but not all of them have concerned the ill effects. The Dutch famine in World War II reduced the availability of wheat and grain products and resulted in the subsequent discovery of celiac disease, as children who had previously failed to thrive did better after removal of sources of gliadin from the diet.14However, the great Chinese famine appears to have involved a total reduction of calories without a disproportionate reduction in specific foods or food groups, although the less rice availability, as a major dietary component, would have reduced carbohydrate intake. Again, whether this change would have disproportionately altered the dietary macronutrient profile was not indicated. Such details may not be available but would be of interest given that carbohydrate would be a major feature of the diet with possible implications for the insulin-resistant phenotype.The great Chinese famine provides an opportunity to assess the effects of starvation on a large scale and in a more homogeneous situation than has been possible in smaller famines with less adequate records. However, famines are not new to China and it is the magnitude of the great famine that makes it particularly important. From 108 BC to 1911 AD, there were 1828 famines in China or almost annually with one famine in at least one province, sometimes with significant mortality.15 The significant famines in more recent times15 include the famine of 1907 with possibly up to 25 million deaths, 1920 to 1921 with a half million deaths, 1928 to 1930 with 3 million deaths, 1936 with possibly 5 million deaths, 1942 to 1943 1 to 2 million deaths, and 1957 to 1962 with death rates ranging from 15 to 55 million deaths or as many as 76 million, if those that failed to be born were included. This famine involved the whole country and resulted from a combination of droughts, flooding, and agricultural policy that was reversed subsequently. The very heavy mortality and the involvement of the total population makes the study of this famine particularly noteworthy.16-18ConclusionsThe study by Li et al1 represents a major advance in demonstrating that a period of very severe famine over a 3-year period impacted the health of at least 2 generations. Hopefully, this study will be extended to be a Framingham-like study assessing how these changes translate into diabetes and cardiovascular outcomes and over how many generations these effects will be seen. Concurrently, molecular biologists can work towards finding undeniable proof of transgenerational inheritance of epigenetic effects in humans.Article InformationSources of FundingNone.DisclosuresD.J.A. Jenkins discloses no conflicts directly, although he has collaborated with the food industry to promote plant based diets.19 The other authors report no conflicts.FootnotesThe opinions expressed in this article are not necessarily those of the American Heart Association.For Sources of Funding and Disclosures, see page 535.Correspondence to: David J.A. Jenkins, Departments of Nutritional Sciences, Medical Sciences Bldg, 5th Floor, Room 5336B, 1 King’s College Cir, Toronto, ON, M5S 1A8. Email david.[email protected]caReferences1. Li J, Yang Q, An R, Sesso HD, Zhong VW, Chan KHK, Madsen TE, Papandonatos GD, Zheng T, Wu W-C, et al.. Famine and Trajectories of Body Mass Index, Waist Circumference, and Blood Pressure in Two Generations: Results From the CHNS From 1993–2015.Hypertension. 2022; 79:518–531. doi: 10.1161/HYPERTENSIONAHA.121.18022LinkGoogle Scholar2. Barker DJ, Osmond C. Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales.Lancet. 1986; 1:1077–1081. doi: 10.1016/s0140-6736(86)91340-1CrossrefMedlineGoogle Scholar3. Stanner SA, Bulmer K, Andrès C, Lantseva OE, Borodina V, Poteen VV, Yudkin JS. Does malnutrition in utero determine diabetes and coronary heart disease in adulthood? Results from the Leningrad siege study, a cross sectional study.BMJ. 1997; 315:1342–1348. doi: 10.1136/bmj.315.7119.1342CrossrefMedlineGoogle Scholar4. Hales CN, Barker DJ. The thrifty phenotype hypothesis.Br Med Bull. 2001; 60:5–20. doi: 10.1093/bmb/60.1.5CrossrefMedlineGoogle Scholar5. Barker DJ. The fetal and infant origins of adult disease.BMJ. 1990; 301:1111. doi: 10.1136/bmj.301.6761.1111CrossrefMedlineGoogle Scholar6. Blake GE, Watson ED. Unravelling the complex mechanisms of transgenerational epigenetic inheritance.Curr Opin Chem Biol. 2016; 33:101–107. doi: 10.1016/j.cbpa.2016.06.008CrossrefMedlineGoogle Scholar7. Rechavi O, Houri-Ze’evi L, Anava S, Goh WSS, Kerk SY, Hannon GJ, Hobert O. Starvation-induced transgenerational inheritance of small RNAs in C. elegans.Cell. 2014; 158:277–287. doi: 10.1016/j.cell.2014.06.020CrossrefMedlineGoogle Scholar8. Koonin EV. Calorie restriction à Lamarck.Cell. 2014; 158:237–238. doi: 10.1016/j.cell.2014.07.004CrossrefMedlineGoogle Scholar9. Voo K, Ching JWH, Lim JWH, Chan SN, Ng AYE, Heng JYY, Lim SS, Pek JW. Maternal starvation primes progeny response to nutritional stress.PLoS Genet. 2021; 17:e1009932. doi: 10.1371/journal.pgen.1009932CrossrefMedlineGoogle Scholar10. Takeda Y, Demura M, Wang F, Karashima S, Yoneda T, Kometani M, Hashimoto A, Aono D, Horike SI, Meguro-Horike M, et al.. Epigenetic regulation of aldosterone synthase gene by sodium and angiotensin II.J Am Heart Assoc. 2018; 7:e008281. doi: 10.1161/JAHA.117.008281LinkGoogle Scholar11. Roseboom TJ, van der Meulen JH, Osmond C, Barker DJ, Ravelli AC, Schroeder-Tanka JM, van Montfrans GA, Michels RP, Bleker OP. Coronary heart disease after prenatal exposure to the Dutch famine, 1944-45.Heart. 2000; 84:595–598. doi: 10.1136/heart.84.6.595CrossrefMedlineGoogle Scholar12. Bleker LS, de Rooij SR, Painter RC, Ravelli AC, Roseboom TJ. Cohort profile: the Dutch famine birth cohort (DFBC)- a prospective birth cohort study in the Netherlands.BMJ Open. 2021; 11:e042078. doi: 10.1136/bmjopen-2020-042078CrossrefMedlineGoogle Scholar13. Veenendaal MV, Painter RC, de Rooij SR, Bossuyt PM, van der Post JA, Gluckman PD, Hanson MA, Roseboom TJ. Transgenerational effects of prenatal exposure to the 1944-45 Dutch famine.BJOG. 2013; 120:548–553. doi: 10.1111/1471-0528.12136CrossrefMedlineGoogle Scholar14. van Berge-Henegouwen GP, Mulder CJ. Pioneer in the gluten free diet: Willem-Karel Dicke 1905-1962, over 50 years of gluten free diet.Gut. 1993; 34:1473–1475. doi: 10.1136/gut.34.11.1473CrossrefMedlineGoogle Scholar15. Contributors w. List of famines in china - https://en.Wikipedia.Org/wiki/list_of_famines_in_china - date retrieved: 6 jan 2022. Wikipedia, the free encyclopedia.Google Scholar16. Smil V. China’s great famine: 40 years later.BMJ. 1999; 319:1619–1621. doi: 10.1136/bmj.319.7225.1619CrossrefMedlineGoogle Scholar17. Gráda CÓ. Making famine history.J Econ Lit. 2007; 45:5–38.CrossrefGoogle Scholar18. Meng X, Qian N, Yared P. The institutional causes of China’s great famine, 1959–1961.Rev Econ Stud. 2015; 82:1568–1611. doi: 10.1093/restud/rdv016CrossrefGoogle Scholar19. Jenkins DJA, Dehghan M, Mente A, Bangdiwala SI, Rangarajan S, Srichaikul K, Mohan V, Avezum A, Díaz R, Rosengren A, et al.. Glycemic index, glycemic load, and cardiovascular disease and mortality.N Engl J Med. 2021; 384:1312–1322. doi: 10.1056/NEJMoa2007123CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesHypertension-Mediated Organ Damage: Prevalence, Correlates, and Prognosis in the CommunityRamachandran S. Vasan, et al. Hypertension. 2022;79:505-515 March 2022Vol 79, Issue 3Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.121.18546PMID: 35138871 Originally publishedFebruary 9, 2022 PDF download Advertisement SubjectsHigh Blood PressureHypertensionLifestyle" @default.
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• W4211048696 title "Great Chinese Famine and the Effects on Cardiometabolic Health for Future Generations" @default.
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