Association of Prenatal Famine Exposure With Inflammatory Markers and Its Impact on Adulthood Liver Function Across Consecutive Generations

Although there has been increasing recognition that famine exposure in the fetal stage damages liver function in adulthood, this deteriorated effect could be extended to the next generation remains vague. This study aimed to explore whether famine exposure was associated with liver function in the two consecutive generations, and its association with the mediation role of inflammatory markers. We analyzed the data of 2,681 participants from Suihua rural area, Heilongjiang Province, China. According to the date of birth, the participants were classified as fetal exposed and nonexposed. The F2 subjects were classified as having no parents exposed to famine, maternal famine exposure, paternal famine exposure, or parental famine exposure. In the mixed-effect models, prenatal exposure to famine was associated with the elevation of Δ aspartate aminotransferase (ΔAST) (β: 0.22, 95% CI: 0.01, 0.43) and Δ alanine aminotransferase (ΔALT) (β: 0.42, 95% CI: 0.19, 0.66) levels in F1 adults. The mediation analysis showed that the inflammatory markers including serum C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-α) might mediate the famine-liver function association. This longitudinal data were consistent with the hypothesis that the inflammatory markers explained part of the influence of prenatal famine exposure on liver function injury, and the natal mechanism was needed to be elucidated in the future study.

Early-Life Exposure to Famine and Risk of MetabolicAssociated Fatty Liver Disease in Chinese Adults

Background: Early-life exposure to the Chinese famine has been related to the risk of obesity, type 2 diabetes, and nonalcoholic fatty liver disease later in life. Nevertheless, the long-term impact of famine exposure on metabolic associated fatty liver disease (MAFLD), a recently proposed term to describe liver disease associated with known metabolic dysfunction, remains unknown. The aim of our study was to explore the relationship between early famine exposure and MAFLD in adulthood. Methods: A total of 26,821 participants (10,994 men, 15,827 women) were recruited from a cohort study of Chinese adults in Shanghai. We categorized participants into four famine exposure subgroups based on the birth year as nonexposed (1963–1967), fetal-exposed (1959–1962), childhood-exposed (1949–1958), and adolescence-exposed (1941–1948). MAFLD was defined as liver steatosis detected by ultrasound plus one of the following three criteria: overweight/obesity, type 2 diabetes, or evidence of metabolic dysregulation. Multivariable logistic regression models were performed to examine the association between famine exposure and MAFLD. Results: The mean ± standard deviation age of the participants was 60.8 ± 6.8 years. The age-adjusted prevalence of MAFLD was 38.3, 40.8, 40.1, and 36.5% for the nonexposed, fetal-exposed, childhood-exposed, and adolescence-exposed subgroups, respectively. Compared with nonexposed participants, fetal-exposed participants showed an increased risk of adulthood MAFLD (OR = 1.10, 95% CI 1.00–1.21). The significant association between fetal famine exposure and MAFLD was observed in women (OR = 1.22, 95% CI 1.08–1.37), but not in men (OR = 0.88, 95% CI 0.75–1.03). In age-balanced analyses combining pre-famine and post-famine births as the reference, women exposed to famine in the fetal stage still had an increased risk of MAFLD (OR = 1.15, 95% CI 1.05–1.26). Conclusions: Prenatal exposure to famine showed a sex-specific association with the risk of MAFLD in adulthood.

Ideal Cardiovascular Health Metrics Modify the Association Between Exposure to Chinese Famine in Fetal and Cardiovascular Disease: A Prospective Cohort Study

Background: No study has explored the modification effect of ideal cardiovascular health metrics (ICVHMs) on the association between famine exposure and risk of cardiovascular disease (CVD) so far. We aim to examine the effect of ICVHMs on the association between exposure to famine early in life and the risk of CVD in adulthood.Methods: A total of 61,527 participants free of CVD were included in this study from the Kailuan Study. All participants were divided into three groups, included nonexposed, fetal-exposed, and childhood-exposed groups. Cox regression was used to estimate the effect of famine exposure and ICVHMs on CVD risk.Results: After a median of 13.0 (12.7–13.2) years follow-up, 4,814 incident CVD cases were identified. Compared with nonexposed participants, the CVD risk increased in participants with fetal famine exposure (hazard ratio [HR]: 1.21; 95% CI: 1.07–1.37), but not in childhood famine-exposed participants. After stratifying by the number of ICVHMs, the increased CVD risk associated with fetal famine exposure was only observed in participants with less ICVHMs ( ≤ 2) (HR: 1.30; 95% CI: 1.11–1.52, P for interaction=0.008), but disappeared in those with three or more ICVHMs. The modified effect of ICVHMs was sex specific (P for sex interaction = 0.031).Conclusions: Exposing to famine in the fetal period could increase the risk of CVD in late life; however, ICVHMs might modify the effect of famine exposure on CVD risk, especially in men.

Individual and Combined Effect of Famine Exposure and Obesity Parameters on Dyslipidemia in Mid-Aged and Older Adult: A Population-Based Cross-Sectional Study

Background: Undernutrition in early life may have a lifelong effect on adult health. The associations between undernutrition and obesity parameters and dyslipidemia were inconsistent. The present study aimed to investigate the individual and combined effects of famine exposure and obesity parameters on dyslipidemia in middle-aged and older Chinese.Method: Data were selected from the China Health and Retirement Longitudinal Study Wave2011. The analytic sample included 9427 subjects aged 45 to 90. The present study analyzed data from 9427 middle-aged and older Chinese selected from the China Health and Retirement Longitudinal Study (CHARLS Wave2011). Differences between baseline characteristics and famine exposure/BMI levels/WC levels were evaluated using the Chi-square test, t-test, and F-test. Then, the difference in the prevalence of dyslipidemia between characteristic groups was also estimated by the Chi-square and t-test. Finally, multivariable-adjusted logistic regression models examined associations of famine exposure and obesity parameters with odds of prevalence of dyslipidemia.Results: Among the 9427 participants, 1097(11.64%) participants had been exposed to the Chinese famine during the fetal stage, whereas 3763(39.92%) participants and 3251(34.49%) participants had been exposed to the famine during childhood and adolescence/adult stage, respectively. Regarding the participants with BMI measurements,2771(29.39%) were overweight and 1105(11.72%) were obese, whereas 3955(41.95%) of the participants with WC measurements were obese, respectively. Furthermore, 1899(43.23%) reported having dyslipidemia in males and 1860(36.95%) in females. In multivariable-adjusted model, famine exposure and obesity parameters were associated with prevalence of dyslipidemia independently in total populations[(1) Model three c, famine exposure with prevalence of dyslipidemia: the fatal exposed vs no exposed group, 1.32 (95% CI 1.12, 1.56); childhood-exposed vs no exposed group, 1.49 (95% CI 1.30, 1.70); the adolescence/adult-exposed vs no exposed group, 1.49 (95%CI 1.30, 1.71) ; P for trend=0.000; (2) Model three e, famine exposure with prevalence of dyslipidemia: the fatal exposed vs no exposed group, 1.29 (95% CI 1 .09, 1.52); childhood-exposed vs no exposed group, 1.39 (95% CI 1.22, 1.59); the adolescence/adult-exposed vs no exposed group, 1.27 (95%CI 1.11, 1.46) ; P for trend=0.002; (3) Model three g, BMI levels with prevalence of dyslipidemia: overweight vs normal, 2.06 (95%CI 1.86, 2.27); obesity vs normal, 2.82(95% CI 2.42, 3.27); P for trend=0.000; (4) WC levels with prevalence of dyslipidemia: overweight vs normal, 2.24 (95% CI 2.05, 2.45)]. When stratified by sex, the results in females were mostly similar to those in the total population. In a multivariable logistic regression model three c, associations between famine exposure and dyslipidemia were not observed [fatal exposed group vs non-exposed group: 0.98 (95% CI 0.75, 1.28); childhood-exposed group vs non-exposed group: 0.96 (95% CI 0.78, 1.19); adolescence/adult exposed group vs non-exposed group: 0.86 (95% CI 0.69, 1.07)] independently of BMI only (P for trend =0.110). However, in a multivariable logistic regression model three e, associations between famine exposure and dyslipidemia in male were partly observed [fatal exposed group vs non-exposed group: 0.97 (95% CI 0.74, 1.26); childhood-exposed group vs non-exposed group: 0.91 (95% CI 0.74, 1.13); adolescence/adult exposed group vs non-exposed group: 0.73 (95% CI 0.59, 0.91)] independently of BMI only (P for trend =0.001). In general, the significant synergism between famine exposure and obesity parameters in lowering the prevalence of dyslipidemia was observed in males while the significant synergism in increasing prevalence of dyslipidemia was observed in females (P-interaction =0.000).Conclusion: Individual and combined associations of obesity parameters and famine exposure with the prevalence of dyslipidemia were observed in middle-aged and elderly Chinese.

Combined Effect of Famine Exposure and Obesity Parameters on Hypertension in the Midaged and Older Adult: A Population-Based Cross-Sectional Study

Objectives. Undernutrition early in life may increase the incidence of adverse effects on adult health. The relations between undernutrition and obesity parameters (body mass index (BMI) and WC (waist circle)) and hypertension were often contradictory. Our study is aimed at identifying the combined effects of famine exposure and obesity parameters on hypertension in middle-aged and older Chinese. Design. A population-based cross-sectional study. Setting. Data were selected from the China Health and Retirement Longitudinal Study Wave2011 (CHARLS Wave2011). Participants. The sample included 12945 individuals aged 45 to 96. Main Outcome Measurements. The study analyzed data from 12945 middle-aged and older Chinese selected from CHARLS Wave2011. Differences between baseline characteristics and famine exposure/BMI levels/WC levels were evaluated using the t -, Chi-square- ( χ 2 -), and F -test. Then, the difference in the prevalence of hypertension between baseline characteristics was estimated by the t - and χ 2 -test. Finally, multivariable-adjusted logistic regression models were used to explore the associations of famine exposure and obesity parameters with odds of prevalence of hypertension. Results. Among the 12945 participants, 1548 (11.96%) participants had been exposed to the Chinese famine during the fetal group, whereas 5101 (39.41%) participants and 4362 (33.70%) participants had been exposed to the famine during childhood and adolescence/adult group, respectively. Regarding the participants with BMI levels, 3746 (28.94%) were overweight, and 1465 (11.32%) were obese, whereas 5345 (41.29%) of the participants with WC levels were obese, respectively. Furthermore, 1920 (31.17%) had hypertension in males and 2233 (32.91%) in females. In multivariable-adjusted models, famine exposure and obesity parameters were related with prevalence of hypertension independently in total populations ((1) model threec, famine exposure with prevalence of hypertension: the fatal-exposed vs. no-exposed group (OR1.27; 95% CI 1.08, 1.49); childhood-exposed vs. no-exposed group (OR1.64; 95% CI 1.44, 1.87); the adolescence/adult-exposed vs. no-exposed group (OR3.06; 95% CI 2.68, 3.50); P for trend < 0.001 ; (2) model threee, famine exposure with prevalence of hypertension: the fatal-exposed vs. no-exposed group (OR1.25; 95% CI 1.06, 1.47); childhood-exposed vs. no-exposed group (OR1.52; 95% CI 1.34, 1.73); the adolescence/adult-exposed vs. no-exposed group (OR2.66; 95% CI 2.33, 3.03); P for trend < 0.001 ; (3) model threeg, BMI levels with prevalence of hypertension: overweight vs. normal (OR1.75; 95% CI 1.60, 1.91); obesity vs. normal (OR2.79; 95% CI 2.48, 3.15); P for trend < 0.001 ; (4) WC levels with prevalence of hypertension: overweight vs. normal (OR1.42; 95% CI 1.36, 1.48)). When stratified by sex, results in both males and females were mostly similar to those in the total population. In general, interaction analysis in the multivariable-adjusted model, compared with the combination of normal BMI/WC levels and no-exposed famine group, all groups trended towards higher odds of prevalence of hypertension (the greatest increase in odds, adolescence/adult-exposed group with obesity in BMI levels: (OR8.13; 95% CI 6.18, 10.71); adolescence/adult-exposed group with obesity in WC levels: (OR6.36; 95% CI 5.22, 7.75); P for interaction < 0.001 ). When stratified by sex, the results in both males and females were also similar to those in the total population. Conclusion. Our data support a strongly positive combined effect of famine exposure and obesity parameters on hypertension in middle-aged and elderly Chinese.

Individual and combined association analysis of famine exposure and serum uric acid with hypertension in the mid-aged and older adult: a population-based cross-sectional study

Background Malnutrition in early life may affect health in later life. The associations between malnutrition and serum uric acid (SUA) and hypertension were inconsistent. The present study aimed to investigate the individual and combined association between famine exposure and serum uric acid and hypertension in middle-aged and older Chinese. Methods Data were selected from the China Health and Retirement Longitudinal Study (CHARLS) Wave2011. The analytic sample included 9368 individuals aged 45 to 90. Differences between baseline characteristics and famine exposure/SUA level were evaluated using the Chi-square test, t-test, and F-test. Then, the differences in the prevalence of hypertension between characteristic groups was also estimated by the Chi-square and t-test. Finally, multivariable-adjusted logistic regression models examined association of famine exposure and serum uric acid with odds of prevalence of hypertension. Results A total of 9368 individuals were enrolled in the study, 4366 (46.61%) and 5002 (53.39%) were male and female, respectively. Among males, 459 (10.51%) had been exposed to the Chinese famine during the fetal stage, whereas 1760 (40.31%) and 1645 (37.68%) had been exposed to the famine during childhood and adolescence/adult stage, respectively. Among females, 635 (12.69%) had been exposed to the Chinese famine during the fetal stage, whereas 1988 (39.74%) and 1569 (31.37%) had been exposed to the famine during childhood and adolescence/adult stage, respectively. Regarding the participants with SUA level measurements, 290 (6.64%) reported having Hyperuricemia (HUA) in males and 234 (4.68%) in the females. Furthermore, 1357 (31.08%) reported having hypertension in male and 1619 (32.37%) in the female. In multivariable-adjusted model, famine exposure and serum uric acid were associated with prevalence of hypertension independently in total populations [(1) Model fourd, fatal exposed group vs non-exposed group: 1.25 (95% CI 1.03, 1.52); childhood-exposed group vs non-exposed group:1.60 (95% CI 1.37, 1.87); adolescence/adult exposed group vs non-exposed group: 2.87 (95% CI 2.44, 3.37), P for trend < 0.001; (2) Model four e, high vs normal:1.73 (95% CI 1.44, 2.08)]. When stratified by sex, the results in both males and females were similar to those in the total population. In general, interaction analysis in the multivariable-adjusted model, compared with the combination of normal SUA level and no-exposed famine stage, all groups trended towards higher odds of prevalence of hypertension [the greatest increase in odds, adolescence/adult exposed stage and high SUA level in total participants: OR4.34; 95%CI 3.24, 5.81; P for interaction < 0.001]. When stratified by sex, the results in both males and females were also similar to those in the total population. Conclusion Our data support a strongly positive individual and combined association of famine exposure and serum uric acid with hypertension in middle-aged and elderly Chinese.

Cardiometabolic Traits Mediated the Relationship from Early Life Famine Exposure to Adulthood Nonalcoholic Fatty Liver Disease Risk

Early life exposure to famine was associated with adulthood metabolic syndrome and nonalcoholic fatty liver disease (NAFLD), and NAFLD was also affected by cardiometabolic traits. However, the role of cardiometabolic traits in the associations from famine exposure to NAFLD was largely unknown. This study aimed to investigate whether the relationship between early life famine exposure and adulthood NAFLD risk was mediated by cardiometabolic traits. Overall, 7,578 subjects aged 56.0 ± 3.7 years in the Dongfeng-Tongji cohort were included and classified into late-exposed (1952-1954), middle-exposed (1954-1956), early-childhood-exposed (1956-1958), fetal-exposed (1959-1961), and nonexposed (1962-1966, reference) group according to the birth year. NAFLD was diagnosed by experienced physicians via abdominal B-type ultrasound inspection. Mediation analysis was used to evaluate the mediating effects of cardiometabolic traits. Compared with those nonexposed, after multivariable adjustment, participants in fetal-exposed group (OR: 1.37; 95% CI: 1.08-1.73) had 37% higher risk to develop NAFLD, and the overall childhood-exposed group had marginally significant association with NAFLD (OR: 1.39; 95% CI: 0.99-1.94). Stratification analysis found the famine-NAFLD associations more evident in women and those born in areas severely affected by famine. Mediation analysis showed that cardiometabolic traits such as TC, TyG index, γ-GT, ALP, and ALT mediated 6.7%-22.2% of the relation from famine exposure to higher NAFLD risk. Early life exposure to famine was related to increased adulthood NAFLD risk, and this relationship was partly mediated by cardiometabolic traits.

222Long-term mortality after early famine exposure: findings from the China Kadoorie Biobank

Background Previous studies suggested that increased risks of chronic diseases in China might be attributable to early experience of the Chinese Great Famine during last century, but the reliable evidence for adult mortality was rare. This study is to investigate the association of early famine exposure with death risks in the middle age. Methods A number of 94 051 participants from China Kadoorie Biobank were categorized as non-famine births (born between 10/1/1956 and 9/30/1958, and 10/1/1962 and 9/30/1964) and famine births (born between 10/1/1959 and 9/30/1961). The outcomes were total and cause specific mortality. Cox regression was used to estimate hazard ratio (HR) for famine exposure. Results During a median 10.2 years of follow-up, we documented 2802 total deaths in all participants. Prenatal famine exposure was only associated with the risks of ischemic heart disease (IHD) mortality in adulthood (310 deaths, HR [95% CI]: 1.34 [1.02, 1.75]), compared with non-famine births. We also observed the association of famine with total mortality (HR [95% CI]: 1.42 [1.12, 1.78]) in daily alcohol drinkers, but not in non-daily drinkers (P for interaction: 0.025). Conclusions This study indicated that early famine exposure was associated with an increased death risk of heart disease and such risk may be modified by adult alcohol consumption. Key messages Early Chinese famine experience might impact adult IHD deaths. Coexistence of early famine experience and adult alcohol consumption was associated with higher risks of total mortality.

Early-Life Exposure to the Chinese Famine and Risk of Hyperuricemia in Adult Females in Qingdao

Purpose: We aimed to explore whether exposure to the Chinese famine in early life was associated with hyperuricemia in adulthood. Methods and Results: Two population-based cross-sectional surveys involving randomly selected Chinese adults aged 35–74 years were conducted in Qingdao, China in 2006 and 2009. 9055 subjects from the two surveys were grouped into four birth groups of fetal/infant exposed(born between 1959/1/1 and 1962/12/31), childhood exposed(born between 1950/1/1 and 1958/12/31), adolescence exposed(born between 1942/1/1 and 1949/12/31) and the unexposed(born before 1941 and after 1963). Multivariate logistic regression models were used to calculate the odd ratios (ORs) and 95% confidence intervals (CIs) of hyperuricemia in different exposed groups. Overall, famine exposure in the fetal/infant period, childhood and adolescence was not associated with adulthood hyperuricemia (all P>0.05). In females, childhood exposed group(OR=1.59, 95%CI:1.25-2.02) and adolescence exposed group(OR=1.74, 95%CI:1.30-2.33) both had higher risks to have hyperuricemia in adult. However, this difference was not found in fetal/infant exposed group. In males, no significant relation was observed in any famine exposed group (all P>0.05). Conclusions: Exposure to famine in childhood and adolescence is associated with an increased risk of hyperuricemia for adulthood of females, but not in males. Adequate nutrition during early life appears to be beneficial to prevent hyperuricemia of adult females.