BACKGROUND AND OBJECTIVES: Childhood obesity is increasing. However, little is known about the changes in di-etary factors and supportive facilities associated with childhood obesity. We aimed to document the changes in various dietary factors and supportive facilities and their associations with obesity among pre-school children. METHODS AND STUDY DESIGN: Among 42,531 children 4-5 years old, recruited between 2004 and 2013 in the Jiax-ing Birth Cohort, we examined the changes in the prevalence of various dietary factors and supportive facilities and overweight/obesity over 10 years. We used logistic regression to investigate the cross-sectional association between these factors and childhood overweight/obesity risk, adjusting for potential confounders. RESULTS: The prevalence of childhood overweight/obesity increased steadily from 11.8% (boy: 14.8%; girl: 9%) during 2004-2005 to 18% (boy: 21.4%%; girl: 15%) during 2012-2013. The prevalence of meal/snack frequency 3 times /day decreased substantially from 23% during 2004-2005 to 8% during 2012-2013, with more children having 5 times /day: from 32% to 45.6%. Children with a fair/bad appetite, compared with those with a good appetite, had a 45% (OR: 0.55; 95% CI: 0.49, 0.62) lower risk of overweight/obesity. Children with a meal frequency >=6 times/day (compared with 3 times/day) had a 0.12 (95% CI: 0.03, 0.2) higher BMI-z-score. CONCLUSIONS: The prevalence of childhood overweight/obesity has increased substantially within a decade in southeast China. A better appetite and greater eating frequency were associated with the increased prevalence.

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.

Background: The melanocortin-4 receptor (MC4R) plays a pivotal role in the regulation of appetite and eating behavior. Variants in the MC4R gene have been related to appetite and obesity.Objective: We aimed to examine whether weight-loss diets modified the effect of the "obesity-predisposing" MC4R genotype on appetite-related measures in a randomized controlled trial.Methods: A total of 811 overweight and obese subjects [25 </= body mass index (BMI; kg/m(2)) </= 40] aged 30-70 y were included in the 2-y POUNDS Lost (Preventing Overweight Using Novel Dietary Strategies) trial. We genotyped MC4R rs7227255 in 735 overweight adults and assessed appetite-related characteristics, including craving, fullness, hunger, and prospective consumption, as well as a composite appetite score. We examined the effects of the genotype-by-weight-loss diet intervention interaction on appetite variables by using general linear models in both the whole population and in white participants only.Results: We found that dietary protein intake (low compared with high: 15% of energy compared with 25% of energy, respectively) significantly modified MC4R genetic effects on changes in appetite score and craving (P-interaction = 0.03 and 0.02, respectively) at 2 y, after adjustment for age, sex, ethnicity, baseline BMI, weight change, and baseline perspective phenotype. The obesity-predisposing A allele was associated with a greater increase in overall appetite score (beta = 0.10, P = 0.05) and craving (beta = 0.13, P = 0.008) compared with the non-A allele among participants who consumed a high-protein diet. MC4R genotype did not modify the effects of fat or carbohydrate intakes on appetite measures. Similar interaction patterns were observed in whites.Conclusion: Our data suggest that individuals with the MC4R rs7227255 A allele rather than the non-A allele might experience greater increases in appetite and food craving when consuming a high-protein weight-loss diet. This trial was registered at clinicaltrials.gov as NCT00072995.

Salivary and pancreatic amylases (encoded by AMY1 and AMY2 genes, respectively) are responsible for digesting starchy foods. AMY1 and AMY2 show copy number variations that affect differences in amylase amount and activity, and AMY1 copies have been associated with adiposity. We investigated whether genetic variants determining amylase gene copies are associated with 2-year changes in adiposity among 692 overweight and obese individuals who were randomly assigned to diets varying in macronutrient content. We found that changes in body weight (BW) and waist circumference (WC) were significantly different according to the AMY1-AMY2 rs11185098 genotype. Individuals carrying the A allele (indicating higher amylase amount and activity) showed a greater reduction in BW and WC at 6, 12, 18, and 24 months than those without the A allele (P < 0.05 for all). The association was stronger for long-term changes compared with short-term changes of these outcomes. The genetic effects on these outcomes did not significantly differ across diet groups. In conclusion, the genetic variant determining starch metabolism influences the response to weight-loss dietary intervention. Overweight and obese individuals carrying the AMY1-AMY2 rs11185098 genotype associated with higher amylase activity may have greater loss of adiposity during low-calorie diet interventions.

Background: Coffee consumption has been associated with glucose metabolism and risk of type 2 diabetes.Objective: We examined whether the genetic variation determining habitual coffee consumption affected glycemic changes in response to weight-loss dietary intervention.Design: A genetic risk score (GRS) was calculated based on 8 habitual coffee consumption-associated single nucleotide polymorphisms. We used general linear models to test changes in glycemic traits in groups randomly assigned to high- and low-fat diets according to tertiles of the GRS.Results: We observed significant interactions between the GRS and low compared with high dietary fat intake on 6-mo changes in fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) (P-interaction = 0.023 and 0.022, respectively), adjusting for age, sex, race, physical activity, smoking, alcohol, seasonal variation, and baseline values of the respective outcomes. Participants with a higher GRS of habitual coffee consumption showed a greater reduction in fasting insulin and a marginally greater decrease in HOMA-IR in the low-fat diet intervention group.Conclusions: Our data suggest that participants with genetically determined high coffee consumption may benefit more by eating a low-fat diet in improving fasting insulin and HOMA-IR in a short term. This trial was registered at clinicaltrials.gov as NCT00072995 and NCT03258203.

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.

[This corrects the article DOI: 10.1371/journal.pgen.1006528.].

Objective To examine whether previous observed inverse associations of dairy intake with systolic blood pressure and risk of hypertension were causal.Design Mendelian randomization study using the single nucleotide polymorphism rs4988235 related to lactase persistence as an instrumental variable.Setting CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium.Participants Data from 22 studies with 171 213 participants, and an additional 10 published prospective studies with 26 119 participants included in the observational analysis.Main outcome measures The instrumental variable estimation was conducted using the ratio of coefficients approach. Using meta-analysis, an additional eight published randomized clinical trials on the association of dairy consumption with systolic blood pressure were summarized.Results Compared with the CC genotype (CC is associated with complete lactase deficiency), the CT/TT genotype (TT is associated with lactose persistence, and CT is associated with certain lactase deficiency) of LCT-13910 (lactase persistence gene) rs4988235 was associated with higher dairy consumption (0.23 (about 55 g/day), 95% confidence interval 0.17 to 0.29) serving/day; P<0.001) and was not associated with systolic blood pressure (0.31, 95% confidence interval -0.05 to 0.68 mm Hg; P=0.09) or risk of hypertension (odds ratio 1.01, 95% confidence interval 0.97 to 1.05; P=0.27). Using LCT-13910 rs4988235 as the instrumental variable, genetically determined dairy consumption was not associated with systolic blood pressure (beta=1.35, 95% confidence interval -0.28 to 2.97 mm Hg for each serving/day) or risk of hypertension (odds ratio 1.04, 0.88 to 1.24). Moreover, meta-analysis of the published clinical trials showed that higher dairy intake has no significant effect on change in systolic blood pressure for interventions over one month to 12 months (intervention compared with control groups: beta=-0.21, 95% confidence interval -0.98 to 0.57 mm Hg). In observational analysis, each serving/day increase in dairy consumption was associated with -0.11 (95% confidence interval -0.20 to -0.02 mm Hg; P=0.02) lower systolic blood pressure but not risk of hypertension (odds ratio 0.98, 0.97 to 1.00; P=0.11).Conclusion The weak inverse association between dairy intake and systolic blood pressure in observational studies was not supported by a comprehensive instrumental variable analysis and systematic review of existing clinical trials.

The genetic variants near the Melanocortin-4 receptor gene (MC4R), a key protein regulating energy balance and adiposity, have been related to obesity and glucose metabolism. We aimed to assess whether the MC4R genotype affected longitudinal changes in body weight and glucose metabolism biomarkers among women with prior gestational diabetes mellitus (GDM). The MC4R genotype, postpartum weight reduction, and glycemic changes between after delivery and pregnancy were assessed in a cohort of 1208 Chinese women who had experienced GDM. The adiposity-increasing allele (C) of the MC4R variant rs6567160 was associated with greater postpartum increase of HbA1c (beta = 0.08%; P = 0.03) and 2-hour OGTT glucose concentrations (beta = 0.25 mmol/L; P = 0.02). In addition, we found an interaction between the MC4R genotype and postpartum weight reduction on changes in fasting plasma glucose (P-interaction = 0.03). We found that the MC4R genotype was associated with postpartum glycemic changes; and the association with fasting glucose were significantly modified by postpartum weight reduction in women who had experienced GDM.

Context: Maternal hypertensive disorders during pregnancy are suggested to affect obesity risk in offspring. However, little is known about the prospective association of rise in maternal blood pressure within normal range during pregnancy with this risk for obesity. Objective: To clarify the associations of diastolic and systolic blood pressure during pregnancy among normotensive women with the risk for obesity in offspring. Design: Prospective cohort study. Setting: Southeast China. Participants: Up to 2013, a total of 88,406 mother-child pairs with anthropometric measurements of offspring age 4 to 7 years were included in the present analysis. Main Outcome Measures: Overweight/obesity risk in offspring. Results: Among normotensive women, second- and third-trimester diastolic and systolic blood pressures were positively associated with risk for overweight/obesity in offspring: odds ratios per 10-mm Hg higher second- and third-trimester diastolic blood pressure were 1.05 [95% confidence interval (CI), 1.01 to 1.09] and 1.05 (95% CI, 1.02 to 1.10), respectively, and for systolic blood pressure were 1.08 (95% CI, 1.05 to 1.11) and 1.06 (95% CI, 1.03 to 1.09). Each 10-mm Hg greater rise in blood pressure between first and third trimesters was associated with a higher risk for offspring overweight/obesity: diastolic, 1.06 (95% CI, 1.01 to 1.10); systolic, 1.05 (95% CI, 1.02 to 1.07). Among all women (combining normotensive and hypertensive women), maternal hypertension in the second and third trimesters was associated with 49% and 14% higher risks for overweight/obesity in offspring, respectively. Conclusions: These results suggest that rise in maternal blood pressure during pregnancy and hypertension during pregnancy, independent of maternal body size before pregnancy, are risk factors for offspring childhood obesity.

Modulation of n-3 fatty acids on genetic susceptibility to type 2 diabetes (T2D) is still not clear. In a case-control study of 622 Chinese T2D patients and 293 healthy controls, a genetic risk score (GRS) was created based on nine T2D genetic variants. Logistic regression was used to examine the interaction of the GRS with erythrocyte phospholipid n-3 fatty acids for T2D risk. Every 1-unit (corresponding to 1 risk allele) increase in GRS was associated with 12% (Odds ratio (OR): 1.12; 95% confidence intervals (CI): 1.04-1.20) higher risk of T2D. Compared with the lowest quartile, participants had lower T2D risk in the 2nd (OR: 0.55; 95% CI: 0.36-0.84), 3rd (OR: 0.58; 95% CI: 0.38-0.88) and 4th (OR: 0.67; 95% CI: 0.44-1.03) quartile of alpha-linolenic acid (ALA) levels. Significant interaction (p-interaction = 0.029) of GRS with ALA for T2D risk was observed. Higher ALA levels were associated with lower T2D risk only among participants within the lowest GRS tertile, with ORs 0.51 (95% CI: 0.26-1.03), 0.44 (95% CI: 0.22-0.89) and 0.49 (95% CI: 0.25-0.96) for the 2nd, 3rd and 4th ALA quartile, compared with the 1st. This study suggests that higher erythrocyte ALA levels are inversely associated with T2D risk only among participants with low T2D genetic risk, with high genetic risk abolishing the ALA-T2D association.

Renal ischemia-reperfusion is a main cause of acute kidney injury (AKI), which is associated with high mortality. Here we show that extracellular vesicles (EVs) secreted from hiPSC-MSCs play a critical role in protection against renal I/R injury. hiPSC-MSCs-EVs can fuse with renal cells and deliver SP1 into target cells, subsequently active SK1 expression and increase S1P formation. Chromatin immunoprecipitation (ChIP) analyses and luciferase assay were used to confirm SP1 binds directly to the SK1 promoter region and promote promoter activity. Moreover, SP1 inhibition (MIT) or SK1 inhibition (SKI-II) completely abolished the renal protective effect of hiPSC-MSCs-EVs in rat I/R injury mode. However, pre-treatment of necroptosis inhibitor Nec-1 showed no difference with the administration of hiPSC-MSCs-EVs only. We then generated an SP1 knockout hiPSC-MSC cell line by CRISPR/Cas9 system and found that SP1 knockout failed to show the protective effect of hiPSC-MSCs-EVs unless restoring the level of SP1 by Ad-SP1 in vitro and in vivo. In conclusion, this study describes an anti-necroptosis effect of hiPSC-MSCs-EVs against renal I/R injury via delivering SP1 into target renal cells and intracellular activating the expression of SK1 and the generation of S1P. These findings suggest a novel mechanism for renal protection against I/R injury, and indicate a potential therapeutic approach for a variety of renal diseases and renal transplantation.

Background: Previous studies have indicated that the cardioprotective effects of long-chain (LC) n-3 (omega-3) polyunsaturated fatty acids (PUFAs) may vary across various ethnic populations. Emerging evidence has suggested that the gene-environment interaction may partly explain such variations. Proprotein convertase subtilisin/kexin type 9 (PCSK9) was shown to have a mutually regulating relation with LC n-3 PUFAs and also to reduce the risk of cardiovascular diseases (CVDs). Therefore, we hypothesized that certain PCSK9 genetic variants may modify the association between LC n-3 PUFA intake and CVD risk.Objective: We determined whether a PCSK9 variant (rs11206510), which has been identified for early onset myocardial infarction (MI), modified the association of LC n-3 PUFAs with nonfatal MI risk in Costa Rican Hispanics.Design: We analyzed cross-sectional data from 1932 case subjects with a first nonfatal MI and 2055 population-based control subjects who were living in Costa Rica to examine potential gene-environment interactions. Two-sided P values <0.05 were considered significant.Results: We observed a significant interaction between the PCSK9 rs11206510 genotype and LC n-3 PUFA intake on nonfatal MI risk (P-interaction = 0.012). The OR of nonfatal MI was 0.84 (95% CI: 0.72, 0.98) per 0.1% increase in total energy intake from LC n-3 PUFAs in protective-allele (C-allele) carriers, whereas the corresponding OR (95% CI) in non-C-allele carriers was 1.02 (95% CI: 0.95, 1.10). Similar results were observed when we examined the association between docosahexaenoic acid, which is one type of LC n-3 PUFA, and nonfatal MI risk (P-interaction = 0.003).Conclusion: LC n-3 PUFA intake is associated with a lower risk of nonfatal MI in C-allele carriers of PCSK9 rs11206510 (n = 799) but not in non-C-allele carriers (n = 3188).

BACKGROUND: Whether habitual coffee consumption interacts with the genetic predisposition to obesity in relation to body mass index (BMI) and obesity is unknown. METHODS: We analyzed the interactions between genetic predisposition and habitual coffee consumption in relation to BMI and obesity risk in 5116 men from the Health Professionals Follow-up Study (HPFS), in 9841 women from the Nurses' Health Study (NHS), and in 5648 women from the Women's Health Initiative (WHI). The genetic risk score was calculated based on 77 BMI-associated loci. Coffee consumption was examined prospectively in relation to BMI. RESULTS: The genetic association with BMI was attenuated among participants with higher consumption of coffee than among those with lower consumption in the HPFS (P interaction = 0.023) and NHS (P interaction = 0.039); similar results were replicated in the WHI (P interaction = 0.044). In the combined data of all cohorts, differences in BMI per increment of 10-risk allele were 1.38 (standard error (SE), 0.28), 1.02 (SE, 0.10), and 0.95 (SE, 0.12) kg/m(2) for coffee consumption of < 1, 1-3 and > 3 cup(s)/day, respectively (P interaction < 0.001). Such interaction was partly due to slightly higher BMI with higher coffee consumption among participants at lower genetic risk and slightly lower BMI with higher coffee consumption among those at higher genetic risk. Each increment of 10-risk allele was associated with 78% (95% confidence interval (CI), 59-99%), 48% (95% CI, 36-62%), and 43% (95% CI, 28-59%) increased risk for obesity across these subgroups of coffee consumption (P interaction = 0.008). From another perspective, differences in BMI per increment of 1 cup/day coffee consumption were 0.02 (SE, 0.09), -0.02 (SE, 0.04), and -0.14 (SE, 0.04) kg/m(2) across tertiles of the genetic risk score. CONCLUSIONS: Higher coffee consumption might attenuate the genetic associations with BMI and obesity risk, and individuals with greater genetic predisposition to obesity appeared to have lower BMI associated with higher coffee consumption.

Whether change in physical activity over time modifies the genetic susceptibility to long-term weight gain is unknown. We calculated a BMI-genetic risk score (GRS) based on 77 BMI-associated single nucleotide polymorphisms (SNPs) and a body fat percentage (BF%)-GRS based on 12 BF%-associated SNPs in 9,390 women from the Nurses' Health Study (NHS) and 5,291 men from the Health Professionals Follow-Up Study (HPFS). We analyzed the interactions between each GRS and change in physical activity on BMI/body weight change within five 4-year intervals from 1986 to 2006 using multivariable generalized linear models with repeated-measures analyses. Both the BMI-GRS and the BF%-GRS were associated with long-term increases in BMI/weight, and change in physical activity consistently interacted with the BF%-GRS on BMI change in the NHS (P for interaction = 0.025) and HPFS (P for interaction = 0.001). In the combined cohorts, 4-year BMI change per 10-risk allele increment was -0.02 kg/m(2) among participants with greatest increase in physical activity and 0.24 kg/m(2) among those with greatest decrease in physical activity (P for interaction < 0.001), corresponding to 0.01 kg versus 0.63 kg weight changes every 4 years (P for interaction = 0.001). Similar but marginal interactions were observed for the BMI-GRS (P for interaction = 0.045). Our data indicate that the genetic susceptibility to weight gain may be diminished by increasing physical activity.

Age of complementary foods introduction is associated with childhood anemia, but the ideal age for the introduction of complementary foods to infants is a continuing topic of debate. We examined the longitudinal association between complementary foods introduction age and risk of anemia in 18,446 children from the Jiaxing Birth Cohort, who had detailed complementary feeding records at 3 and 6 months of age and had hemoglobin concentrations measured at 4-6 years. Early introduction of complementary foods at 3-6 months of age was significantly associated with a higher risk of anemia (odds ratio = 1.14; 95% confidence interval: 1.01-1.28) and a lower hemoglobin concentration of -0.84 g/L (95% confidence interval: -1.33 to -0.35) in children aged 4-6 years, compared with those fed complementary foods starting at 6 months of age. When it comes to the specific type of complementary foods, early introduction of all plant-based foods was associated with increased anemia risks and lower hemoglobin concentrations, while early introduction of most animal-based foods was not. These findings may be informative regarding the appropriate time to introduce complementary foods in infants.

Context: Adiponectin plays key roles in regulating appetite and food intake. Objective: To investigate interactions between the genetic risk score (GRS) for adiponectin levels and weight-loss diets varying in macronutrient intake on long-term changes in appetite and adiponectin levels. Design, Setting, and Participants: A GRS was calculated based on 5 adiponectin-associated variants in 692 overweight adults from the 2-year Preventing Overweight Using Novel Dietary Strategies trial. Main Outcome Measures: Repeated measurements of plasma adiponectin levels and appetite-related traits, including cravings, fullness, prospective consumption, and hunger. Results: Dietary fat showed nominally significant interactions with the adiponectin GRS on changes in appetite score and prospective consumption from baseline to 6 months (P for interaction = 0.014 and 0.017, respectively) after adjusting for age, sex, ethnicity, baseline body mass index, and baseline respective outcome values. The GRS for lower adiponectin levels was associated with a greater decrease in appetite (P < 0.001) and prospective consumption (P = 0.008) among participants consuming a high-fat diet, whereas no significant associations were observed in the low-fat group. Additionally, a significant interaction was observed between the GRS and dietary fat on 6-month changes in adiponectin levels (P for interaction = 0.021). The lower GRS was associated with a greater increase in adiponectin in the low-fat group (P = 0.02), but it was not associated with adiponectin changes in the high-fat group (P = 0.31). Conclusions: Our findings suggest that individuals with varying genetic architecture of circulating adiponectin may respond divergently in appetite and adiponectin levels to weight-loss diets varying in fat intake.