Systolic blood pressure as a critical mediator in the association between adult height and 25-year risk of stroke.

BACKGROUND: Adult height is associated with the risk of stroke. However, the underlying mechanism remains unclear. We explored the mediating role of metabolic factors in the association between adult height and stroke incidence. METHODS: We used data from 3306 community-dwelling participants with complete information on adult height, metabolic factors, and 25-year cardiovascular outcomes. Participants were classified into three adult height groups based on sex-specific height quartiles: short (Q1), average (Q2-Q3), and tall (Q4). The primary endpoint was the occurrence of cardiovascular disease, including coronary artery disease and stroke. RESULTS: Taller adult height was associated with a lower risk of stroke. Compared with the short group the risk of stroke reduced with taller height with a hazard ratio (HR) of 0.68 in the average group (95% confidence interval [CI]: 0.50-0.93), and 0.45 in the tall group (95% CI: 0.31-0.65). Low systolic blood pressure was considered as a protective mediator in the effect of adult height on the risk of stroke in the average (HR: 0.86; 95% CI: 0.82-0.93) and the tall group (HR: 0.85; 95% CI: 0.78-0.91). Systolic blood pressure significantly contributed to height-related stroke risk (proportion mediated: 0.41; 95% CI: 0.19-1.56). CONCLUSIONS: This study found an inverse association between adult height and stroke risk, which is partly driven by lower systolic blood pressure. These findings highlight the importance of systolic blood pressure management as a potential preventive strategy against stroke.

Associations of central precocious puberty with blood pressure trajectories: prospective cohort study.

BACKGROUND: Sex differences in blood pressure (BP) appear during childhood and adolescence, but the role of central precocious puberty (CPP) remains unclear. In this study, we aimed to examine the association of CPP with the risk of early hypertension and BP trajectories in girls and boys. METHODS: We analyzed trajectories of BP before and after puberty in girls aged 6-13 years (n = 305) and boys aged 10-15 years (n = 153) in the Taiwan Pubertal Longitudinal Study. The timing of puberty onset was defined as the month at which the children reached Tanner stage 2. We examined the association of CPP with the risk of early hypertension and BP trajectories before and after puberty onset. RESULTS: Among boys, CPP was found to be associated with early hypertension (odds ratio, 7.45 [95% CI, 1.15-48.06]), whereas no such association was observed among girls. Boys with CPP had higher systolic BP than did those with normal puberty onset before puberty onset (mean difference, 6.51 [95% CI, 0.58-12.43]) and after puberty onset (mean difference, 8.92 [95% CI, 8.58-15.26]). CONCLUSION: A large proportion of the higher systolic BP observed in boys with CPP compared with in those with normal puberty onset is accrued after puberty. IMPACT: We examined the sex-specific association of central precocious puberty with blood pressure trajectories to better understand whether central precocious puberty was associated with early hypertension. Central precocious puberty was associated with differences in systolic blood pressure trajectories, especially after puberty onset in boys. For boys only, central precocious puberty was associated with early hypertension. A large proportion of the higher systolic blood pressure observed in boys with central precocious puberty compared with in those with normal puberty onset was accrued after puberty. Interventions targeting central precocious puberty are likely to influence systolic blood pressure in early adulthood.

Maternal Omega-3 Supplementation During Pregnancy, but Not Childhood Supplementation, Reduces the Risk of Food Allergy Diseases in Offspring.

BACKGROUND: Omega-3 supplementation has been reported to modulate immune responses and prevent food allergies among children; however, findings are inconsistent, and the timing of supplementation, which is critical, has not been thoroughly investigated. OBJECTIVE: To assess optimal timing (maternal vs childhood intake) of omega-3 supplementation for reducing food allergy risk among children in 2 periods (the first 3 years and beyond 3 years of age). METHODS: We performed a meta-analysis to assess the effects of maternal or childhood omega-3 supplementation on preventing the development of infant food allergies and food sensitizations. The PubMed/MEDLINE, Embase, Scopus, and Web of Science databases were searched for related studies published until October 30, 2022. We conducted dose-response and subgroup analyses to investigate the effects of omega-3 supplementation. RESULTS: We found that maternal omega-3 supplementation during pregnancy and lactation was significantly associated with decreased risks of infant egg sensitization (relative risk [RR]: 0.58, 95% confidence interval [95% CI]: 0.47-0.73, P < .01) and peanut sensitization (RR: 0.62, 95% CI: 0.47-0.80, P < .01) among children. Similar results were found in subgroup analyses for food allergy, egg sensitization, and peanut sensitization during the first 3 years of age and peanut sensitization and cashew nut sensitization beyond 3 years of age. Dose-response analysis showed a linear relationship between maternal omega-3 supplementation and infant egg sensitization risk during early life. By contrast, intake of omega-3 polyunsaturated fatty acid during childhood did not appear to significantly protect against food allergies. CONCLUSIONS: Maternal omega-3 supplementation during pregnancy and lactation, rather than childhood intake, reduces the risk of infant food allergy and food sensitization.

Corrigendum: Systolic blood pressure as the mediator of the effect of early menarche on the risk of coronary artery disease: A Mendelian randomization study.

[This corrects the article DOI: 10.3389/fcvm.2022.1023355.].

Hypertension as a Novel Link for Shared Heritability in Age at Menarche and Cardiometabolic Traits.

CONTEXT: Extremely early age at menarche, also called precocious puberty, has been associated with various cardiometabolic traits, but their shared heritability remains unclear. OBJECTIVES: This work aimed to identify new shared genetic variants and their pathways for age at menarche and cardiometabolic traits and to investigate the influence of central precocious puberty on childhood cardiometabolic traits. METHODS: Using the conjunction false discovery rate method, this study analyzed genome-wide association study data from the menarche-cardiometabolic traits among 59 655 females of Taiwanese ancestry and systemically investigated pleiotropy between age at menarche and cardiometabolic traits. To support the novel hypertension link, we used the Taiwan Puberty Longitudinal Study (TPLS) to investigate the influence of precocious puberty on childhood cardiometabolic traits. RESULTS: We discovered 27 novel loci, with an overlap between age at menarche and cardiometabolic traits, including body fat and blood pressure. Among the novel genes discovered, SEC16B, CSK, CYP1A1, FTO, and USB1 are within a protein interaction network with known cardiometabolic genes, including traits for obesity and hypertension. These loci were confirmed through demonstration of significant changes in the methylation or expression levels of neighboring genes. Moreover, the TPLS provided evidence regarding a 2-fold higher risk of early-onset hypertension that occurred in girls with central precocious puberty. CONCLUSION: Our study highlights the usefulness of cross-trait analyses for identifying shared etiology between age at menarche and cardiometabolic traits, especially early-onset hypertension. The menarche-related loci may contribute to early-onset hypertension through endocrinological pathways.

Systolic blood pressure as the mediator of the effect of early menarche on the risk of coronary artery disease: A Mendelian randomization study.

Background: Menarche timing may not be directly associated with the risk of coronary artery disease (CAD). Therefore, we investigated the roles of metabolic factors in explaining the effect of age at menarche on CAD risk. Methods: We identified women with age at menarche and CAD by using three analytical methods: Mendelian randomization (MR), logistic regression analysis, and Cox proportional hazard regression. The first two analyses were performed in the Taiwan Biobank (N = 71,923) study, and the last analysis was performed in the Chin-Shan Community Cardiovascular Cohort study (N = 1,598). We further investigated the role of metabolic factors in mediating the effect of age at menarche on CAD risk by using three complementary methods with mediation analyses. Results: One standard deviation of earlier age at menarche was associated with a 2% higher CAD risk [odds ratio = 1.02, 95% confidence interval (CI) = 1.001-1.03] in the MR analysis, an 11% higher risk (odds ratio = 1.11, 95% CI = 1.02-1.21) in the logistic regression analysis, and a 57% higher risk (hazard ratio = 1.57, 95% CI = 1.12-2.19) in the Cox proportional hazard regression. All the analyses consistently supported the role of systolic blood pressure in mediating this effect. The MR results indicated that 29% (95% CI = 26%-32%) of the effect of genetically predicted earlier age at menarche on CAD risk was mediated by genetically predicted systolic blood pressure. Conclusion: The results obtained using different analytical methods suggest that interventions aimed at lowering systolic blood pressure can reduce the cases of CAD attributable to earlier age at menarche.

Targeted next-generation sequencing for genetic variants of left ventricular mass status among community-based adults in Taiwan.

Background: Left ventricular mass is a highly heritable disease. Previous studies have suggested common genetic variants to be associated with left ventricular mass; however, the roles of rare variants are still unknown. We performed targeted next-generation sequencing using the TruSight Cardio panel, which provides comprehensive coverage of 175 genes with known associations to 17 inherited cardiac conditions. Methods: We conducted next-generation sequencing using the Illumina TruSight Cardiomyopathy Target Genes platform using the 5% and 95% extreme values of left ventricular mass from community-based participants. After removing poor-quality next-generation sequencing subjects, including call rate <98% and Mendelian errors, 144 participants were used for the analysis. We performed downstream analysis, including quality control, alignment, coverage length, and annotation; after setting filtering criteria for depths more than 60, we found a total of 144 samples and 165 target genes for further analysis. Results: Of the 12,287 autosomal variants, most had minor allele frequencies of <1% (rare frequency), and variants had minor allele frequencies ranging from 1% to 5%. In the multi-allele variant analyses, 16 loci in 15 genes were significant using the false discovery rate of less than .1. In addition, gene-based analyses using continuous and binary outcomes showed that three genes (CASQ2, COL5A1, and FXN) remained to be associated with left ventricular mass status. One single-nucleotide polymorphism (rs7538337) was enriched for the CASQ2 gene expressed in aorta artery (p = 4.6 × 10-18), as was another single-nucleotide polymorphism (rs11103536) for the COL5A1 gene expressed in aorta artery (p = 2.0 × 10-9). Among the novel genes discovered, CASQ2, COL5A1, and FXN are within a protein-protein interaction network with known cardiovascular genes. Conclusion: We clearly demonstrated candidate genes to be associated with left ventricular mass. Further studies to characterize the target genes and variants for their functional mechanisms are warranted.

Maternal Vegetable and Fruit Consumption during Pregnancy and Its Effects on Infant Gut Microbiome.

Maternal nutrition intake during pregnancy may affect the mother-to-child transmission of bacteria, resulting in gut microflora changes in the offspring, with long-term health consequences in later life. Longitudinal human studies are lacking, as only a small amount of studies showing the effect of nutrition intake during pregnancy on the gut microbiome of infants have been performed, and these studies have been mainly conducted on animals. This pilot study explores the effects of high or low fruit and vegetable gestational intake on the infant microbiome. We enrolled pregnant women with a complete 3-day dietary record and received postpartum follow-up. The 16S rRNA gene sequence was used to characterize the infant gut microbiome at 2 months (n = 39). Principal coordinate analysis ordination revealed that the infant gut microbiome clustered differently for high and low maternal fruit and vegetable consumption (p < 0.001). The linear discriminant analysis effect size and feature selection identified 6 and 17 taxa from both the high and low fruit and vegetable consumption groups. Among the 23 abundant taxa, we observed that six maternal intake nutrients were associated with nine taxa (e.g., Erysipelatoclostridium, Isobaculum, Lachnospiraceae, Betaproteobacteria, Burkholderiaceae, Sutterella, Clostridia, Clostridiales, and Lachnoclostridium). The amount of gestational fruit and vegetable consumption is associated with distinct changes in the infant gut microbiome at 2 months of age. Therefore, strategies involving increased fruit and vegetable consumption during pregnancy should be employed for modifying the gut microbiome early in life.

Adolescent Tri-ponderal Mass Index Growth Trajectories and Incident Diabetes Mellitus in Early Adulthood.

PURPOSE: Studies have reported the influence of adolescent obesity on development of adult diabetes, but the effect of the growth pattern during this period has rarely been explored. Also, the tri-ponderal mass index (TMI) was thought to be a better estimation of adolescent body fat levels than the body mass index (BMI), so we sought to investigate whether growth trajectories derived by these two indices could predict incident diabetes. METHODS: We conducted a study by using the Taipei City Hospital Radiation Building Database, a longitudinal cohort established in 1996. Physical exam results including blood test results were collected annually and the BMI z-score/TMI growth trajectory groups during 13 to 18 years of age were identified using growth mixture modeling. A Cox proportional hazard model for incident diabetes was used to examine the risk of baseline obese status and different BMI/TMI growth trajectories. RESULTS: Five growth trajectory groups were identified for the BMI z-score and the TMI. During approximately 20 400 person-years follow-up, 33 of 1387 participants developed diabetes. Baseline obesity defined by the BMI z-score and the TMI were both related to adult diabetes. The persistent increase TMI growth trajectory exhibited a significantly increased risk of diabetes after adjusting for baseline obese status and other correlated covariates (hazard ratio: 2.85, 95% confidence interval: 1.01-8.09). There was no association between BMI growth trajectory groups and incident diabetes. CONCLUSIONS: A specific TMI growth trajectory pattern during adolescence might be critical for diabetes prevention efforts.

Nutrient Intake through Childhood and Early Menarche Onset in Girls: Systematic Review and Meta-Analysis.

Among the genetic and environmental risk factors, nutrition plays a crucial role in determining the timing of puberty. Early menarche onset (EMO) is defined as when girls reach menarche onset at an age which is earlier than the mean/median age of menarche, between 12 and 13 years of age, according to individual ethnicity. The present study examined the association between nutrient intake in childhood and EMO risk in healthy girls by performing a systematic review and meta-analysis of prospective studies. We screened EMBASE, Cochrane Library, PubMed/MEDLINE, and Web of Science databases for 16 eligible studies with all medium-to-high quality scores ranging from 3 to 5 of 6 possible points with 10,884 subjects. Higher intakes of energy (risk ratio (RR) = 3.32, 95% confidence interval (CI) = 1.74-6.34, I2 = 97%), and protein (RR = 3.15, 95% CI = 2.87-3.44, I2 = 0%) were associated with EMO risk. For each additional 1 g/day animal protein intake in childhood, the age at menarche was approximately two months earlier (ß = -0.13, I2 = 55%), and high iron intake was associated with EMO (RR = 1.20, 95% CI = 1.03-1.40, I2 = 0%). Polyunsaturated fatty acid (PUFAs) intake was associated with EMO risk with a dose-response effect (RR = 1.25, 95% CI = 1.05-1.49, I2 = 44%). Girls with a high intake of fiber and monosaturated fatty acids (MUFAs) in childhood experienced later menarche onset (RR = 0.83, 95% CI = 0.69-1.00, I2 = 31%; RR = 0.66, 95% CI = 0.50-0.86, I2 = 0%, respectively). Thus, adherence to a high intake of animal proteins-, iron- and PUFA-rich food diet makes girls more likely to have EMO, while a high intake of fiber- and MUFA-rich foods may protect girls from EMO. Further studies are expected to investigate the role of specific types of PUFAs and MUFAs on EMO to promote healthy sexual maturity in girls.

Effects of real-time feedback on cardiopulmonary resuscitation quality on outcomes in adult patients with cardiac arrest: A systematic review and meta-analysis.

AIM: To investigate the relationship between the implementation of real-time audiovisual cardiopulmonary resuscitation (CPR) feedback devices with cardiac arrest patient outcomes, such as return of spontaneous circulation (ROSC), short-term survival, and neurological outcome. METHODS: We systematically searched PubMed, Embase, and the Cochrane CENTRAL from inception date until April 30, 2020, for eligible randomized and nonrandomized studies. Pooled odds ratio (OR) for each binary outcome was calculated using R system. The primary patient outcome was ROSC. The secondary outcomes were short-term survival and favorable neurological outcomes (cerebral performance category scores: 1 or 2). RESULTS: We identified 11 studies (8 nonrandomized and 3 randomized studies) including 4851 patients. Seven studies documented patients with out-of-hospital cardiac arrest and four studies documented patients with in-hospital cardiac arrest. The pooled results did not confirm the effectiveness of CPR feedback device, possibly because of the high heterogeneity in ROSC (OR: 1.42, 95% CI: 1.03-1.94, I2: 80%, tau2: 0.1875, heterogeneity test p <  0.01) and survival-to-discharge (OR: 1.27, 95% CI: 0.74-2.18, I2: 86%, tau2: 0.4048, heterogeneity test p <  0.01). The subgroup analysis results revealed that heterogeneity was due to the types of devices used. Patient outcomes were more favorable in studies investigating portable devices than in studies investigating automated external defibrillator (AED)-associated devices. CONCLUSIONS: Whether real-time CPR feedback devices can improve patient outcomes (ROSC and short-term survival) depend on the type of device used. Portable devices led to better outcomes than did AED-associated devices. Future studies comparing different types of devices are required to reach robust conclusion. PROTOCOL REGISTRATION: Prospero registration ID CRD42020155388.

Early pubertal maturation and risk of childhood asthma: A Mendelian randomization and longitudinal study.

BACKGROUND: Studies on early puberty and incident asthma have reported inconsistent results and are mainly performed in females. In this longitudinal study, we investigated the causal relationship between pubertal maturation and asthma through Mendelian randomization (MR) and explored the joint effect of overweightness and early pubertal maturation on asthma. METHODS: We used data from the Taiwan Children Health Study with longitudinal follow-ups of 2991 children aged 11-17 years. Six puberty-related single-nucleotide polymorphisms (combined into a weighted allelic score) were used to yield genetic instrumental variables for early puberty. Early pubertal maturation was defined as reaching a certain pubertal stage earlier than the median age for that stage. Incident asthma cases were calculated by excluding children with a history of asthma prior to that age. RESULTS: The results of MR analysis revealed that early pubertal maturation was associated with active asthma (OR = 1.18; 95% CI: 1.08-1.28); this effect was significant in male children. Early pubertal maturation significantly increased the risk of incident asthma outcomes at 12 and 17 years of age in both sexes (hazard ratio = 2.15; 95% CI: 1.21-3.84). Taking non-overweight and non-early puberty children as the reference group, we observed a synergistic effect of overweightness and early pubertal maturation on asthma risk (OR = 1.08; 95% CI: 1.04-1.11) in children of both sexes. CONCLUSIONS: Early screening and intervention for obesity are recommended to prevent future early pubertal onset and asthma occurrence.

Body mass index growth trajectories, early pubertal maturation, and short stature.

BACKGROUND: Childhood body mass index (BMI) trajectory classes are rarely linked to early puberty risk, particularly among Chinese children. We estimated early puberty risk across BMI trajectory classes, investigated factors contributing to pubertal development, and examined differences in final adult height between children exhibiting early and nonearly pubertal maturation across the classes. METHODS: The Taiwan Children Health Study recruited 10-year-old children in 2010 from 14 Taiwanese communities and resurveyed them at age 11, 12, and 18 years. The study comprised 3109 children (50.4% boys) with available data for BMI (age 6-11 years) and pubertal stages (age 11, 12, and 18 years). RESULTS: Classes 1-4 were persistently healthy weight, rapid BMI growth, chronically overweight/obese, and early transient overweight/obese. Children in class 3 exhibited the highest risk of early pubertal maturation. Puberty genetic score, low sleep quality, and high fat-free mass collectively explained 15% of the variance in Tanner stages among class 3 children. Early pubertal maturation was considered to cause short and tall stature in boys and girls, respectively. CONCLUSIONS: Modifying sleep quality and fat-free mass may reduce early puberty risk in children with chronic overweight/obesity. Vigorous physical activity may reduce adiposity and increase the final adult height in the children.

Association between Depressive Symptoms and Food Insecurity among Indonesian Adults: Results from the 2007-2014 Indonesia Family Life Survey.

BACKGROUND: Depressive symptoms and food insecurity are two of the public health concerns in developing countries. Food insecurity is linked to several chronic diseases, while little is known about the association between food insecurity and depressive symptoms among adults. A person with limited or uncertain availability or access to nutritionally sufficient, socially relevant, and safe foods is defined as a food-insecure person. MATERIALS AND METHODS: Data were obtained from 8613 adults who participated in the Indonesia Family Life Survey (IFLS) in 2007 and 2014. The 10 items of the food frequency questionnaire (FFQ) were used in food consumption score analysis to assess food insecurity based on the concept of the World Food Program (WFP). Depressive symptoms were assessed using 10 items of the self-reported Center for Epidemiologic Studies Depression (CES-D) questionnaire. A linear and multiple logistic regression model with a generalized estimating equation was used to test the hypothesis while accounting for the health behaviors and sociodemographic characteristics. RESULTS: Food consumption score was negatively associated with CES-D 10 score (ß-coefficients: -9.71 × 10-3 to -1.06 × 10-2; 95% CIs: -7.46 × 10-3 to -1.26 × 10-2). The borderline and poor food consumption group was positively associated with the depressive symptoms, both in the unadjusted and adjusted models (exponentiated ß-coefficients: 1.13 to 1.18; 95% CIs: 1.06 to 1.28). Conclusions: Depressive symptoms were positively significantly associated with food insecurity. Thus, health professionals must be aware of the issue, and should consider health and nutrition programs for adults at risk of food insecurity.

Assessing causality between childhood adiposity and early puberty: A bidirectional Mendelian randomization and longitudinal study.

AIMS: Obesity and early puberty have been reported to be mutually causative. We investigated the causal relationship between adiposity and early puberty by performing bidirectional Mendelian randomization (MR) and longitudinal data analyses. METHODS: We used information from the Taiwan Children Health Study (3109 adolescents aged 11-12 years) with 17 body mass index (BMI)- and 10 puberty-related single-nucleotide polymorphisms (SNPs) to produce genetic instrumental variables (IVs). The two-stage least squares (2SLS) method, MR sensitivity analysis, and survival analysis were used to explore and confirm causality. RESULTS: Regression estimates from IVs revealed that significantly increased association of BMI with early puberty was noted (coefficients: 0.13, 0.10, and 0.09; 95% CI: 0.07-0.19, 0.02-0.19, and 0.02-0.16 for all participants, male adolescents, and female adolescents, respectively). Genetic IVs for puberty were not associated with BMI. MR sensitivity and two-sample MR analyses produced similar results. Longitudinal analysis results revealed that prepubertal overweight and obesity could predict early onset of puberty. However, after excluding children with a history of overweight and obesity at the age of 7-12 years, early puberty was not found to trigger new-onset of overweight and obesity at the age of 18 years in either sex. CONCLUSIONS: Higher adiposity may lead to early puberty. However, the causal effects of early puberty on adiposity accumulation were not supported by our data. Targeted interventions to reduce childhood obesity are strongly recommended to prevent obesity-related comorbidities, as well as early puberty onset.

Where and How Centenarians Die? The Role of Hospice Care.

The effect of hospice care on place of death among centenarians remained unexplored. Using data obtained from National Health Insurance Research Database (2002-2010), we compared the differences in place and cause of death between centenarians and noncentenarians. These data were stratified into centenarian (n = 2495) and noncentenarian (n = 820 563) death. Data in place and cause of death and hospice care interventions were retrieved. Poisson regression models were used to evaluate factors associated with the centenarians' place of death. Time series models were used to predict the number of centenarian deaths until 2025. Most (63.8%) of the centenarians died at their own homes, followed by 30.5% who died in hospital. Hospice home care was involved in only 0.3% of the centenarian deaths but in 1.8% of the noncentenarian deaths. The leading causes of death among centenarians were respiratory diseases (16.6%), circulatory diseases (15.2%), and pneumonia (14.8%). Among the centenarians, those who died of circulatory disease, old age, and respiratory diseases were more likely to die at their own homes. We forecasted the number of annual centenarian deaths to reach 800 in 2025. Therefore, an increase in the provision of advanced care planning and earlier home hospice care intervention may enable centenarians to die at their own residence.

Causal relationships between adiposity and childhood asthma: bi-directional Mendelian Randomization analysis.

BACKGROUND/OBJECTIVES: Obesity and asthma are common chronic diseases and have been reported to be mutually causative. We investigated the causal direction of the relationship between adiposity and asthma using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis. SUBJECTS/METHODS: We used data from the Taiwan Children Health Study with 24 body mass index (BMI)-single-nucleotide polymorphisms (SNPs, combined into a weighted allelic score) and 16 asthma-SNPs (combined into two weighted allelic scores, separately for asthma inflammatory and antioxidative genes) to yield genetic IVs for adiposity and asthma, respectively. RESULTS: The weighted allele score for BMI was strongly associated with adiposity (p = 2 × 10-16) and active asthma (p = 0.03). The two-stage least square regression risk ratio (RR) for the effect of BMI on asthma was 1.04 (95% confidence interval: 1.00-1.07, p = 0.03). Although the weighted asthma genetic scores were significantly associated with asthma (p = 8.4 × 10-3), no association was seen for genetically instrumented asthma with BMI using MR. Central obesity was the most accurate predictor of asthma. Adiposity showed higher causal effects on asthma in boys and children with non-atopic asthma. Sensitivity analysis for MR revealed no directional genetic pleiotropy effects. The causal effect RRs of BMI on asthma were 1.04, 1.08, and 1.03 for inverse-variance weighted, MR-Egger regression (slope), and weighted median methods, respectively, all in accordance with the MR estimates. CONCLUSIONS: High adiposity may lead to asthma, whereas the effects of asthma on adiposity accumulation are likely to be small.

Birthweight, time-varying adiposity growth and early menarche in girls: A Mendelian randomisation and mediation analysis.

OBJECTIVE: To explore the causal effect of time-varying z-BMI growth on early menarche using Mendelian randomisation (MR); to identify critical adiposity predictors of early menarche; to compare the effects of birthweight and time-varying z-BMI growth as mediators of the path from genes to early menarche using mediation analysis. METHODS: We used data from the Taiwan Children Health Study with 21 obesity-related single-nucleotide polymorphisms (SNPs) to yield genetic (instrumental variable)IVs for adiposity. Children with available data on genotyping, birthweight, adiposity, and menarcheal age were included. RESULTS: In MR analyses, results based on the time-varying z-BMI growth show more statistical power and capture more information of adiposity growth (p=0.01) than those based on single point z-BMI (p=0.02). Among adiposity measures, critical predictors of early menarche are fat free mass (RR=1.33, 95% CI 1.07-1.65) and waist/height ratio (RR=1.27, 95% CI 1.03-1.56). Other potential predictors of early menarche are sum of skinfold (RR=1.24, 95% CI 1.03-1.48) and total body fat (RR=1.20, 95% CI 1.05-1.38). In both one-mediation and multi-mediation analyses, time-varying z-BMI growth in the prepubertal years plays a crucial mediator in the pathway from the genes to early menarche. CONCLUSIONS: This study discovered that greater prepubertal adiposity growth is a crucial mediator in the path from genes to early menarche. For girls with genes positively associated with obesity; and/or of lower birthweight, a strategy to prevent childhood adiposity should be implemented in order to avoid early menarche development.