Genetic determinants of serum bilirubin using inferred native American gene variants in Chilean adolescents.

Gene variants in the UGT1A1 gene are strongly associated with circulating bilirubin levels in several populations, as well as other variants of modest effect across the genome. However, the effects of such variants are unknown regarding the Native American ancestry of the admixed Latino population. Our objective was to assess the Native American genetic determinants of serum bilirubin in Chilean admixed adolescents using the local ancestry deconvolution approach. We measured total serum bilirubin levels in 707 adolescents of the Chilean Growth and Obesity Cohort Study (GOCS) and performed high-density genotyping using the Illumina-MEGA array (>1.7 million genotypes). We constructed a local ancestry reference panel with participants from the 1000 Genomes Project, the Human Genome Diversity Project, and our GOCS cohort. Then, we inferred and isolated haplotype tracts of Native American, European, or African origin to perform genome-wide association studies. In the whole cohort, the rs887829 variant and others near UGT1A1 were the unique signals achieving genome-wide statistical significance (b = 0.30; p = 3.34 × 10-57). After applying deconvolution methods, we found that significance is also maintained in Native American (b = 0.35; p = 3.29 × 10-17) and European (b = 0.28; p = 1.14 × 10-23) ancestry components. The rs887829 variant explained a higher percentage of the variance of bilirubin in the Native American (37.6%) compared to European ancestry (28.4%). In Native American ancestry, carriers of the TT genotype of this variant averaged 4-fold higher bilirubinemia compared to the CC genotype (p = 2.82 × 10-12). We showed for the first time that UGT1A1 variants are the primary determinant of bilirubin levels in Native American ancestry, confirming its pan-ethnic relevance. Our study illustrates the general value of the local ancestry deconvolution approach to assessing isolated ancestry effects in admixed populations.

Relation between Body Composition Trajectories from Childhood to Adolescence and Nonalcoholic Fatty Liver Disease Risk.

NAFLD has become the leading cause of chronic liver disease in children, as a direct consequence of the high prevalence of childhood obesity. This study aimed to characterize body composition trajectories from childhood to adolescence and their association with the risk of developing nonalcoholic fatty liver disease (NAFLD) during adolescence. The participants were part of the 'Chilean Growth and Obesity Cohort Study', comprising 784 children who were followed prospectively from age 3 years. Annual assessments of nutritional status and body composition were conducted, with ultrasound screening for NAFLD during adolescence revealing a 9.8% prevalence. Higher waist circumference measures were associated with NAFLD from age 3 years (p = 0.03), all skin folds from age 4 years (p < 0.01), and DXA body fat measurements from age 12 years (p = 0.01). The fat-free mass index was higher in females (p = 0.006) but not in males (p = 0.211). The second and third tertiles of the fat mass index (FMI) had odds ratios for NAFLD during adolescence of 2.19 (1.48-3.25, 95% CI) and 6.94 (4.79-10.04, 95% CI), respectively. Elevated waist circumference, skin folds, and total body fat were identified as risk factors for future NAFLD development. A higher FMI during childhood was associated with an increased risk of NAFLD during adolescence.

Differential methylation pattern in pubertal girls associated with biochemical premature adrenarche.

Biochemical premature adrenarche is defined by elevated serum DHEAS [≥40 µg/dL] before age 8 y in girls. This condition is receiving more attention due to its association with obesity, hyperinsulinemia, dyslipidemia, and polycystic ovary syndrome. Nevertheless, the link between early androgen excess and these risk factors remains unknown. Epigenetic modifications, and specifically DNA methylation, have been associated with the initiation and progression of numerous disorders, including obesity and insulin resistance. The aim of this study was to determine if prepubertal androgen exposure is associated with a different methylation profile in pubertal girls. Eighty-six healthy girls were studied. At age 7 y, anthropometric measurements were begun and DHEAS levels were determined. Girls were classified into Low DHEAS (LD) [<42 µg/dL] and High DHEAS (HD) [≥42 µg/dL] groups. At Tanner stages 2 and 4 a DNA methylation microarray was performed to identify differentially methylated CpG positions (DMPs) between HD and LD groups. We observed a differential methylation pattern between pubertal girls with and without biochemical PA. Moreover, a set of DNA methylation markers, selected by the LASSO method, successfully distinguished between HD and LD girls regardless of Tanner stage. Additionally, a subset of these markers were significantly associated with glucose-related measures such as insulin level, HOMA-IR, and glycaemia. This pilot study provides evidence consistent with the hypothesis that high DHEAS concentration, or its hormonally active metabolites, may induce a unique blood methylation signature in pubertal girls, and that this methylation pattern is associated with altered glucose metabolism.

New insights from GWAS on BMI-related growth traits in a longitudinal cohort of admixed children with Native American and European ancestry.

Body-mass index (BMI) is a hallmark of adiposity. In contrast with adulthood, the genetic architecture of BMI during childhood is poorly understood. The few genome-wide association studies (GWAS) on children have been performed almost exclusively in Europeans and at single ages. We performed cross-sectional and longitudinal GWAS for BMI-related traits on 904 admixed children with mostly Mapuche Native American and European ancestries. We found regulatory variants of the immune gene HLA-DQB3 strongly associated with BMI at 1.5 - 2.5 years old. A variant in the sex-determining gene DMRT1 was associated with the age at adiposity rebound (Age-AR) in girls (P = 9.8 × 10 - 9 ). BMI was significantly higher in Mapuche than in Europeans between 5.5 and 16.5 years old. Finally, Age-AR was significantly lower (P = 0.004 ) by 1.94 years and BMI at AR was significantly higher (P = 0.04 ) by 1.2 kg/ m 2 , in Mapuche children compared with Europeans.

Circulating citric acid cycle metabolites and risk of cardiovascular disease in the PREDIMED study.

BACKGROUND AND AIM: Plasma citric acid cycle (CAC) metabolites might be likely related to cardiovascular disease (CVD). However, studies assessing the longitudinal associations between circulating CAC-related metabolites and CVD risk are lacking. The aim of this study was to evaluate the association of baseline and 1-year levels of plasma CAC-related metabolites with CVD incidence (a composite of myocardial infarction, stroke or cardiovascular death), and their interaction with Mediterranean diet interventions. METHODS AND RESULTS: Case-cohort study from the PREDIMED trial involving participants aged 55-80 years at high cardiovascular risk, allocated to MedDiets or control diet. A subcohort of 791 participants was selected at baseline, and a total of 231 cases were identified after a median follow-up of 4.8 years. Nine plasma CAC-related metabolites (pyruvate, lactate, citrate, aconitate, isocitrate, 2-hydroxyglutarate, fumarate, malate and succinate) were measured using liquid chromatography-tandem mass spectrometry. Weighted Cox multiple regression was used to calculate hazard ratios (HRs). Baseline fasting plasma levels of 3 metabolites were associated with higher CVD risk, with HRs (for each standard deviation, 1-SD) of 1.46 (95%CI:1.20-1.78) for 2-hydroxyglutarate, 1.33 (95%CI:1.12-1.58) for fumarate and 1.47 (95%CI:1.21-1.78) for malate (p of linear trend <0.001 for all). A higher risk of CVD was also found for a 1-SD increment of a combined score of these 3 metabolites (HR = 1.60; 95%CI: 1.32-1.94, p trend <0.001). This result was replicated using plasma measurements after one-year. No interactions were detected with the nutritional intervention. CONCLUSION: Plasma 2-hydroxyglutarate, fumarate and malate levels were prospectively associated with increased cardiovascular risk. CLINICAL TRIAL NUMBER: ISRCTN35739639.

Lung Injury in COVID-19 Has Pulmonary Edema as an Important Component and Treatment with Furosemide and Negative Fluid Balance (NEGBAL) Decreases Mortality.

The SARS-CoV2 promotes dysregulation of Renin-Angiotensin-Aldosterone. The result is excessive retention of water, producing a state of noxious hypervolemia. Consequently, in COVID-19 injury lung is pulmonary edema. Our report is a case-control study, retrospective. We included 116 patients with moderate-severe COVID-19 lung injury. A total of 58 patients received standard care (Control group). A total of 58 patients received a standard treatment with a more negative fluid balance (NEGBAL group), consisting of hydric restriction and diuretics. Analyzing the mortality of the population studied, it was observed that the NEGBAL group had lower mortality than the Control group, p = 0.001. Compared with Controls, the NEGBAL group had significantly fewer days of hospital stay (p < 0.001), fewer days of ICU stay (p < 0.001), and fewer days of IMV (p < 0.001). The regressive analysis between PaO2/FiO2BAL and NEGBAL demonstrated correlation (p = 0.04). Compared with Controls, the NEGBAL group showed significant progressive improvement in PaO2/FiO2 (p < 0.001), CT score (p < 0.001). The multivariate model, the vaccination variables, and linear trends resulted in p = 0.671 and quadratic trends p = 0.723, whilst the accumulated fluid balance is p < 0.001. Although the study has limitations, the promising results encourage more research on this different therapeutic approach, since in our research it decreases mortality.

Mental Disorder Diagnosis from EEG Signals Employing Automated Leaning Procedures Based on Radial Basis Functions.

Purpose: In this paper, a new automated procedure based on deep learning methods for schizophrenia diagnosis is presented. Methods: To this aim, electroencephalogram signals obtained using a 32-channel helmet are prominently used to analyze high temporal resolution information from the brain. By these means, the data collected is employed to evaluate the class likelihoods using a neuronal network based on radial basis functions and a fuzzy means algorithm. Results: The results obtained with real datasets validate the high accuracy of the proposed classification method. Thus, effectively characterizing the changes in EEG signals acquired from schizophrenia patients and healthy volunteers. More specifically, values of accuracy better than 93% has been obtained in the present research. Additionally, a comparative study with other approaches based on well-knows machine learning methods shows that the proposed method provides better results than recently proposed algorithms in schizophrenia detection. Conclusion: The proposed method can be used as a diagnostic tool in the detection of the schizophrenia, helping for early diagnosis and treatment.

Dynamic relationships between body fat and circulating adipokine levels from adolescence to young adulthood: The Santiago Longitudinal Study.

BACKGROUND AND AIMS: Adipose tissue secretes adipokines such as adiponectin and leptin, playing important roles in energy metabolism. The longitudinal associations between such adipokines and body fat accumulation have not been established, especially during adolescence and young adulthood and in diverse populations. The study aims to assess the longitudinal association between body fat measured with dual X-ray absorptiometry and plasma adipokines from adolescence to young adulthood. METHODS AND RESULTS: Among Hispanic/Latino participants (N = 537) aged 16.8 (SD: 0.3) years of the Santiago Longitudinal Study, we implemented structural equation modeling to estimate the sex-specific associations between adiposity (body fat percent (BF%) and proportion of trunk fat (PTF)) and adipokines (adiponectin and leptin levels) during adolescence (16 y) and these values after 6 years of follow-up (22 y). In addition, we further investigated whether the associations differed by baseline insulin resistance (IR) status. We found evidence for associations between 16 y BF% and 22 y leptin levels (ß (SE): 0.58 (0.06) for females; 0.53 (0.05) for males), between 16 y PTF and 22 y adiponectin levels (ß (SE): -0.31 (0.06) for females; -0.18 (0.06) for males) and between 16 y adiponectin levels and 22 y BF% (ß (SE): 0.12 (0.04) for both females and males). CONCLUSION: We observed dynamic relationships between adiposity and adipokines levels from late adolescence to young adulthood in a Hispanic/Latino population further demonstrating the importance of this period of the life course in the development of obesity.

A replication study of JTC bias, genetic liability for psychosis and delusional ideation.

BACKGROUND: This study attempted to replicate whether a bias in probabilistic reasoning, or 'jumping to conclusions'(JTC) bias is associated with being a sibling of a patient with schizophrenia spectrum disorder; and if so, whether this association is contingent on subthreshold delusional ideation. METHODS: Data were derived from the EUGEI project, a 25-centre, 15-country effort to study psychosis spectrum disorder. The current analyses included 1261 patients with schizophrenia spectrum disorder, 1282 siblings of patients and 1525 healthy comparison subjects, recruited in Spain (five centres), Turkey (three centres) and Serbia (one centre). The beads task was used to assess JTC bias. Lifetime experience of delusional ideation and hallucinatory experiences was assessed using the Community Assessment of Psychic Experiences. General cognitive abilities were taken into account in the analyses. RESULTS: JTC bias was positively associated not only with patient status but also with sibling status [adjusted relative risk (aRR) ratio : 4.23 CI 95% 3.46-5.17 for siblings and aRR: 5.07 CI 95% 4.13-6.23 for patients]. The association between JTC bias and sibling status was stronger in those with higher levels of delusional ideation (aRR interaction in siblings: 3.77 CI 95% 1.67-8.51, and in patients: 2.15 CI 95% 0.94-4.92). The association between JTC bias and sibling status was not stronger in those with higher levels of hallucinatory experiences. CONCLUSIONS: These findings replicate earlier findings that JTC bias is associated with familial liability for psychosis and that this is contingent on the degree of delusional ideation but not hallucinations.

Genetic determinants of metabolic biomarkers and their associations with cardiometabolic traits in Hispanic/Latino adolescents.

BACKGROUND: Metabolic regulation plays a significant role in energy homeostasis, and adolescence is a crucial life stage for the development of cardiometabolic disease (CMD). This study aims to investigate the genetic determinants of metabolic biomarkers-adiponectin, leptin, ghrelin, and orexin-and their associations with CMD risk factors. METHODS: We characterized the genetic determinants of the biomarkers among Hispanic/Latino adolescents of the Santiago Longitudinal Study (SLS) and identified the cumulative effects of genetic variants on adiponectin and leptin using biomarker polygenic risk scores (PRS). We further investigated the direct and indirect effect of the biomarker PRS on downstream body fat percent (BF%) and glycemic traits using structural equation modeling. RESULTS: We identified putatively novel genetic variants associated with the metabolic biomarkers. A substantial amount of biomarker variance was explained by SLS-specific PRS, and the prediction was improved by including the putatively novel loci. Fasting blood insulin and insulin resistance were associated with PRS for adiponectin, leptin, and ghrelin, and BF% was associated with PRS for adiponectin and leptin. We found evidence of substantial mediation of these associations by the biomarker levels. CONCLUSIONS: The genetic underpinnings of metabolic biomarkers can affect the early development of CMD, partly mediated by the biomarkers. IMPACT: This study characterized the genetic underpinnings of four metabolic hormones and investigated their potential influence on adiposity and insulin biology among Hispanic/Latino adolescents. Fasting blood insulin and insulin resistance were associated with polygenic risk score (PRS) for adiponectin, leptin, and ghrelin, with evidence of some degree of mediation by the biomarker levels. Body fat percent (BF%) was also associated with PRS for adiponectin and leptin. This provides important insight on biological mechanisms underlying early metabolic dysfunction and reveals candidates for prevention efforts. Our findings also highlight the importance of ancestrally diverse populations to facilitate valid studies of the genetic architecture of metabolic biomarker levels.

High DHEAS in girls and metabolic features throughout pubertal maturation.

CONTEXT: An association between premature adrenarche and metabolic syndrome at presentation has been described. Our aim was to assess whether the presence of high dehydroepiandrosterone sulphate (DHEAS [HD]) at the adrenarche determines the risk of metabolic syndrome during puberty, taking into account body mass index (BMI) and birth weight. DESIGN: Prospective observational. PATIENTS: Five hundred four girls from the Growth and Obesity Chilean Cohort Study were followed from birth through puberty. At age ~7, subjects were classified by DHEAS concentrations into the HD (>75th percentile) or normal DHEAS (ND, ≤75th percentile) subgroups. MEASUREMENTS: Anthropometrics, semiannual clinical pubertal staging and hormonal and metabolic levels. The relationships among DHEAS at age ~7, metabolic syndrome, and each of its components independently, were analyzed by linear and logistic regression models during puberty and 1-year postmenarche, adjusted by confounders. RESULTS: Girls with HD at 7 years exhibited higher BMI, more central fat and higher serum androgen and insulin like growth factor (IGF)-I levels throughout puberty. Also, girls with HD had a greater prevalence of hyperglycemia at B2 and B4 breast stages, and of low HDL at B4. At 1 year after menarche, HD girls had a higher prevalence of metabolic syndrome, and those with BMI > 1 SD score had a higher metabolic score and insulin levels than ND girls with similar BMI. CONCLUSIONS: Our observations suggest that girls with HD at the age of adrenarche may be at greater risk for metabolic syndrome at adolescence, especially in those who are overweight or obese. Our results emphasize the importance of lifestyle interventions for childhood overweight and obesity among girls with HD.

Pulmonary Edema in COVID-19 Treated with Furosemide and Negative Fluid Balance (NEGBAL): A Different and Promising Approach.

In COVID-19, pulmonary edema has been attributed to "cytokine storm". However, it is known that SARS-CoV2 promotes angiotensin-converting enzyme 2 deficit, increases angiotensin II, and this triggers volume overload. Our report is based on COVID-19 patients with tomographic evidence of pulmonary edema and volume overload to whom established a standard treatment with diuretic (furosemide) guided by objectives: Negative Fluid Balance (NEGBAL approach). Retrospective observational study. We reviewed data from medical records: demographic, clinical, laboratory, blood gas, and chest tomography (CT) before and while undergoing NEGBAL, from 20 critically ill patients. Once the NEGBAL strategy was started, no patient required mechanical ventilation. All cases reverted to respiratory failure with NEGBAL, but subsequently two patients died from sepsis and acute myocardial infarction (AMI). The regressive analysis between PaO2/FiO2BAL and NEGBAL demonstrated correlation (p < 0.032). The results comparing the Pao2Fio2 between admission to NEGBAL to NEGBAL day 4, were statistically significant (p < 0.001). We noted between admission to NEGBAL and day 4 improvement in CT score (p < 0.001), decrease in the superior vena cava diameter (p < 0.001) and the decrease of cardiac axis (p < 0.001). Though our study has several limitations, we believe the promising results encourage further investigation of this different pathophysiological approach.

Novel loci and Mapuche genetic ancestry are associated with pubertal growth traits in Chilean boys.

Puberty is a complex developmental process that varies considerably among individuals and populations. Genetic factors explain a large proportion of the variability of several pubertal traits. Recent genome-wide association studies (GWAS) have identified hundreds of variants involved in traits that result from body growth, like adult height. However, they do not capture many genetic loci involved in growth changes over distinct growth phases. Further, such GWAS have been mostly performed in Europeans, but it is unknown how these findings relate to other continental populations. In this study, we analyzed the genetic basis of three pubertal traits; namely, peak height velocity (PV), age at PV (APV) and height at APV (HAPV). We analyzed a cohort of 904 admixed Chilean children and adolescents with European and Mapuche Native American ancestries. Height was measured on roughly a [Formula: see text]month basis from childhood to adolescence between 2006 and 2019. We predict that, in average, HAPV is 4.3 cm higher in European than in Mapuche adolescents (P = 0.042), and APV is 0.73 years later in European compared with Mapuche adolescents (P = 0.023). Further, by performing a GWAS on 774, 433 single-nucleotide polymorphisms, we identified a genetic signal harboring 3 linked variants significantly associated with PV in boys (P [Formula: see text]). This signal has never been associated with growth-related traits.

Genome-wide association study identifying novel variant for fasting insulin and allelic heterogeneity in known glycemic loci in Chilean adolescents: The Santiago Longitudinal Study.

BACKGROUND: The genetic underpinnings of glycemic traits have been understudied in adolescent and Hispanic/Latino (H/L) populations in comparison to adults and populations of European ancestry. OBJECTIVE: To identify genetic factors underlying glycemic traits in an adolescent H/L population. METHODS: We conducted a genome-wide association study (GWAS) of fasting glucose (FG) and fasting insulin (FI) in H/L adolescents from the Santiago Longitudinal Study. RESULTS: We identified one novel variant positioned in the CSMD1 gene on chromosome 8 (rs77465890, effect allele frequency = 0.10) that was associated with FI (ß = -0.299, SE = 0.054, p = 2.72×10-8 ) and was only slightly attenuated after adjusting for body mass index z-scores (ß = -0.252, SE = 0.047, p = 1.03×10-7 ). We demonstrated directionally consistent, but not statistically significant results in African and Hispanic adults of the Population Architecture Using Genomics and Epidemiology Consortium. We also identified secondary signals for two FG loci after conditioning on known variants, which demonstrate allelic heterogeneity in well-known glucose loci. CONCLUSION: Our results exemplify the importance of including populations with diverse ancestral origin and adolescent participants in GWAS of glycemic traits to uncover novel risk loci and expand our understanding of disease aetiology.

Eating behaviour in contrasting adiposity phenotypes: Monogenic obesity and congenital generalized lipodystrophy.

Most known types of nonsyndromic monogenic obesity are caused by rare mutations in genes of the leptin-melanocortin pathway controlling appetite and adiposity. In contrast, congenital generalized lipodystrophy represents the most extreme form of leanness in humans caused by recessive mutations in four genes involved in phospholipid/triglyceride synthesis and lipid droplet/caveolae structure. In this disease, the inability to store triglyceride in adipocytes results in hypoleptinemia and ectopic hepatic and muscle fat accumulation leading to fatty liver, hypertriglyceridemia and severe insulin resistance. As a result of hypoleptinemia, patients with lipodystrophy show alterations in eating behaviour characterized by constant increased energy intake. As it occurs in obesity caused by genetic leptin deficiency, exogenous leptin rapidly reduces hunger scores in patients with congenital generalized lipodystrophy, with additional beneficial effects on glucose homeostasis and metabolic profile normalization. The melanocortin-4 receptor agonist setmelanotide has been used in the treatment of monogenic obesities. There is only one report on the effect of setmelanotide in a patient with partial lipodystrophy resulting in mild reductions in hunger scores, with no improvements in metabolic status. The assessment of contrasting phenotypes of obesity/leanness represents an adequate strategy to understand the pathophysiology and altered eating behaviour associated with adipose tissue excessive accumulation/paucity.

Eating behavior and body composition in Chilean young adults.

BACKGROUND: Notable weight gain is observed during young adulthood, compared to other adult age groups, yet the relation between eating behavior and body composition at this stage remains poorly understood. OBJECTIVE: The aim of this cross-sectional study was to assess the association between eating behavior scores (cognitive restraint, uncontrolled eating, and emotional eating), and body composition in a sample of Chilean young adults. METHODS: Logistic and linear regression models assessed the independent associations between cognitive restraint, uncontrolled eating, and emotional eating, derived from the Three Factor Eating Questionnaire-R18, and body mass index (BMI), percent body fat by dual-energy X-ray absorptiometry, and central obesity, accounting for demographic covariates, stratified by sex, in a sample of 555 participants of the Santiago Longitudinal Study (mean age 22.6 years [SD 0.4]). RESULTS: Cognitive restraint was positively associated with obesity, defined by BMI, % body fat, and central obesity. Emotional eating was related to obesity, defined by % body fat and central obesity in men and women and to obesity, defined by BMI, in women. Cognitive restraint was related to BMI in men and % body fat in women. Uncontrolled eating was not associated with adiposity in men or women. CONCLUSIONS: In Chilean young adults, cognitive restraint and emotional eating scores were associated with higher BMI, elevated percent body fat, and greater central obesity.

Fructose, Omega 3 Fatty Acids, and Vitamin E: Involvement in Pediatric Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is currently the most common form of liver disease in both adults and children, becoming the leading cause for liver transplant in many countries. Its prevalence has increased considerably in recent years, mainly due to the explosive increase in pediatric obesity rates. NAFLD is strongly associated with central obesity, diabetes, dyslipidemia and insulin resistance, and it has been considered as the hepatic manifestation of the metabolic syndrome. Its complex pathophysiology involves a series of metabolic, inflammatory and oxidative stress processes, among others. Given the sharp increase in the prevalence of NAFLD and the lack of an appropriate pharmacological approach, it is crucial to consider the prevention/management of the disease based on lifestyle modifications such as the adoption of a healthy nutrition pattern. Herein, we review the literature and discuss the role of three key nutrients involved in pediatric NAFLD: fructose and its participation in metabolism, Omega-3 fatty acids and its anti-inflammatory effects and vitamin E and its action on oxidative stress.

Association between indicators of systemic inflammation biomarkers during puberty with breast density and onset of menarche.

BACKGROUND: Systemic inflammation may play a role in shaping breast composition, one of the strongest risk factors for breast cancer. Pubertal development presents a critical window of breast tissue susceptibility to exogenous and endogenous factors, including pro-inflammatory markers. However, little is known about the role of systemic inflammation on adolescent breast composition and pubertal development among girls. METHODS: We investigated associations between circulating levels of inflammatory markers (e.g., interleukin-6 (IL-6), tumor necrosis factor receptor 2 (TNFR2), and C-reactive protein (CRP)) at Tanner stages 2 and 4 and breast composition at Tanner stage 4 in a cohort of 397 adolescent girls in Santiago, Chile (Growth and Obesity Cohort Study, 2006-2018). Multivariable linear models were used to examine the association between breast composition and each inflammatory marker, stratifying by Tanner stage at inflammatory marker measurement. Accelerated failure time models were used to evaluate the association between inflammatory markers concentrations at each Tanner stage and time to menarche. RESULTS: In age-adjusted linear regression models, a doubling of TNFR2 at Tanner 2 was associated with a 26% (95% CI 7-48%) increase in total breast volume at Tanner 4 and a 22% (95% CI 10-32%) decrease of fibroglandular volume at Tanner 4. In multivariable models further adjusted for body fatness and other covariates, these associations were attenuated to the null. The time to menarche was 3% (95% CI 1-5%) shorter among those in the highest quartile of IL-6 at Tanner 2 relative to those in the lowest quartile in fully adjusted models. Compared to those in the lowest quartile of CRP at Tanner 4, those in the highest quartile experienced 2% (95% CI 0-3%) longer time to menarche in multivariable models. CONCLUSIONS: Systemic inflammation during puberty was not associated with breast volume or breast density at the conclusion of breast development among pubertal girls after adjusting for body fatness; however, these circulating inflammation biomarkers, specifically CRP and IL-6, may affect the timing of menarche onset.

PPARGC1A Gene Promoter Methylation as a Biomarker of Insulin Secretion and Sensitivity in Response to Glucose Challenges.

Methylation in CpG sites of the PPARGC1A gene (encoding PGC1-α) has been associated with adiposity, insulin secretion/sensitivity indexes and type 2 diabetes. We assessed the association between the methylation profile of the PPARGC1A gene promoter gene in leukocytes with insulin secretion/sensitivity indexes in normoglycemic women. A standard oral glucose tolerance test (OGTT) and an abbreviated version of the intravenous glucose tolerance test (IVGTT) were carried out in n = 57 Chilean nondiabetic women with measurements of plasma glucose, insulin, and C-peptide. Bisulfite-treated DNA from leukocytes was evaluated for methylation levels in six CpG sites of the proximal promoter of the PPARGC1A gene by pyrosequencing (positions -816, -783, -652, -617, -521 and -515). A strong correlation between the DNA methylation percentage of different CpG sites of the PPARGC1A promoter in leukocytes was found, suggesting an integrated epigenetic control of this region. We found a positive association between the methylation levels of the CpG site -783 with the insulin sensitivity Matsuda composite index (rho = 0.31; p = 0.02) derived from the OGTT. The CpG hypomethylation in the promoter position -783 of the PPARGC1A gene in leukocytes may represent a biomarker of reduced insulin sensitivity after the ingestion of glucose.