The association of genetically controlled CpG methylation (cg158269415) of protein tyrosine phosphatase, receptor type N2 (PTPRN2) with childhood obesity.
ABSTRACT: Protein tyrosine phosphatase, receptor type N2 (PTPRN2) encodes a major islet autoantigen in type-1 diabetes. Previous genetic studies have shown its significant association with obesity. PTPRN2 plays an important role in epigenetic regulation of metabolic diseases and cancers. We investigated CpG methylations (cg17429772 and cg158269415) in PTPRN2 by pyrosequencing from blood samples of childhood obesity (n?=?638). cg158269415 had significant positive correlations with body mass index (BMI) and waist-hip ratio (WHR). Case-control analysis showed that cg158269415 methylation in blood sample was significantly more hypermethylated in obese cases (n?=?252), an average of 2.93% more than that that in controls (n?=?386). The cg158269415 methylation has a trimodal distribution pattern with strong dependency on nearby located rs1670344 G?>?A genotype. Correlations of cg158269415 with BMI and WHR were significant and strong in major G allele carriers (GG?+?GA). Our study showed that an epigenetic association of PTPRN2 gene with childhood obesity was under certain genetic background. The genetic and epigenetic interplay of PTPRN2 gene may implicate a mechanism of childhood obesity. Whether these small changes in DNA methylation from whole blood are causally or consequently related to childhood obesity outcome and their clinical relevance remains to be determined. However, this study presents a promising obesity risk marker that warrants further investigation.
Project description:Epigenetic mechanisms are increasingly being recognized as an important factor for obesity. The serotonin transporter gene (SLC6A4) has a critical role in regulating food intake, body weight and energy balance. This study examines the potential association between SLC6A4 promoter methylation and obesity measures in a monozygotic (MZ) twin sample.We studied 84 MZ twin pairs drawn from the Vietnam Era Twin Registry. Obesity measures include body mass index (BMI), body weight, waist circumference (WC) and waist-hip ratio (WHR). The SLC6A4 promoter methylation profile in peripheral blood leukocytes was quantified by bisulfite pyrosequencing. The association between methylation variation and obesity parameters was examined by mixed-model regression and matched pair analysis, adjusting for age, smoking, alcohol consumption, physical activity and total daily energy intake. Multiple testing was controlled using the adjusted false discovery rate (q-value).Mean methylation level was positively correlated with BMI (r=0.29; P=0.0002), body weight (r=0.31; P<0.0001) and WC (r=0.20; P=0.009), but not WHR. Intra-pair differences in mean methylation were significantly correlated with intra-pair differences in BMI, body weight and WC, but not WHR. On average, a 1% increase in mean methylation was associated with 0.33?kg?m(-2) increase in BMI (95% CI: 0.02-0.65; P=0.03), 1.16?kg increase in body weight (95% CI, 0.16-2.16; P=0.02) and 0.78?cm increase in WC (95% CI, 0.05-1.50; P=0.03) after controlling for potential confounders.SLC6A4 promoter hypermethylation is significantly associated with an increased prevalence of obesity within a MZ twin study.
Project description:Low-density lipoprotein Receptor Related Protein 1B (LRP1B) is homologous to the gigantic lipoprotein receptor-related protein 1 that belongs to the family of Low-density lipoprotein receptors. Previous genetic association studies of the LRP1B gene have shown its genetic association with obesity. Through exome sequencing of the LRP1B gene from a childhood severe obesity cohort (n = 692), we found novel single nucleotide polymorphism (rs431809) in intron 4, which has been significantly correlated with both body mass index (BMI) and waist-hip-ratio (WHR). Three methylations of CpG sites (cg141441481, cg01852095 and cg141441470) in the same intron were also significantly correlated with BMI and WHR. All CpG methylations had bimodal patterns, and were dependent on rs431809 genotypes. The genetic influences of obesity on the LRP1B gene may be linked to the interplay of CpG methylations in the same intron. Heritability of SNP interacts with epigenetic crosstalk in LRP1B. Genetic and epigenetic crosstalk of LRP1B gene may be implicated in the prevention and therapeutic approach to childhood obesity.
Project description:Worldwide increasing childhood obesity is due to interactions between environmental and genetic factors, linked together by epigenetic mechanisms such as DNA methylation.82 obese children (>95th BMI percentile , age: 3-18 years) were included. Anthropometric data, metabolic parameters, 25-OH vitamin D (25OHD), and pubertal status were recorded, 24-hour blood pressure monitoring was performed. BMI standard deviation score (SDS) was calculated. Using candidate gene approach, obesity- (insulin-like growth factor 2 (IGF2), proopiomelanocortin (POMC)) and vitamin D metabolism-related genes (1-alfa-hydroxylase (CYP27B1), VDR) regulated by DNA methylation were selected. After isolating DNA from peripheral blood, bisulfite conversion, bisulfite specific polymerase chain reaction (BS-PCR), and pyrosequencing were carried out.No significant correlation between 25-OHD and metabolic parameters and DNA methylation status, but a tendency of positive correlation between VDR methylation status and 25-OHD (r = 0.2053,p = 0.066) were observed. Significant positive correlations between BMI SDS and CYP27B1 hypermethylation (r = 0.2371,p = 0.0342) and a significant negative correlation between IGF2 hypomethylation and BMI SDS (r = -0.305,p = 0.0059) were found. Conclusions Rate of obesity shows correlation with DNA methylation. Hypomethylation of IGF2 and hypermethylation of CYP27B1 genes might positively influence the rate of BMI observed in obese children.
Project description:OBJECTIVE:Childhood socioeconomic disadvantage is associated with adulthood obesity risk; however, epigenetic mechanisms are poorly understood. This work's objective was to evaluate whether associations of childhood socioeconomic disadvantage with adulthood body mass index (BMI) are mediated by DNA methylation. METHODS:Participants were 141 men and women from the New England Family Study, prospectively followed prenatally through a mean age of 47 years. Epigenomewide DNA methylation was evaluated in peripheral blood and adipose tissue obtained at adulthood, using the Infinium HumanMethylation450K BeadChip. Childhood socioeconomic status (SES) at age 7 years was assessed directly from parents' reports. Offspring adiposity was directly assessed using BMI at a mean age of 47 years. Associations of SES, DNA methylation, and BMI were estimated using least square estimators. Statistical mediation analyses were performed using joint significance test and bootstrapping. RESULTS:Of CpG sites significant at the 25% false discovery rate level in epigenomewide methylation BMI analyses, 91 sites in men and 71 sites in women were additionally significant for SES-methylation associations (p < .001) in adipose tissue. Many involved genes biologically relevant for development of obesity, including fatty acid synthase, transmembrane protein 88, signal transducer and activator of transcription 3, and neuritin 1. There was no evidence of epigenetic mediation in peripheral blood leukocytes. CONCLUSIONS:DNA methylation at specific genes may be mediators of associations between childhood socioeconomic disadvantage and mid-life BMI in adipose tissue. Findings motivate continued efforts to study if and how childhood socioeconomic disadvantage is biologically embedded at the level of the epigenome in regions etiologically relevant for adiposity.
Project description:Gene polymorphisms associated so far with body mass index (BMI) can explain only 1.18-1.45% of observed variation in BMI. Recent studies suggest that epigenetic modifications, especially DNA methylation, could contribute to explain part of the missing heritability, and two epigenetic genome-wide analysis studies (EWAS) have reported that Hypoxia Inducible Factor 3 Alpha Subunit (HIF3A) methylation was associated with BMI or BMI change. We therefore assessed whether the HIF3A methylation is associated with obesity and other obesity-related phenotypes in Chinese children. The subjects included 110 severe obese cases aged 7-17y and 110 normal-weight controls matched by age and gender for measurement of blood DNA methylation levels at the HIF3A gene locus using the Sequenom's MassARRAY system. We observed significantly higher methylation levels in obese children than in controls at positions 46801642 and 46801699 in HIF3A gene (P<0.05), and found positive associations between methylation and alanine aminotransferase (ALT) levels adjusted by gender, age and BMI at the position 46801699 (r = 0.226, P = 0.007). These results suggest that HIF3A DNA methylation is associated with childhood obesity, and has a BMI-independent association with ALT. The results provide evidence for identifying epigenetic factors of elivated ALT and may be useful for risk assessment and personalized medicine of liver diseases such as non-alcoholic fatty liver disease (NAFLD).
Project description:BACKGROUND:Epigenetics could facilitate greater understanding of disparities in the emergence of childhood obesity. While blood is a common tissue used in human epigenetic studies, saliva is a promising tissue. Our prior findings in non-obese preschool-aged Hispanic children identified 17 CpG dinucleotides for which differential methylation in saliva at baseline was associated with maternal obesity status. The current study investigated to what extent baseline DNA methylation in salivary samples in these 3-5-year-old Hispanic children predicted the incidence of childhood obesity in a 3-year prospective cohort. METHODS:We examined a subsample (n =?92) of Growing Right Onto Wellness (GROW) trial participants who were randomly selected at baseline, prior to randomization, based on maternal phenotype (obese or non-obese). Baseline saliva samples were collected using the Oragene DNA saliva kit. Objective data were collected on child height and weight at baseline and 36?months later. Methylation arrays were processed using standard protocol. Associations between child obesity at 36?months and baseline salivary methylation at the previously identified 17 CpG dinucleotides were evaluated using multivariable logistic regression models. RESULTS:Among the n =?75 children eligible for analysis, baseline methylation of Cg1307483 (NRF1) was significantly associated with emerging childhood obesity at 36-month follow-up (OR?=?2.98, p =?0.04), after adjusting for child age, gender, child baseline BMI-Z, and adult baseline BMI. This translates to a model-estimated 48% chance of child obesity at 36-month follow-up for a child at the 75th percentile of NRF1 baseline methylation versus only a 30% chance of obesity for a similar child at the 25th percentile. Consistent with other studies, a higher baseline child BMI-Z during the preschool period was associated with the emergence of obesity 3?years later, but baseline methylation of NRF1 was associated with later obesity even after adjusting for child baseline BMI-Z. CONCLUSIONS:Saliva offers a non-invasive means of DNA collection and epigenetic analysis. Our proof of principle study provides sound empirical evidence supporting DNA methylation in salivary tissue as a potential predictor of subsequent childhood obesity for Hispanic children. NFR1 could be a target for further exploration of obesity in this population.
Project description:There is increasing evidence that metabolic diseases originate in early life, and epigenetic changes have been implicated as key drivers of this early life programming. This led to the hypothesis that epigenetic marks present at birth may predict an individual’s future risk of obesity and type 2 diabetes. In this study, we assessed whether epigenetic marks in blood of newborn children were associated with BMI and insulin sensitivity later in childhood. DNA methylation was measured in neonatal blood spot samples of 439 children using the Illumina Infinium 450k BeadChip. Associations were assessed between DNA methylation at birth and BMI z-scores, body fat mass, fasting plasma glucose, insulin and HOMA-IR at age 5 years, as well as birthweight, maternal BMI and smoking status. No individual methylation sites at birth were associated with obesity or insulin sensitivity measures at 5 years. DNA methylation in 69 genomic regions at birth was associated with BMI z-scores at age 5 years, and in 63 regions with HOMA-IR. The methylation changes were generally small (<5%), except for a region near the non-coding RNA nc886 (VTRNA2-1) where a clear link between methylation status at birth and BMI in childhood was observed (P=0.001). Associations were also found between DNA methylation, maternal smoking, and birth weight. We identified a number of DNA methylation regions at birth that were associated with obesity or insulin sensitivity measurements in childhood. These findings support the mounting evidence on the role of epigenetics in programming of metabolic health. Whether many of these small changes in DNA methylation are causally related to the health outcomes, and of clinical relevance, remains to be determined, but the nc886 region represents a promising obesity risk marker that warrants further investigation. Overall design: Illumina HumanMethylation450K BeadChip arrays were used for genome-wide methylation profiling of blood DNA samples of 438 children at birth and 148 children at age 5 years.
Project description:Importance:While prenatal nutrition and maternal obesity are recognized as important contributors to epigenetic changes and childhood obesity, the role of paternal obesity in the epigenome of offspring has not been well studied. Objectives:To test whether periconception paternal body mass index (BMI) is associated with DNA methylation patterns in newborns, to examine associations between maternal and paternal BMI and the epigenome of offspring, and to examine persistence of epigenetic marks at ages 3 and 7 years. Design, Setting, and Participants:Project Viva is a prebirth cohort study of mothers and children including 2128 live births that enrolled mothers from April 1999 to July 2002 and followed offspring to adolescence. This study analyzed the subset of participants with available data on paternal BMI and DNA methylation in offspring blood in the newborn period, at age 3 years, and at age 7 years. Data were analyzed from July 2017 to October 2019. Exposures:The primary exposure was paternal periconception BMI; associations were adjusted for maternal prepregnancy BMI and stratified according to maternal BMI above or below 25. Main Outcomes and Measures:The primary outcome was genome-wide DNA methylation patterns in offspring blood collected at birth, age 3 years, and age 7 years. Results:A total of 429 father-mother-infant triads were included. The mean (SD) periconception paternal BMI was 26.4 (4.0) and mean maternal prepregnancy BMI was 24.5 (5.2); 268 fathers had BMI greater than or equal to 25 (mean [SD], 28.5 [3.3]) and 161 had BMI less than 25 (mean [SD], 22.8 [1.8]). Paternal BMI greater than or equal to 25 was associated with increased offspring birth weight compared with paternal BMI less than 25 (mean [SD] z score, 0.38 [0.91] vs 0.11 [0.96]; P?=?.004). Cord blood DNA methylation at 9 CpG sites was associated with paternal BMI independent of maternal BMI (q?<?.05). Methylation at cg04763273, between TFAP2C and BMP7, decreased by 5% in cord blood with every 1-unit increase in paternal BMI (P?=?3.13?×?10-8); hypomethylation at this site persisted at ages 3 years and 7 years. Paternal BMI was associated with methylation at cg01029450 in the promoter region of the ARFGAP3 gene; methylation at this site was also associated with lower infant birth weight (??=?-0.0003; SD?=?0.0001; P?=?.03) and with higher BMI z score at age 3 years. Conclusions and Relevance:In this study, paternal BMI was associated with DNA methylation, birth weight, and childhood BMI z score in offspring.
Project description:Differential methylations of the HIF3A (hypoxia-inducible factor 3a) gene have been linked to body mass index (BMI). To explore the association of these methylations to childhood obesity, we measured 5 CpG methylation sites (cg27146050, cg46801562, cg22891070, cg16672562 and cg46801675) in intron 1 of the HIF3A gene by pyrosequencing, in the Korean population (mean age: 13.9 yrs, 305 obese cases and 387 controls). Two CpG methylations, cg46801562 and cg16672562, had statistically significant association with childhood obesity (P = 2.09E-9 and 1.66E-7, respectively). Notably, in the case of cg16672562, all correlations were significantly positive with BMI (beta = 0.285, P = 1.652E-13), waist-hip ratio (beta = 0.0028, P = 1.42E-15) and fasting plasma glucose level (beta = 0.0645, P = 2.61E-4), when analyzed by linear regression, with age and sex as covariates. We investigated any genetic effect of cg16672562 methylation by using 14 single nucleotide polymorphisms (SNP) identified by exome sequencing of the HIF3A locus cg16672562 methylation showed no statistically significant changes due to the 14 polymorphisms. In this study, we show that cg16672562 is the most significant blood DNA methylation marker for childhood obesity in the Korean population, and might be independent of any underlying HIF3A genetic background.
Project description:The cg07814318 hypermethylation of Kruppel-like factor 13 (KLF13) gene has been reported for its relevancy with Body Mass Index (BMI) from European origin. We explored the cg07814318 methylation and its cis-meQTL (cis-methylation quantitative loci) of KLF13 from a childhood obesity cohort. The cg07814318 methylation in blood was significantly associated with obesity and correlated with several obesity-related physical and biochemical traits. We examined the same loci from purified three human cell types (n?=?47), i.e., pre-adipocytes, adipocytes and islets. The cg07814318 methylation pattern in pre-adipocytes and islets were significant higher in cells from subjects with a higher BMI compared with control subjects. By exome sequencing of KLF13 gene in blood with the same cohort, we found nine SNPs (single nucleotide polymorphisms) within its gene body, and two SNPs (rs11537749 and rs12595641) were as cis-meQTL of cg07814318. There was the 2.01% methylation change of cg07814318 between homozygous dominant and recessive genotypes, especially, in rs12595641. The sequencing variations within KLF13 genes could drive dynamic modifications of obesity-related CpG methylation. Differential DNA methylation patterns in the KLF13 gene determined from separate blood samples showed that this criterion could be used as a surrogate for representing overall epigenetic changes in cells related to obesity.