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Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity.

ABSTRACT: Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 × 10^-7, range P = 9.2 × 10^-8 to 6.0 × 10^-46; n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 × 10^-6, range P = 5.5 × 10^-6 to 6.1 × 10^-35, n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 × 10^-54). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.

SUBMITTER: Wahl S

PROVIDER: S-EPMC5570525 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity.

Wahl Simone S Drong Alexander A Lehne Benjamin B Loh Marie M Scott William R WR Kunze Sonja S Tsai Pei-Chien PC Ried Janina S JS Zhang Weihua W Yang Youwen Y Tan Sili S Fiorito Giovanni G Franke Lude L Guarrera Simonetta S Kasela Silva S Kriebel Jennifer J Richmond Rebecca C RC Adamo Marco M Afzal Uzma U Ala-Korpela Mika M Albetti Benedetta B Ammerpohl Ole O Apperley Jane F JF Beekman Marian M Bertazzi Pier Alberto PA Black S Lucas SL Blancher Christine C Bonder Marc-Jan MJ Brosch Mario M Carstensen-Kirberg Maren M de Craen Anton J M AJ de Lusignan Simon S Dehghan Abbas A Elkalaawy Mohamed M Fischer Krista K Franco Oscar H OH Gaunt Tom R TR Hampe Jochen J Hashemi Majid M Isaacs Aaron A Jenkinson Andrew A Jha Sujeet S Kato Norihiro N Krogh Vittorio V Laffan Michael M Meisinger Christa C Meitinger Thomas T Mok Zuan Yu ZY Motta Valeria V Ng Hong Kiat HK Nikolakopoulou Zacharoula Z Nteliopoulos Georgios G Panico Salvatore S Pervjakova Natalia N Prokisch Holger H Rathmann Wolfgang W Roden Michael M Rota Federica F Rozario Michelle Ann MA Sandling Johanna K JK Schafmayer Clemens C Schramm Katharina K Siebert Reiner R Slagboom P Eline PE Soininen Pasi P Stolk Lisette L Strauch Konstantin K Tai E-Shyong ES Tarantini Letizia L Thorand Barbara B Tigchelaar Ettje F EF Tumino Rosario R Uitterlinden Andre G AG van Duijn Cornelia C van Meurs Joyce B J JB Vineis Paolo P Wickremasinghe Ananda Rajitha AR Wijmenga Cisca C Yang Tsun-Po TP Yuan Wei W Zhernakova Alexandra A Batterham Rachel L RL Smith George Davey GD Deloukas Panos P Heijmans Bastiaan T BT Herder Christian C Hofman Albert A Lindgren Cecilia M CM Milani Lili L van der Harst Pim P Peters Annette A Illig Thomas T Relton Caroline L CL Waldenberger Melanie M Järvelin Marjo-Riitta MR Bollati Valentina V Soong Richie R Spector Tim D TD Scott James J McCarthy Mark I MI Elliott Paul P Bell Jordana T JT Matullo Giuseppe G Gieger Christian C Kooner Jaspal S JS Grallert Harald H Chambers John C JC

Nature 20161221 7635

Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. Here we use epigenome-wide association to show that body mass index ...[more]

PMID: 28002404

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Project description:BackgroundDNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits.MethodsWe examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment.ResultsDNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P < 1.06 × 10-7, with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth Penrichment = 1; childhood Penrichment = 2.00 × 10-4; adolescence Penrichment = 2.10 × 10-7).ConclusionsThere were only minimal associations of DNA methylation with childhood and adolescent BMI. With the advancing age of the participants across childhood and adolescence, we observed increasing overlap with altered DNA methylation loci reported in association with adult BMI. These findings may be compatible with the hypothesis that DNA methylation differences are mostly a consequence rather than a cause of obesity.

Project description:BackgroundObesity is a well-established risk factor for both adverse pregnancy outcomes (APOs) and cardiovascular disease (CVD). However, it is not known whether APOs are mediators or markers of the obesity-CVD relationship. This study examined the association between body mass index, APOs, and postpartum CVD risk factors.MethodsThe sample included adults from the nuMoM2b (Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-To-Be) Heart Health Study who were enrolled in their first trimester (6 weeks-13 weeks 6 days gestation) from 8 United States sites. Participants had a follow-up visit at 3.7 years postpartum. APOs, which included hypertensive disorders of pregnancy, preterm birth, small-for-gestational-age birth, and gestational diabetes, were centrally adjudicated. Mediation analyses estimated the association between early pregnancy body mass index and postpartum CVD risk factors (hypertension, hyperlipidemia, and diabetes) and the proportion mediated by each APO adjusted for demographics and baseline health behaviors, psychosocial stressors, and CVD risk factor levels.ResultsAmong 4216 participants enrolled, mean±SD maternal age was 27±6 years. Early pregnancy prevalence of overweight was 25%, and obesity was 22%. Hypertensive disorders of pregnancy occurred in 15%, preterm birth in 8%, small-for-gestational-age birth in 11%, and gestational diabetes in 4%. Early pregnancy obesity, compared with normal body mass index, was associated with significantly higher incidence of postpartum hypertension (adjusted odds ratio, 1.14 [95% CI, 1.10-1.18]), hyperlipidemia (1.11 [95% CI, 1.08-1.14]), and diabetes (1.03 [95% CI, 1.01-1.04]) even after adjustment for baseline CVD risk factor levels. APOs were associated with higher incidence of postpartum hypertension (1.97 [95% CI, 1.61-2.40]) and hyperlipidemia (1.31 [95% CI, 1.03-1.67]). Hypertensive disorders of pregnancy mediated a small proportion of the association between obesity and incident hypertension (13% [11%-15%]) and did not mediate associations with incident hyperlipidemia or diabetes. There was no significant mediation by preterm birth or small-for-gestational-age birth.ConclusionsThere was heterogeneity across APO subtypes in their association with postpartum CVD risk factors and mediation of the association between early pregnancy obesity and postpartum CVD risk factors. However, only a small or nonsignificant proportion of the association between obesity and CVD risk factors was mediated by any of the APOs, suggesting APOs are a marker of prepregnancy CVD risk and not a predominant cause of postpartum CVD risk.

Project description:ImportanceBody mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is a commonly used estimate of obesity, which is a complex trait affected by genetic and lifestyle factors. Marked weight gain and loss could be associated with adverse biological processes.ObjectiveTo evaluate the association between BMI variability and incident cardiovascular disease (CVD) events in 2 distinct cohorts.Design, setting, and participantsThis cohort study used data from the Million Veteran Program (MVP) between 2011 and 2018 and participants in the UK Biobank (UKB) enrolled between 2006 and 2010. Participants were followed up for a median of 3.8 (5th-95th percentile, 3.5) years. Participants with baseline CVD or cancer were excluded. Data were analyzed from September 2022 and September 2023.ExposureBMI variability was calculated by the retrospective SD and coefficient of variation (CV) using multiple clinical BMI measurements up to the baseline.Main outcomes and measuresThe main outcome was incident composite CVD events (incident nonfatal myocardial infarction, acute ischemic stroke, and cardiovascular death), assessed using Cox proportional hazards modeling after adjustment for CVD risk factors, including age, sex, mean BMI, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, smoking status, diabetes status, and statin use. Secondary analysis assessed whether associations were dependent on the polygenic score of BMI.ResultsAmong 92 363 US veterans in the MVP cohort (81 675 [88%] male; mean [SD] age, 56.7 [14.1] years), there were 9695 Hispanic participants, 22 488 non-Hispanic Black participants, and 60 180 non-Hispanic White participants. A total of 4811 composite CVD events were observed from 2011 to 2018. The CV of BMI was associated with 16% higher risk for composite CVD across all groups (hazard ratio [HR], 1.16; 95% CI, 1.13-1.19). These associations were unchanged among subgroups and after adjustment for the polygenic score of BMI. The UKB cohort included 65 047 individuals (mean [SD] age, 57.30 (7.77) years; 38 065 [59%] female) and had 6934 composite CVD events. Each 1-SD increase in BMI variability in the UKB cohort was associated with 8% increased risk of cardiovascular death (HR, 1.08; 95% CI, 1.04-1.11).Conclusions and relevanceThis cohort study found that among US veterans, higher BMI variability was a significant risk marker associated with adverse cardiovascular events independent of mean BMI across major racial and ethnic groups. Results were consistent in the UKB for the cardiovascular death end point. Further studies should investigate the phenotype of high BMI variability.

Project description:This study investigated the association between pre-pregnancy body mass index (BMI) and adverse pregnancy outcomes among women participated in the National Free Preconception Health Examination Project in Guangdong Province, China, and explored these associations according to maternal age. Pre-pregnancy BMI was classified into underweight (BMI < 18.5 kg/m2), healthy weight (18.5-23.9 kg/m2), overweight (24.0-27.9 kg/m2), and obesity (≥ 28.0 kg/m2) according to Chinese criteria. Outcomes were preterm birth (PTB, delivery before 37 weeks of gestation), large for gestational age (LGA, birthweight above the 90th percentile for gestational age by infants' sex), small for gestational age (SGA, birthweight below the 10th percentile for gestational age by infants' sex), primary caesarean delivery, shoulder dystocia or birth injury, and stillbirth. Adjusted incidence risk ratios (aIRR) were calculated for underweight, overweight and obesity, respectively. Compared with healthy weight, underweight was associated with increased risk of PTB (aIRR 1.06, 95%CI 1.04-1.09) and SGA (1.23, 1.22-1.26) but inversely associated with LGA (0.83, 0.82-0.85), primary caesarean delivery (0.88, 0.87-0.90) and stillbirth (0.73, 0.53-0.99). Overweight was associated with increased risk of LGA (1.17, 1.14-1.19), primary caesarean delivery (1.18, 1.16-1.20) and stillbirth (1.44, 1.03-2.06), but inversely associated with SGA (0.92, 0.90-0.95) and shoulder dystocia or birth injury (0.86, 0.79-0.93). Obesity was associated with increased risk of PTB (1.12, 1.05-1.20), LGA (1.32, 1.27-1.37), primary caesarean delivery (1.45, 1.40-1.50), but inversely associated with SGA (0.92, 0.87-0.97). The aIRRs for underweight, overweight and obesity in relation to these adverse pregnancy outcomes ranged from 0.65 to 1.52 according to maternal age. In Chinese population, maternal pre-pregnancy BMI was significantly associated with the risk of adverse pregnancy outcomes and the risk differs according to maternal age. Further investigation is warranted to determine whether and how counselling and interventions for women with low or increased BMI before pregnancy can reduce the risk of adverse pregnancy outcomes.

Project description:BACKGROUND:Prospective data are sparse for active commuting to work and body weight in Asia. We assessed the association of 5-year changes in commuting mode with body mass index (BMI) and the indicators of abdominal obesity in Japanese working adults. METHODS:In this longitudinal study, we studied 29,758 participants (25,808 men and 3950 women) in Japan aged 30 to 64 years at baseline who underwent further health examination 5 years after the baseline examination. Changes in BMI were calculated from objectively measured body height and weight at baseline and follow-up examination. Visceral and subcutaneous fat areas and waist circumference measured by computed tomography scans were used as indicators for abdominal adiposity. Linear regression was applied to estimate the association of changes in commuting mode with the obesity outcomes. RESULTS:Within the 5-year study period, adults who maintained inactive commuting gained weight, and compared with this group, adults who switched to inactive commuting had higher weight gain; conversely, adults who switched to active or public transportation commuting and especially those who maintained active or public transportation commuting experienced less weight gain. Subgroup analysis showed similar tendency across the different transitions of leisure-time exercise or occupational physical activity. For example, among adults who maintained no exercise (n = 16,087), the adjusted mean (95% confidence intervals) of the BMI change over 5 years in kg/m2 were 0.27 (0.24 to 0.30) for maintained inactive commuting group (reference), 0.34 (0.30 to 0.38) for switching to inactive commuting group (P = 0.046), 0.20 (0.18 to 0.22) for switching to active commuting or public transportation group (P = 0.001), and 0.09 (0.06 to 0.13) for maintained active commuting or public transportation group (P < 0.001). Maintained inactive commuting tended to be associated with larger gain in abdominal adiposity indicators. CONCLUSION:Switching from inactive commuting mode to more physically active commuting mode and maintaining active commuting can promote body weight control among working adults across different levels of occupational or leisure-time physical activity.

Dataset Information

Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity.

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Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity.

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