Impact of BMI and waist circumference on epigenome-wide DNA methylation and identification of epigenetic biomarkers in blood: an EWAS in multi-ethnic Asian individuals

Abstract

Background The prevalence of obesity and its related chronic diseases have been increasing especially in Asian countries. Obesity-related genetic variants have been identified, but these explain little of the variation in BMI. Recent studies reported associations between DNA methylation and obesity, mostly in non-Asian populations. Methods We performed an epigenome-wide association study (EWAS) on general adiposity (body mass index, BMI) and abdominal adiposity (waist circumference, WC) in 409 multi-ethnic Asian individuals and replicated BMI and waist-associated DNA methylation CpGs identified in other populations. The cross-lagged panel model and Mendelian randomization were used to assess the temporal relationship between methylation and BMI. The temporal relationship between the identified CpGs and inflammation and metabolic markers was also examined. Results EWAS identified 116 DNA methylation CpGs independently associated with BMI and eight independently associated with WC at false discovery rate PFDR < 0.05 in 409 Asian samples. We replicated 110 BMI-associated CpGs previously reported in Europeans and identified six novel BMI-associated CpGs and two novel WC-associated CpGs. We observed high consistency in association direction of effect compared to studies in other populations. Causal relationship analyses indicated that BMI was more likely to be the cause of DNA methylation alteration, rather than the consequence. The causal analyses using BMI-associated methylation risk score also suggested that higher levels of the inflammation marker IL-6 were likely the consequence of methylation change. Conclusion Our study provides evidence of an association between obesity and DNA methylation in multi-ethnic Asians and suggests that obesity can drive methylation change. The results also suggested possible causal influence that obesity-related methylation changes might have on inflammation and lipoprotein levels.

The potential of DNA methylation as a biomarker for obesity and smoking

“…The majority of the alterations in methylation arise as a consequence of fat accumulation, leading to metabolic disturbances through various routes, as demonstrated by Mendelian randomization analyses [75,76,91] and longitudinal studies [92].…”

“…In addition, some of the CpGs can also be specific to ethnicity. However, there has been limited research on population heterogeneity in obesityrelated methylation sites [75,91]. Finally, distinct obesity-related comorbidities or metabolic characteristics may exist among study participants that are not accounted for by BMI, the most commonly studied obesity measure.…”

“…The majority of the alterations in methylation arise as a consequence of fat accumulation, leading to metabolic disturbances through various routes, as demonstrated by Mendelian randomization analyses [75, 76, 91] and longitudinal studies [92]. Studies on children and adolescents show little evidence on the connection between early life BMI and DNA methylation [93].…”

“…For instance, a methylation risk score of 82 CpGs was found to be strongly predictive of incident T2D [75], yielding better predictions than traditional risk factors such as high BMI. Another recent study showed that the baseline methylation score based on 116 CpGs could predict levels of interleukin‐6, an inflammatory marker elevated in obesity [91]. Further, a population‐based DNA methylation study on habitual diet with a relatively large sample size ( n = 6662 European, 2702 African, and 360 Hispanic ancestry) provided evidence for the link between diet‐associated DNA methylation and metabolic disorders as well as all‐cause mortality [94].…”

Correlation between Abdominal Circumference and Serum High-Sensitivity C-Reactive Protein Concentration at Age 35–64 Years

“…[3][4][5] Recently, obesity has increased in Asia, along with rapid economic growth. 6 In Indonesia, according to Riskesdas in 2018, there were 31% of the population aged 15 years and over suffering central obesity, where the highest was in the aged group 45-54 years old (42.3%), followed by 44 years old (39.2%) and in the aged group 55-64 years old (39.1%). 7 This prevalence is higher if we compare it to 2013.…”