Epigenome-wide meta-analysis of BMI in nine cohorts: Examining the utility of epigenetically predicted BMI

This study sought to examine the association between DNA methylation and body mass index (BMI) and the potential of BMI-associated cytosine-phosphate-guanine (CpG) sites to provide information about metabolic health. We pooled summary statistics from six trans-ethnic epigenome-wide association studies (EWASs) of BMI representing nine cohorts (n = 17,034), replicated these findings in the Women's Health Initiative (WHI, n = 4,822), and developed an epigenetic prediction score of BMI. In the pooled EWASs, 1,265 CpG sites were associated with BMI (p < 1E−7) and 1,238 replicated in the WHI (FDR < 0.05). We performed several stratified analyses to examine whether these associations differed between individuals of European and African descent, as defined by self-reported race/ethnicity. We found that five CpG sites had a significant interaction with BMI by race/ethnicity. To examine the utility of the significant CpG sites in predicting BMI, we used elastic net regression to predict log-normalized BMI in the WHI (80% training/20% testing). This model found that 397 sites could explain 32% of the variance in BMI in the WHI test set. Individuals whose methylome-predicted BMI overestimated their BMI (high epigenetic BMI) had significantly higher glucose and triglycerides and lower HDL cholesterol and LDL cholesterol compared to accurately predicted BMI. Individuals whose methylome-predicted BMI underestimated their BMI (low epigenetic BMI) had significantly higher HDL cholesterol and lower glucose and triglycerides. This study confirmed 553 and identified 685 CpG sites associated with BMI. Participants with high epigenetic BMI had poorer metabolic health, suggesting that the overestimation may be driven in part by cardiometabolic derangements characteristic of metabolic syndrome

Associations between DNA methylation and BMI vary by metabolic health status: a potential link to disparate cardiovascular outcomes

Background: Body mass index (BMI), a well-known risk factor for poor cardiovascular outcomes, is associated with differential DNA methylation (DNAm). Similarly, metabolic health has also been associated with changes in DNAm. It is unclear how overall metabolic health outside of BMI may modify the relationship between BMI and methylation profiles, and what consequences this may have on downstream cardiovascular disease. The purpose of this study was to identify cytosine-phosphate-guanine (CpG) sites at which the association between BMI and DNAm could be modified by overall metabolic health. Results: The discovery study population was derived from three Women’s Health Initiative (WHI) ancillary studies (n = 3977) and two Atherosclerosis Risk in Communities (ARIC) ancillary studies (n = 3520). Findings were validated in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort (n = 1200). Generalized linear models regressed methylation β values on the interaction between BMI and metabolic health Z score (BMI × MHZ) adjusted for BMI, MHZ, cell composition, chip number and location, study characteristics, top three ancestry principal components, smoking, age, ethnicity (WHI), and sex (ARIC). Among the 429,566 sites examined, differential associations between BMI × MHZ and DNAm were identified at 22 CpG sites (FDR q < 0.05), with one site replicated in MESA (cg18989722, in the TRAPPC9 gene). Three of the 22 sites were associated with incident coronary heart disease (CHD) in WHI. For each 0.01 unit increase in DNAm β value, the risk of incident CHD increased by 9% in one site and decreased by 6–10% in two sites over 25 years. Conclusions: Differential associations between DNAm and BMI by MHZ were identified at 22 sites, one of which was validated (cg18989722) and three of which were predictive of incident CHD. These sites are located in several genes related to NF-kappa-B signaling, suggesting a potential role for inflammation between DNA methylation and BMI-associated metabolic health

Cost-effectiveness of a Stepwise Approach vs Standard Care for Diabetes Prevention in India.

Question Is a stepwise approach to identifying, delaying, and preventing diabetes in individuals with high risk in a low-income to middle-income country setting cost-effective? Findings In this economic evaluation study, conducted within a randomized clinical trial during a 3-year period, it would cost 145 international dollars to screen for and reduce diabetes incidence by 1 percentage point, 14 &amp; x202f;539 international dollars per diabetes case prevented and/or delayed, and 14 &amp; x202f;986 international dollars per quality-adjusted life-year gained. Meaning The findings of this study suggest that a stepwise approach for identification of high-risk individuals and diabetes prevention is likely cost-effective, even in a low-income to middle-income country setting.This economic evaluation estimates the cost-effectiveness of a stepwise approach to diabetes prevention among adults in India participating in the Diabetes Community Lifestyle Improvement Program.Importance A stepwise approach that includes screening and lifestyle modification followed by the addition of metformin for individuals with high risk of diabetes is recommended to delay progression to diabetes; however, there is scant evidence regarding whether this approach is cost-effective. Objective To estimate the cost-effectiveness of a stepwise approach in the Diabetes Community Lifestyle Improvement Program. Design, Setting, and Participants This economic evaluation study included 578 adults with impaired glucose tolerance, impaired fasting glucose, or both. Participants were enrolled in the Diabetes Community Lifestyle Improvement Program, a randomized clinical trial with 3-year follow-up conducted at a diabetes care and research center in Chennai, India. Interventions The intervention group underwent a 6-month lifestyle modification curriculum plus stepwise addition of metformin; the control group received standard lifestyle advice. Main Outcomes and Measures Cost, health benefits, and incremental cost-effectiveness ratios (ICERs) were estimated from multipayer (including direct medical costs) and societal (including direct medical and nonmedical costs) perspectives. Costs and ICERs were reported in 2019 Indian rupees (INR) and purchasing power parity-adjusted international dollars (INT $). Results The mean (SD) age of the 578 participants was 44.4 (9.3) years, and 364 (63.2$803 [95% CI, INT $771-834]) higher direct costs; INR 5194 (95$395; 95% CI, INT $65-147) higher direct nonmedical costs, an absolute diabetes risk reduction of 10.2$145) per 1 percentage point diabetes risk reduction, INR 191 &amp; x202f;090 (INT 14 & x202f;539) per diabetes case prevented and/or delayed, and INR 196 & x202f;960 (INT 14 &amp; x202f;986) per quality-adjusted life-year gained. In the scenario of a 50% increase or decrease in screening and intervention costs, the mean ICERs varied from INR 855 (INT $65) to INR 2968 (INT$226) per 1 percentage point diabetes risk reduction, from INR 85 &amp; x202f;495 (INT 6505) to INR 296 & x202f;681 (INT 22 &amp; x202f;574) per diabetes case prevented, and from INR 88 &amp; x202f;121 (INT 6705) to INR 305 & x202f;798 (INT 23 &amp; x202f;267) per quality-adjusted life-year gained. Conclusions and Relevance The findings of this study suggest that a stepwise approach for diabetes prevention is likely to be cost-effective, even if screening costs for identifying high-risk individuals are added