Methylome-Wide Association Study of Central Adiposity Implicates Genes Involved in Immune and Endocrine Systems

Justice, Anne E.; Chittoor, Geetha; Gondalia, Rahul; Melton, Phillip E.; Lim, Elise; Grove, Megan L.; Whitsel, Eric A.; Liu, Ching‐Ti; Cupples, L. Adrienne; Fernández-Rhodes, Lindsay; Guan, Weihua; Bressler, Jan; Fornage, Myriam; Boerwinkle, Eric; Li, Yun; Demerath, Ellen W.; Heard‐Costa, Nancy L.; Levy, Daniel; Stewart, James D.; Baccarelli, Andrea A.; Hou, Lifang; Conneely, Karen N.; Mori, Trevor A.; Beilin, Lawrence J.; Huang, Rae Chi; Gordon‐Larsen, Penny; Howard, Annie Green; North, Kari E.

doi:10.2217/epi-2019-0276

Cited by 8 publications

(4 citation statements)

References 93 publications

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“…Other relevant target enrichments were for RREB1, which is also encoded by an Ow-dmCpGhosting gene, and for SREBP1, a partner of E47 in adiponectin expression activation and an extensively studied regulator of FA metabolism (Doran et al, 2008;Jump, 2011). Methylation of selected SREBP1 CpG is also associated with adiposity (Justice et al, 2020). Also, SREBP1 has been implicated in establishing a proatherogenic lipid profile in monocytes (Bowman et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Distinct Associations of BMI and Fatty Acids With DNA Methylation in Fasting and Postprandial States in Men

et al. 2021

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We have previously shown that blood global DNA methylation (DNAm) differs between postprandial state (PS) and fasting state (FS) and is associated with BMI and polyunsaturated fatty acid (PUFA) (negatively and positively, respectively) in 12 metabolically healthy adult Mexican men (AMM cohort) equally distributed among conventional BMI classes. Here, we detailed those associations at CpG dinucleotide level by exploiting the Infinium methylation EPIC array (Illumina). We sought differentially methylated CpG (dmCpG) that were (1) associated with BMI (BMI-dmCpG) and/or fatty acids (FA) (FA-dmCpG) in FS or PS and (2) different across FS and PS within a BMI class. BMI-dmCpG and FA-dmCpG were more numerous in FS compared to PS and largely prandial state-specific. For saturated and monounsaturated FA, dmCpG overlap was higher across than within the respective saturation group. Several BMI- and FA-dmCpG mapped to genes involved in metabolic disease and in some cases matched published experimental data sets. Notably, SETDB1 and MTHFS promoter dmCpG could explain the previously observed associations between global DNAm, PUFA content, and BMI in FS. Surprisingly, overlap between BMI-dmCpG and FA-dmCpG was limited and the respective dmCpG were differentially distributed across functional genomic elements. BMI-dmCpG showed the highest overlap with dmCpG of the saturated FA palmitate, monounsaturated C20:1 and PUFA C20:2. Of these, selected promoter BMI-dmCpG showed opposite associations with palmitate compared to C20:1 and C20:2. As for the comparison between FS and PS within BMI classes, dmCpG were strikingly more abundant and variably methylated in overweight relative to normoweight or obese subjects (∼70–139-fold, respectively). Overweight-associated dmCpG-hosting genes were significantly enriched in targets for E47, SREBP1, and RREB1 transcription factors, which are known players in obesity and lipid homeostasis, but none overlapped with BMI-dmCpG. We show for the first time that the association of BMI and FA with methylation of disease-related genes is distinct in FS and PS and that limited overlap exists between BMI- and FA-dmCpG within and across prandial states. Our study also identifies a transcriptional regulation circuitry in overweight that might contribute to adaptation to that condition or to transition to obesity. Further work is necessary to define the pathophysiological implications of these findings.

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Section: Discussionmentioning

confidence: 99%

Distinct Associations of BMI and Fatty Acids With DNA Methylation in Fasting and Postprandial States in Men

et al. 2021

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“…DMP cg19693031, located in the 3′UTR of the TXNIP gene, was epigenome-wide significantly associated with fasting triglyceride concentration in Ghanaians, and explained 6.2% of the variation in triglyceride levels. In African American and European ancestry populations, this DMP has previously been linked to triglyceride and lipid metabolism, 25 , 26 as well as to other cardiometabolic traits such as weight, 27 blood glucose, 13 blood pressure, 28 and to BMI in a previous RODAM EWAS study. 12 The TXNIP gene encodes for the thioredoxin interacting protein, which is primarily involved in inflammatory, metabolic and apoptotic processes, 29 and plays an important role in the development of diabetes, by influencing insulin production and beta-cell apoptosis.…”

Section: Discussionmentioning

confidence: 89%

Epigenome-wide association study of plasma lipids in West Africans: the RODAM study

Linden¹,

Meeks²,

Chilunga³

et al. 2023

eBioMedicine

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“…This association was further supported by significant DMRs observed for the same phenotypes. The CpG site with the strongest association (cg19693031) with MetS has been extensively studied and has shown links to blood lipid levels [ 38 , 39 ], blood pressure [ 40 ], central obesity [ 41 ], and the prevalence of T2D and type 1 diabetes [ 33 , 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

Genome- and epigenome-wide association studies identify susceptibility of CpG sites and regions for metabolic syndrome in a Korean population

Lee,

Kim,

Park

2024

Clin Epigenet

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Background While multiple studies have investigated the relationship between metabolic syndrome (MetS) and its related traits (fasting glucose, triglyceride, HDL cholesterol, blood pressure, waist circumference) and DNA methylation, our understanding of the epigenetic mechanisms in MetS remains limited. Therefore, we performed an epigenome-wide meta-analysis of blood DNA methylation to identify differentially methylated probes (DMPs) and differentially methylated regions (DMRs) associated with MetS and its components using two independent cohorts comprising a total of 2,334 participants. We also investigated the specific genetic effects on DNA methylation, identified methylation quantitative trait loci (meQTLs) through genome-wide association studies and further utilized Mendelian randomization (MR) to assess how these meQTLs subsequently influence MetS status. Results We identified 40 DMPs and 27 DMRs that are significantly associated with MetS. In addition, we identified many novel DMPs and DMRs underlying inflammatory and steroid hormonal processes. The most significant associations were observed in 3 DMPs (cg19693031, cg26974062, cg02988288) and a DMR (chr1:145440444–145441553) at the TXNIP, which are involved in lipid metabolism. These CpG sites were identified as coregulators of DNA methylation in MetS, TG and FAG levels. We identified a total of 144 cis-meQTLs, out of which only 13 were found to be associated with DMPs for MetS. Among these, we confirmed the identified causal mediators of genetic effects at CpG sites cg01881899 at ABCG1 and cg00021659 at the TANK genes for MetS. Conclusions This study observed whether specific CpGs and methylated regions act independently or are influenced by genetic effects for MetS and its components in the Korean population. These associations between the identified DNA methylation and MetS, along with its individual components, may serve as promising targets for the development of preventive interventions for MetS.

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Methylome-Wide Association Study of Central Adiposity Implicates Genes Involved in Immune and Endocrine Systems

Cited by 8 publications

References 93 publications

Distinct Associations of BMI and Fatty Acids With DNA Methylation in Fasting and Postprandial States in Men

Distinct Associations of BMI and Fatty Acids With DNA Methylation in Fasting and Postprandial States in Men

Epigenome-wide association study of plasma lipids in West Africans: the RODAM study

Genome- and epigenome-wide association studies identify susceptibility of CpG sites and regions for metabolic syndrome in a Korean population

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