Gene-Specific DNA Methylation Association with Serum Levels of C-Reactive Protein in African Americans

Sun, Yan V.; Lazarus, Alicia; Smith, Jennifer A.; Chuang, Yu Hsuan; Zhao, Wei; Turner, Stephen T.; Kardia, Sharon L.R.

doi:10.1371/journal.pone.0073480

Cited by 36 publications

(32 citation statements)

References 43 publications

(45 reference statements)

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“…70,71 To determine if genetic variation influenced DNA methylation, methylation quantitative trait loci (meQTL) were identified by applying the approach described previously 55 to the methylation data from African American subjects in the Grady Trauma Project. 47,[72][73][74] Briefly, the relationship between the proportion of methylation at each CpG site and each SNP within 50 kb of that site was examined via linear regression, where methylation was modeled as a linear function of the number of reference alleles (0, 1, or 2). CpG sites were excluded from the meQTL analysis if the probe sequence contained a SNP with a minor allele frequency greater than 1% in any population, as identified from the 1,000 genomes project (TGP).…”

Section: Discussionmentioning

confidence: 99%

“…39,40 The mechanism underlying the relationship between PTB and the development of chronic disorders later in life is not yet clear, but some suggest that inflammation or immune dysregulation may increase risk for PTB and other chronic disorders. 38,44 DNA methylation patterns regulate the functional properties of immune cells 45,46 and associate with inflammatory markers, 47 chronic disorders, [48][49][50] and PTB. 27,51 We hypothesize that DNA methylation patterns may reveal genes whose regulation is unique to women who deliver preterm or provide insight into its intergenerational risk…”

Section: Introductionmentioning

confidence: 99%

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DNA methylation provides insight into intergenerational risk for preterm birth in African Americans

et al. 2015

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Abbreviations: DOHaD, developmental origin of health and disease; FDR, false discovery rate; GA, gestational age; PTB, preterm birth; SES, socioeconomic status.African Americans are at increased risk for spontaneous preterm birth (PTB). Though PTB is heritable, genetic studies have not identified variants that account for its intergenerational risk, prompting the hypothesis that epigenetic factors may also contribute. The objective of this study was to evaluate DNA methylation from maternal leukocytes to identify patterns specific to PTB and its intergenerational risk. DNA from peripheral leukocytes from African American women that delivered preterm (24-34 weeks; N D 16) or at term (39-41 weeks; N D 24) was assessed for DNA methylation using the HumanMethylation450 BeadChip. In maternal samples, 17,829 CpG sites associated with PTB, but no CpG site remained associated after correction for multiple comparisons. Examination of paired maternal-fetal samples identified 5,171 CpG sites in which methylation of maternal samples correlated with methylation of her respective fetus (FDR < 0.05). These correlated sites were enriched for association with PTB in maternal leukocytes. The majority of correlated CpG sites could be attributed to one or more genetic variants. They were also significantly more likely to be in genes involved in metabolic, cardiovascular, and immune pathways, suggesting a role for genetic and environmental contributions to PTB risk and chronic disease. The results of this study may provide insight into the factors underlying intergenerational risk for PTB and its consequences.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

DNA methylation provides insight into intergenerational risk for preterm birth in African Americans

et al. 2015

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“…Target genes were identified using a web-based gene network and functional annotation tool (genemania.org/) and review of prior human studies investigating the genetic and epigenetic control of inflammation (30,48,(67)(68)(69)(70) (additional details on target gene selection are provided in SI Materials and Methods). A total of 249 target genes were identified.…”

Section: Methodsmentioning

confidence: 99%

Social and physical environments early in development predict DNA methylation of inflammatory genes in young adulthood

McDade

Ryan

Jones

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

112

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Chronic inflammation contributes to a wide range of human diseases, and environments in infancy and childhood are important determinants of inflammatory phenotypes. The underlying biological mechanisms connecting early environments with the regulation of inflammation in adulthood are not known, but epigenetic processes are plausible candidates. We tested the hypothesis that patterns of DNA methylation (DNAm) in inflammatory genes in young adulthood would be predicted by early life nutritional, microbial, and psychosocial exposures previously associated with levels of inflammation. Data come from a population-based longitudinal birth cohort study in metropolitan Cebu, the Philippines, and DNAm was characterized in whole blood samples from 494 participants (age 20–22 y). Analyses focused on probes in 114 target genes involved in the regulation of inflammation, and we identified 10 sites across nine genes where the level of DNAm was significantly predicted by the following variables: household socioeconomic status in childhood, extended absence of a parent in childhood, exposure to animal feces in infancy, birth in the dry season, or duration of exclusive breastfeeding. To evaluate the biological significance of these sites, we tested for associations with a panel of inflammatory biomarkers measured in plasma obtained at the same age as DNAm assessment. Three sites predicted elevated inflammation, and one site predicted lower inflammation, consistent with the interpretation that levels of DNAm at these sites are functionally relevant. This pattern of results points toward DNAm as a potentially important biological mechanism through which developmental environments shape inflammatory phenotypes across the life course.

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“…Zhang et al, 2010), and age – all well known risk factors human diseases (Bocklandt et al, 2011; Teschendorff et al, 2010). Additionally, inflammatory markers have been associated with epigenetics at the gene level in peripheral leukocytes (Sun, Lazarus, et al, 2013; Uddin et al, 2011), which play a critical role in acute and chronic inflammation related to pathophysiology of many human diseases. Studying the epigenome in the well-characterized samples may enable us to discover novel genes and pathways through which genetic factors and environmental exposures influence disease initiation and development, and thereby provide new targets for prevention and treatment (Foley et al, 2009; Jablonka, 2004; Relton & Davey Smith, 2010).…”

Section: Overview Of Omics Technologies and Association Studiesmentioning

confidence: 99%

Integrative Analysis of Multi-omics Data for Discovery and Functional Studies of Complex Human Diseases

Sun

2016

Advances in Genetics

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222

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Complex and dynamic networks of molecules are involved in human diseases. High-throughput technologies enable omics studies interrogating thousands to millions of makers with similar biochemical properties (e.g. transcriptomics for RNA transcripts). However, a single layer of ‘omics’ can only provide limited insights into the biological mechanisms of a disease. In the case of GWAS, although thousands of SNPs have been identified for complex diseases and traits, the functional implications and mechanisms of the associated loci are largely unknown. Additionally, the genomic variants alone are not able to explain the changing disease risk across the life span. DNA, RNA, protein, and metabolite often have complementary roles to jointly perform a certain biological function. Such complementary effects and synergistic interactions between omic layers in the life-course can only be captured by integrative study of multiple molecular layers. Building upon the success in single-omics discovery research, population studies started adopting the multi-omics approach to better understanding the molecular function and disease etiology. Multi-omics approaches integrate data obtained from different omic levels to understand their interrelation and combined influence on the disease processes. Here, we summarize major omics approaches available in population research, and review integrative approaches and methodologies interrogating multiple omic layers, which enhance the gene discovery and functional analysis of human diseases. We seek to provide analytical recommendations for different types of multi-omics data and study designs to guide the emerging multi-omic research, and to suggest improvement of the existing analytical methods.

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Gene-Specific DNA Methylation Association with Serum Levels of C-Reactive Protein in African Americans

Cited by 36 publications

References 43 publications

DNA methylation provides insight into intergenerational risk for preterm birth in African Americans

DNA methylation provides insight into intergenerational risk for preterm birth in African Americans

Social and physical environments early in development predict DNA methylation of inflammatory genes in young adulthood

Integrative Analysis of Multi-omics Data for Discovery and Functional Studies of Complex Human Diseases

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