Epigenome-wide association study of lung function in Latino children and youth with asthma

Abstract Introduction DNA methylation studies have associated methylation levels at different CpG sites or genomic regions with lung function. Moreover, genetic ancestry has been associated with lung function in Latinos. However, no epigenome-wide association study (EWAS) of lung function has been performed in this population. Here, we aimed to identify DNA methylation patterns associated with lung function in pediatric asthma among Latinos. Results We conducted an EWAS in whole blood from 250 Puerto Rican and 148 Mexican American children and young adults with asthma. A total of five CpGs exceeded the genome-wide significance threshold of p = 1.17 × 10−7 in the combined analyses from Puerto Ricans and Mexican Americans: cg06035600 (MAP3K6, p = 6.13 × 10−8) showed significant association with pre-bronchodilator Tiffeneau–Pinelli index, the probes cg00914963 (TBC1D16, p = 1.04 × 10−7), cg16405908 (MRGPRE, p = 2.05 × 10−8), and cg07428101 (MUC2, p = 5.02 × 10−9) were associated with post-bronchodilator forced vital capacity (FVC), and cg20515679 (KCNJ6) with post-bronchodilator Tiffeneau–Pinelli index (p = 1.13 × 10−8). However, these markers did not show significant associations in publicly available data from Europeans (p > 0.05). A methylation quantitative trait loci analysis revealed that methylation levels at these CpG sites were regulated by genetic variation in Latinos and the Biobank-based Integrative Omics Studies (BIOS) consortium. Additionally, two differentially methylated regions in REXOC and AURKC were associated with pre-bronchodilator Tiffeneau–Pinelli index (adjusted p < 0.05) in Puerto Ricans and Mexican Americans. Moreover, we replicated some of the previous differentially methylated signals associated with lung function in non-Latino populations. Conclusions We replicated previous associations of epigenetic markers with lung function in whole blood and identified novel population-specific associations shared among Latino subgroups.

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Novel epigenetic determinants of type 2 diabetes in Mexican-American families

Human Molecular Genetics ◽

10.1093/hmg/ddv232 ◽

2015 ◽

Vol 24 (18) ◽

pp. 5330-5344 ◽

Cited By ~ 75

Author(s):

Hemant Kulkarni ◽

Mark Z. Kos ◽

Jennifer Neary ◽

Thomas D. Dyer ◽

Jack W. Kent ◽

...

Keyword(s):

Type 2 Diabetes ◽

Dna Methylation ◽

Mexican Americans ◽

Mexican American ◽

Fasting Blood Glucose ◽

Phenotypic Traits ◽

High Risk Population ◽

Cpg Sites ◽

Increased Risk

Abstract Although DNA methylation is now recognized as an important mediator of complex diseases, the extent to which the genetic basis of such diseases is accounted for by DNA methylation is unknown. In the setting of large, extended families representing a minority, high-risk population of the USA, we aimed to characterize the role of epigenome-wide DNA methylation in type 2 diabetes (T2D). Using Illumina HumanMethylation450 BeadChip arrays, we tested for association of DNA methylation at 446 356 sites with age, sex and phenotypic traits related to T2D in 850 pedigreed Mexican-American individuals. Robust statistical analyses showed that (i) 15% of the methylome is significantly heritable, with a median heritability of 0.14; (ii) DNA methylation at 14% of CpG sites is associated with nearby sequence variants; (iii) 22% and 3% of the autosomal CpG sites are associated with age and sex, respectively; (iv) 53 CpG sites were significantly associated with liability to T2D, fasting blood glucose and insulin resistance; (v) DNA methylation levels at five CpG sites, mapping to three well-characterized genes (TXNIP, ABCG1 and SAMD12) independently explained 7.8% of the heritability of T2D (vi) methylation at these five sites was unlikely to be influenced by neighboring DNA sequence variation. Our study has identified novel epigenetic indicators of T2D risk in Mexican Americans who have increased risk for this disease. These results provide new insights into potential treatment targets of T2D.

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Epigenome-wide association study of whole blood gene expression in Framingham Heart Study participants provides molecular insight into the potential role of CHRNA5 in cigarette smoking-related lung diseases

Clinical Epigenetics ◽

10.1186/s13148-021-01041-5 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Chen Yao ◽

Roby Joehanes ◽

Rory Wilson ◽

Toshiko Tanaka ◽

Luigi Ferrucci ◽

...

Keyword(s):

Gene Expression ◽

Lung Cancer ◽

Dna Methylation ◽

Cigarette Smoking ◽

Association Study ◽

Whole Blood ◽

Lung Diseases ◽

Epigenetic Modification ◽

Blood Gene Expression ◽

Increased Risk

Abstract Background DNA methylation is a key epigenetic modification that can directly affect gene regulation. DNA methylation is highly influenced by environmental factors such as cigarette smoking, which is causally related to chronic obstructive pulmonary disease (COPD) and lung cancer. To date, there have been few large-scale, combined analyses of DNA methylation and gene expression and their interrelations with lung diseases. Results We performed an epigenome-wide association study of whole blood gene expression in ~ 6000 individuals from four cohorts. We discovered and replicated numerous CpGs associated with the expression of cis genes within 500 kb of each CpG, with 148 to 1,741 cis CpG-transcript pairs identified across cohorts. We found that the closer a CpG resided to a transcription start site, the larger its effect size, and that 36% of cis CpG-transcript pairs share the same causal genetic variant. Mendelian randomization analyses revealed that hypomethylation and lower expression of CHRNA5, which encodes a smoking-related nicotinic receptor, are causally linked to increased risk of COPD and lung cancer. This putatively causal relationship was further validated in lung tissue data. Conclusions Our results provide a large and comprehensive association study of whole blood DNA methylation with gene expression. Expression platform differences rather than population differences are critical to the replication of cis CpG-transcript pairs. The low reproducibility of trans CpG-transcript pairs suggests that DNA methylation regulates nearby rather than remote gene expression. The putatively causal roles of methylation and expression of CHRNA5 in relation to COPD and lung cancer provide evidence for a mechanistic link between patterns of smoking-related epigenetic variation and lung diseases, and highlight potential therapeutic targets for lung diseases and smoking cessation.

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DNA methylation is associated with lung function in never smokers

Respiratory Research ◽

10.1186/s12931-019-1222-8 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 3

Author(s):

Maaike de Vries ◽

◽

Ivana Nedeljkovic ◽

Diana A. van der Plaat ◽

Alexandra Zhernakova ◽

...

Keyword(s):

Dna Methylation ◽

Lung Function ◽

Ribosome Biogenesis ◽

Meta Analysis ◽

Smoking History ◽

Rotterdam Study ◽

Main Risk Factor ◽

Cpg Sites ◽

Never Smokers ◽

Integrative Omics

Abstract Background Active smoking is the main risk factor for COPD. Here, epigenetic mechanisms may play a role, since cigarette smoking is associated with differential DNA methylation in whole blood. So far, it is unclear whether epigenetics also play a role in subjects with COPD who never smoked. Therefore, we aimed to identify differential DNA methylation associated with lung function in never smokers. Methods We determined epigenome-wide DNA methylation levels of 396,243 CpG-sites (Illumina 450 K) in blood of never smokers in four independent cohorts, LifeLines COPD&C (N = 903), LifeLines DEEP (N = 166), Rotterdam Study (RS)-III (N = 150) and RS-BIOS (N = 206). We meta-analyzed the cohort-specific methylation results to identify differentially methylated CpG-sites with FEV1/FVC. Expression Quantitative Trait Methylation (eQTM) analysis was performed in the Biobank-based Integrative Omics Studies (BIOS). Results A total of 36 CpG-sites were associated with FEV1/FVC in never smokers at p-value< 0.0001, but the meta-analysis did not reveal any epigenome-wide significant CpG-sites. Of interest, 35 of these 36 CpG-sites have not been associated with lung function before in studies including subjects irrespective of smoking history. Among the top hits were cg10012512, cg02885771, annotated to the gene LTV1 Ribosome Biogenesis factor (LTV1), and cg25105536, annotated to Kelch Like Family Member 32 (KLHL32). Moreover, a total of 11 eQTMS were identified. Conclusions With the identification of 35 CpG-sites that are unique for never smokers, our study shows that DNA methylation is also associated with FEV1/FVC in subjects that never smoked and therefore not merely related to smoking.

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ANGPT1 methylation and delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage patients

Epigenetics Communications ◽

10.1186/s43682-021-00001-7 ◽

2021 ◽

Vol 1 (1) ◽

Author(s):

Dongjing Liu ◽

Annie I. Arockiaraj ◽

John R. Shaffer ◽

Samuel M. Poloyac ◽

Paula R. Sherwood ◽

...

Keyword(s):

Dna Methylation ◽

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Pooled Analysis ◽

Aneurysm Rupture ◽

Cpg Sites ◽

Significance Threshold ◽

Post Hoc

Abstract Background Delayed cerebral ischemia (DCI) is a common secondary complication and an important cause of disability and mortality among patients who survive aneurysmal subarachnoid hemorrhage (aSAH). Knowledge on DCI pathogenesis, risk factors, and biomarkers are essential for early detection and improved prognosis. To investigate the role of DNA methylation in DCI risk, we conducted an epigenome-wide association study (EWAS) in 68 patients followed up to 1 year after the initial aneurysm rupture. Blood samples were collected within 48 h post hemorrhage and used for DNA methylation profiling at ~ 450k CpG sites. A separate cohort of 175 patients was sequenced for the top CpG sites from the discovery analysis for a replication of the EWAS findings. Results EWAS did not identify any epigenome-wide significant CpGs. The top signal, cg18031596, was annotated to ANGPT1, a gene with critical functions in angiogenesis after vascular injury. Post hoc power calculations indicated a well-powered discovery analysis for cg18031596. Analysis of the replication cohort showed that four out of the five CpG sites sequenced at the ANGPT1 locus passed a Bonferroni-adjusted significance threshold. In a pooled analysis of the entire sample, three out of five yielded a significant p-value, and the top association signal (p-value = 0.004) was seen for a CpG that was not originally measured in the discovery EWAS. However, four ANGPT1 CpG sites had an opposite effect direction in the replication analysis compared to the discovery EWAS, marking a failure of replication. We carefully examined this observed flip in directions and propose several possible explanations in addition to that it was a random chance that ANGPT1 ranked at the top in the discovery EWAS. Conclusions We failed to demonstrate a significant and consistent effect of ANGPT1 methylation in DCI risk in two cohorts. Though the replication attempt to weaken the overall support of this gene, given its relevant function and top rank of significance in the EWAS, our results call for future studies of larger aSAH cohorts to determine its relevance for the occurrence of DCI.

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Epigenome-wide association study identifies Behçet’s disease-associated methylation loci in Han Chinese

Rheumatology ◽

10.1093/rheumatology/kez043 ◽

2019 ◽

Vol 58 (9) ◽

pp. 1574-1584 ◽

Cited By ~ 5

Author(s):

Hongsong Yu ◽

Liping Du ◽

Shenglan Yi ◽

Qingfeng Wang ◽

Yunyun Zhu ◽

...

Keyword(s):

Dna Methylation ◽

Association Study ◽

Mrna Expression ◽

Behcet’S Disease ◽

Behçet's Disease ◽

Han Chinese ◽

Healthy Controls ◽

Behcet's Disease ◽

Cpg Sites ◽

Aberrant Dna Methylation

Abstract Objective The aetiology of Behçet’s disease (BD), known as a systemic vasculitis, is not completely understood. Increasing evidence suggests that aberrant DNA methylation may contribute to the pathogenesis of BD. The aim of this epigenome-wide association study was to identify BD-associated methylation loci in Han Chinese. Methods Genome-wide DNA methylation profiles were compared between 60 BD patients and 60 healthy controls using the Infinium Human Methylation 450 K Beadchip. BD-associated methylation loci were validated in 100 BD patients and 100 healthy controls by pyrosequencing. Gene expression and cytokine production was quantified by real-time PCR and ELISA. Results A total of 4332 differentially methylated CpG sites were associated with BD. Five differentially methylated CpG sites (cg03546163, cg25114611, cg20228731, cg23261343 and cg14290576) revealed a significant hypomethylation status across four different genes (FKBP5, FLJ43663, RUNX2 and NFIL3) and were validated by pyrosequencing. Validation results showed that the most significant locus was located in the 5’UTR of FKBP5 (cg03546163, P = 3.81E-13). Four CpG sites with an aberrant methylation status, including cg03546163, cg25114611, cg23261343 and cg14290576, may serve as a diagnostic marker for BD (area under the receiver operating curve curve = 83.95%, 95% CI 78.20, 89.70%). A significantly inverse correlation was found between the degree of methylation at cg03546163 as well as cg25114611 and FKBP5 mRNA expression. Treatment with a demethylation agent, 5-Aza-2’-deoxycytidine resulted in an increase of FKBP5 mRNA expression and a stimulated IL-1β production. Conclusion Our findings suggest that aberrant DNA methylation, independently of previously known genetic variants, plays a vital role in the pathogenesis of BD. Trial registration Chinese Clinical Trial Registry, chictr.org.cn, ChiCTR-CCC-12002184.

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Cross-national Comparison Examining Breastfeeding and Child Malnutrition Among Mexicans (P11-106-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz048.p11-106-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Ana Paola Campos ◽

Summer Hawkins

Keyword(s):

Risk Factors ◽

National Health ◽

Mexican Americans ◽

Mexican American ◽

Low Birthweight ◽

Child Malnutrition ◽

Foreign Born ◽

Health And Nutrition ◽

Child Overweight ◽

American Children

Abstract Objectives To examine the effects of breastfeeding duration and contextual factors at individual- and household-levels on child malnutrition, including overweight and stunting, in Mexican and Mexican-American children aged 3–35 months. Methods Secondary data analysis of 2,311 Mexican children from the 2012 Mexican National Health and Nutrition Survey and 829 Mexican-American children from the 2007–2014 US National Health and Nutrition Examination Survey, using independent and pooled logistic regression models to examine bivariate and multivariate associations. Results The prevalence of breastfeeding initiation and any breastfeeding for ≥ 3 months was higher in Mexican (94.2% and 83.5%) versus Mexican-American children (76.4% and 43.0%). Among the latter, those with foreign-born household reference person (HRP) were more likely to initiate and continue breastfeeding than US-born counterparts. The prevalence of child overweight did not differ in either population (9.0% in Mexicans versus 8.8% in Mexican-Americans), but among the latter, those with foreign-born HRP had higher prevalence for child overweight than US-born counterparts. The prevalence of child stunting was higher in Mexicans (11.6%) versus Mexican-Americans (2.0%) and no difference was found between children with foreign- or US-born HRP. We found no evidence for an association between any breastfeeding for ≥ 3 months and either measure of child malnutrition among Mexicans or Mexican-Americans when compared to those who were never breastfed. High- and low-birthweight were risk factors across the 2 populations for child overweight (AOR 2.72, 95% CI 1.81-4.08) and stunting (AOR 4.22, 95% CI 2.79-6.40), accordingly. We also identified additional country-specific risk and protective factors. Conclusions Culturally-sensitive interventions should focus on women prenatally using prophylactic strategies to prevent offspring high- and low-birthweight as these were risk factors for child malnutrition. These interventions should also include postnatal strategies to maintain and foster positive maternal health behaviors, including breastfeeding. Funding Sources No funding was received for this research. Supporting Tables, Images and/or Graphs

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DNA Methylation Changes in Whole Blood and CD16+ Neutrophils in Response to Chronic Folic Acid Supplementation in Women of Childbearing Age

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000491 ◽

2017 ◽

Vol 87 (5-6) ◽

pp. 271-278

Author(s):

Deanna C. Shade ◽

Hea Jin Park ◽

Dorothy B. Hausman ◽

Natalie Hohos ◽

Richard B. Meagher ◽

...

Keyword(s):

Dna Methylation ◽

Folic Acid ◽

Whole Blood ◽

White Blood Cells ◽

Folic Acid Supplementation ◽

Water Soluble ◽

Childbearing Age ◽

Acid Yield ◽

Acid Supplementation ◽

Cpg Sites

Abstract. Folate, a water-soluble vitamin, is a key source of one-carbon groups for DNA methylation, but studies of the DNA methylation response to supplemental folic acid yield inconsistent results. These studies are commonly conducted using whole blood, which contains a mixed population of white blood cells that have been shown to confound results. The objective of this study was to determine if CD16+ neutrophils may provide more specific data than whole blood for identifying DNA methylation response to chronic folic acid supplementation. The study was performed in normal weight (BMI 18.5 – 24.9 kg/m2) women (18 – 35 y; n = 12), with blood samples taken before and after 8 weeks of folic acid supplementation at 800 μg/day. DNA methylation patterns from whole blood and isolated CD16+ neutrophils were measured across >485,000 CpG sites throughout the genome using the Infinium HumanMethylation450 BeadChip. Over the course of the 8-week supplementation, 6746 and 7513 CpG sites changed (p < 0.05) in whole blood and CD16+ neutrophils, respectively. DNA methylation decreased in 68.4% (whole blood) and 71.8% (CD16+ neutrophils) of these sites. There were only 182 CpG sites that changed in both the whole blood and CD16+ neutrophils, 139 of which changed in the same direction. These results suggest that the genome-wide DNA methylation response to chronic folic acid supplementation is different between whole blood and CD16+ neutrophils and that a single white blood cell type may function as a more specific epigenetic reporter of folate status than whole blood.

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Genetic and Environmental Determinants of Growth in Mexican-Americans

PEDIATRICS ◽

10.1542/peds.84.5.864 ◽

1989 ◽

Vol 84 (5) ◽

pp. 864-871

Author(s):

Reynaldo Martorell ◽

Fernando S. Mendoza ◽

Ricardo O. Castillo

Keyword(s):

Mexican Americans ◽

Mexican American ◽

Growth Patterns ◽

Nutrition Examination Survey ◽

Hispanic Health ◽

Growth Standards ◽

Health And Nutrition ◽

Reference Curves ◽

American Children ◽

Mexican American Adolescents

Height and weight data from the Mexican-American portion of the Hispanic Health and Nutrition Examination Survey (HHANES) are shown for children of ages 2 to 17 years and compared with data for non-Hispanic white children from the second National Health and Nutrition Examination Survey and with the National Center for Health Statistics (NCHS) reference curves. Differences in stature between the Hispanic Health and Nutrition Examination Survey and the reference populations were minor prior to adolescence and could be entirely attributed to the greater poverty of Mexican-Americans. However, differences increased during adolescence (ie, median stature was less than the 25th percentile of the NCHS reference population at 17 years of age) and, in contrast with earlier ages, were independent of poverty. Similar growth patterns were observed in samples of upper-class subjects from Mexico and Guatemala. Nonetheless, the extent to which the short stature of Mexican-American adolescents is genetic is unclear because there is an apparent time trend toward greater stature in the Mexican-American population. In conclusion, the NCHS reference curves are appropriate growth standards for preadolescent Mexican-American children. Whether they are valid for Mexican-American adolescents remains unclear.

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Locus of Control Orientations of Anglo-and Mexican-American Children

Psychological Reports ◽

10.2466/pr0.1985.57.3f.1121 ◽

1985 ◽

Vol 57 (3_suppl) ◽

pp. 1121-1122 ◽

Cited By ~ 2

Author(s):

Raymond Buriel

Keyword(s):

Locus Of Control ◽

Mexican Americans ◽

Mexican American ◽

Socioeconomic Differences ◽

Single Method ◽

The Mean ◽

American Children

Previous studies comparing the locus of control of Anglo-and Mexican-Americans have usually not controlled for large socioeconomic differences between these groups. Such studies have also tended to rely on single-method approaches of measuring Anglo-Mexican-American differences on this variable. The present study compared Anglo- and Mexican-American children of similar socioeconomic backgrounds on two locus of control scales. Analyses of variance indicated no significant differences in the mean scores of the two groups of children. There was no significant correlation between the two locus of control scales for both groups of children.

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