7~16岁儿童青少年肥胖与DNA甲基化相关性的双生子研究

目的 基于肥胖不一致双生子人群,在全基因组范围内探索与儿童青少年肥胖相关的DNA甲基化位点。方法 2016年在北京市朝阳区、延庆区及房山区招募90对6~17周岁双生子,通过问卷调查和体格检查收集双生子个人信息以及身高、体重、腰围等;通过美国Illumina公司EPIC芯片进行全基因组甲基化检测,采用R 3.3.1软件进行DNA甲基化数据读取、质量控制和统计学分析。利用肥胖不一致同卵双生子对,采用经验贝叶斯配对调整t检验和Levene检验,分别探索与肥胖相关的DNA甲基化差异位点和DNA甲基化变异差异位点。结果 根据研究定义,共纳入23对肥胖不一致同卵双生子对,年龄范围7~16岁。共有817 471个合格CpG位点纳入全基因组相关分析,未发现满足多重校正标准的肥胖相关DNA甲基化阳性位点,P值最小的DNA甲基化差异位点为12号染色体上的位点cg05684382（P=1.26E-06,FDR>0.05）,P值最小的DNA甲基化变异差异位点为16号染色体CMIP基因主体上的位点cg26188191（P=6.44E-06,FDR>0.05）,均为EPIC芯片新增位点。结论 基于本研究人群,研究未发现满足显著性要求的肥胖相关DNA甲基化阳性位点,但分析提示cg05684382、cg26188191可能与肥胖发生相关。     

CpG Sites Associated with Cigarette Smoking: Analysis of Epigenome-Wide Data from the Sister Study

Background: Smoking increases the risk of many diseases, and it is also linked to blood DNA methylation changes that may be important in disease etiology.Objectives: We sought to identify novel CpG sites associated with cigarette smoking.Methods: We used two epigenome-wide data sets from the Sister Study to identify and confirm CpG sites associated with smoking. One included 908 women with methylation measurements at 27,578 CpG sites using the HumanMethylation27 BeadChip; the other included 200 women with methylation measurements for 473,844 CpG sites using the HumanMethylation450 BeadChip. Significant CpGs from the second data set that were not included in the 27K assay were validated by pyrosequencing in a subset of 476 samples from the first data set.Results: Our study successfully confirmed smoking associations for 9 previously established CpGs and identified 2 potentially novel CpGs: cg26764244 in GNG12 (p = 9.0 × 10^–10) and cg22335340 in PTPN6 (p = 2.9 × 10^–05). We also found strong evidence of an association between smoking status and cg02657160 in CPOX (p = 7.3 × 10^–7), which has not been previously reported. All 12 CpGs were undermethylated in current smokers and showed an increasing percentage of methylation in former and never-smokers.Conclusions: We identified 2 potentially novel smoking related CpG sites, and provided independent replication of 10 previously reported CpGs sites related to smoking, one of which is situated in the gene CPOX. The corresponding enzyme is involved in heme biosynthesis, and smoking is known to increase heme production. Our study extends the evidence base for smoking-related changes in DNA methylation.Citation: Harlid S, Xu Z, Panduri V, Sandler DP, Taylor JA. 2014. CpG sites associated with cigarette smoking: analysis of epigenome-wide data from the Sister Study. Environ Health Perspect 122:673–678; http://dx.doi.org/10.1289/ehp.1307480     

Gene-Specific Differential DNA Methylation and Chronic Arsenic Exposure in an Epigenome-Wide Association Study of Adults in Bangladesh

Background: Inorganic arsenic is one of the most common naturally occurring contaminants found in the environment. Arsenic is associated with a number of health outcomes, with epigenetic modification suggested as a potential mechanism of toxicity.Objective: Among a sample of 400 adult participants, we evaluated the association between arsenic exposure, as measured by blood and urinary total arsenic concentrations, and epigenome-wide white blood cell DNA methylation.Methods: We used linear regression models to examine the associations between arsenic exposure and methylation at each CpG site, adjusted for sex, age, and batch. Differentially methylated loci were subsequently examined in relation to corresponding gene expression for functional evidence of gene regulation.Results: In adjusted analyses, we observed four differentially methylated CpG sites with urinary total arsenic concentration and three differentially methylated CpG sites with blood arsenic concentration, based on the Bonferroni-corrected significance threshold of p < 1 × 10^–7. Methylation of PLA2G2C (probe cg04605617) was the most significantly associated locus in relation to both urinary (p = 3.40 × 10^–11) and blood arsenic concentrations (p = 1.48 × 10^–11). Three additional novel methylation loci—SQSTM1 (cg01225779), SLC4A4 (cg06121226), and IGH (cg13651690)—were also significantly associated with arsenic exposure. Further, there was evidence of methylation-related gene regulation based on gene expression for a subset of differentially methylated loci.Conclusions: We observed significant associations between arsenic exposure and gene-specific differential white blood cell DNA methylation, suggesting that epigenetic modifications may be an important pathway underlying arsenic toxicity. The specific differentially methylated loci identified may inform potential pathways for future interventions.Citation: Argos M, Chen L, Jasmine F, Tong L, Pierce BL, Roy S, Paul-Brutus R, Gamble MV, Harper KN, Parvez F, Rahman M, Rakibuz-Zaman M, Slavkovich V, Baron JA, Graziano JH, Kibriya MG, Ahsan H. 2015. Gene-specific differential DNA methylation and chronic arsenic exposure in an epigenome-wide association study of adults in Bangladesh. Environ Health Perspect 123:64–71; http://dx.doi.org/10.1289/ehp.1307884     

Racial Differences in DNA-Methylation of CpG Sites Within Preterm-Promoting Genes and Gene Variants

Objective To evaluate the role DNA methylation may play in genes associated with preterm birth for higher rates of preterm births in African-American women. Methods Fetal cord blood samples from births collected at delivery and maternal demographic and medical information were used in a cross-sectional study to examine fetal DNA methylation of genes implicated in preterm birth among black and non-black infants. Allele-specific DNA methylation analysis was performed using a methylation bead array. Targeted maximum likelihood estimation was applied to examine the relationship between race and fetal DNA methylation of candidate preterm birth genes. Receiver-operating characteristic analyses were then conducted to validate the CpG site methylation marker within the two racial groups. Bootstrapping, a method of validation and replication, was employed. Results 42 CpG sites were screened within 20 candidate gene variants reported consistently in the literature as being associated with preterm birth. Of these, three CpG sites on TNFAIP8 and PON1 genes (corresponding to: cg23917399; cg07086380; and cg07404485, respectively) were significantly differentially methylated between black and non-black individuals. The three CpG sites showed lower methylation status among infants of black women. Bootstrapping validated and replicated results. Conclusion for Practice Our study identified significant differences in levels of methylation on specific genes between black and non-black individuals. Understanding the genetic/epigenetic mechanisms that lead to preterm birth may lead to enhanced prevention strategies to reduce morbidity and mortality by eventually providing a means to identify individuals with a genetic predisposition to preterm labor.     

Vitamin D insufficiency in obese children and relation with lipid profile

Abstract

Vitamin D (25OHD) deficiency is reported in obese children. Low 25OHD levels are associated with dyslipidemia and increased risk of cardiovascular complication in adulthood. Within an observational study, 120 obese subjects in pediatric age were enrolled: 59 had 25OHD <20?ng/ml (group A) while 61 had 25OHD >20?ng/ml (group B). Group A versus Group B showed elevated total cholesterol (TC), p?=?0.017, low-density lipoprotein cholesterol (LDL-C), p?=?0.045, and parathormone (PTH), p?=?0.008. Apolipoprotein B (ApoB) showed a similar trend, p?=?0.074. Negative correlations were found between 25OHD and the following parameters: TC (ρ?=??0.22, p?=?0.01), LDL (ρ?=??0.22; p?=?0.03), ApoB (ρ?=??0.20; p?=?0.03), and PTH (ρ?=??0.33, p?=?0.003). No differences in High Lipoprotein Cholesterol (HDL-C) were found. In multivariate regression the most powerful predictor for explaining 25OHD variation were TC (p?=?0.048) and PTH (p?=?0.055). Within a pediatric obese population an association between 25OHD low levels and unfavourable lipid patterns has been found.     

Smoking-Associated DNA Methylation Biomarkers and Their Predictive Value for All-Cause and Cardiovascular Mortality

Background

With epigenome-wide mapping of DNA methylation, a number of novel smoking-associated loci have been identified.

Objectives

We aimed to assess dose–response relationships of methylation at the top hits from the epigenome-wide methylation studies with smoking exposure as well as with total and cause-specific mortality.

Methods

In a population-based prospective cohort study in Germany, methylation was quantified in baseline blood DNA of 1,000 older adults by the Illumina 450K assay. Deaths were recorded during a median follow-up of 10.3 years. Dose–response relationships of smoking exposure with methylation at nine CpGs were modeled by restricted cubic spline regression. Associations of individual and aggregate methylation patterns with all-cause, cardiovascular, and cancer mortality were assessed by multiple Cox regression.

Results

Clear dose–response relationships with respect to current and lifetime smoking intensity were consistently observed for methylation at six of the nine CpGs. Seven of the nine CpGs were also associated with mortality outcomes to various extents. A methylation score based on the top two CpGs (cg05575921 and cg06126421) showed the strongest associations with all-cause, cardiovascular, and cancer mortality, with adjusted hazard ratios (95% CI) of 3.59 (2.10, 6.16), 7.41 (2.81, 19.54), and 2.48 (1.01, 6.08), respectively, for participants with methylation levels in the lowest quartile at both CpGs. Adding methylation at those two CpGs into a model that included the variables of the Systematic Coronary Risk Evaluation chart for fatal cardiovascular risk prediction improved the predictive discrimination.

Conclusion

The novel methylation biomarkers are highly informative for both smoking exposure and smoking-related mortality outcomes. In particular, these biomarkers may substantially improve cardiovascular risk prediction. Nevertheless, the findings of the present study need to be further validated in additional large longitudinal studies.

Citation

Zhang Y, Schöttker B, Florath I, Stock C, Butterbach K, Holleczek B, Mons U, Brenner H. 2016. Smoking-associated DNA methylation biomarkers and their predictive value for all-cause and cardiovascular mortality. Environ Health Perspect 124:67–74; http://dx.doi.org/10.1289/ehp.1409020     

DNA甲基化介导BMI对胰岛素-妊娠期糖尿病的中介效应

  目的  探索DNA甲基化是否为BMI和胰岛素-妊娠期糖尿病(insulin-treated gestational diabetes mellitus, I-GDM)之间的中介变量,并估计其中介效应。  方法  研究资料来自基因表达数据库(gene expression omnibus, GEO),检索号为GSE88929,由产科医生收集44例I-GDM病例和64例对照,共纳入212 991个胞嘧啶-磷酸-鸟嘌呤双核苷酸(cytosine-phosphate-guanine pairs of nucleotides, CpG)位点。采用因果推断检验(causal inference test, CIT)筛选出潜在的中介CpG位点。调整孕龄、胎儿性别和胎龄三个混杂因素,进一步通过CpG位点估计BMI对I-GDM的中介效应。  结果  CIT过程第一步结果表明BMI与I-GDM有关联(OR=1.057, 95% CI: 1.014~1.105, P=0.010);第二步调整BMI,采用伪发现率(false discorery rate, FDR)方法进行多重检验校正,共筛选出与I-GDM相关联的6 348个CpG位点纳入下一步分析;第三步调整I-GDM后,确定529个CpG位点分别与BMI有关联;第四步分别调整6个CpG位点后,BMI与I-GDM相互独立。因此,CIT检验出6个CpG位点(cg00542041、cg08589721、cg25775742、cg15819225、cg26824326、cg15110463)作为BMI与I-GDM的中介变量。进一步采用中介分析因果推断模型,证实上述6个CpG存在中介效应。  结论  本研究发现6个DNA甲基化CpG位点在BMI和I-GDM之间发挥了中介作用,均可能作为I-GDM发病机制中新的生物标记物,为研究BMI和I-GDM之间复杂的生物学机制提供了参考依据。     

Residential and GPS-Defined Activity Space Neighborhood Noise Complaints,Body Mass Index and Blood Pressure Among Low-Income Housing Residents in New York City

Little is known about how neighborhood noise influences cardiovascular disease (CVD) risk among low-income populations. The aim of this study was to investigate associations between neighborhood noise complaints and body mass index (BMI) and blood pressure (BP) among low-income housing residents in New York City (NYC), including the use of global positioning system (GPS) data. Data came from the NYC Low-Income Housing, Neighborhoods and Health Study in 2014, including objectively measured BMI and BP data (N?=?102, Black?=?69%), and 1 week of GPS data. Noise reports from “NYC 311” were used to create a noise complaints density (unit: 1000 reports/km²) around participants’ home and GPS-defined activity space neighborhoods. In fully-adjusted models, we examined associations of noise complaints density with BMI (kg/m²), and systolic and diastolic BP (mmHg), controlling for individual- and neighborhood-level socio-demographics. We found inverse relationships between home noise density and BMI (B?=??2.7 [kg/m²], p?=?0.009), and systolic BP (B?=??5.3 mmHg, p?=?0.008) in the fully-adjusted models, and diastolic BP (B?=??3.9 mmHg, p?=?0.013) in age-adjusted models. Using GPS-defined activity space neighborhoods, we observed inverse associations between noise density and systolic BP (B?=??10.3 mmHg, p?=?0.019) in fully-adjusted models and diastolic BP (B?=??7.5 mmHg, p?=?0.016) in age-adjusted model, but not with BMI. The inverse associations between neighborhood noise and CVD risk factors were unexpected. Further investigation is needed to determine if these results are affected by unobserved confounding (e.g., variations in walkability). Examining how noise could be related to CVD risk could inform effective neighborhood intervention programs for CVD risk reduction.     

DNA hypomethylation in association with internal and external markers of traffic exposure in a panel of healthy adults

Traffic-related air pollution (TRAP) exposure is associated with negative health outcomes. Changes in DNA methylation level may be an important mechanism through which air pollution can induce its effects. The objective of this study was to evaluate the association between DNA methylation in blood and personally measured TRAP exposure. Global DNA methylation in whole blood was analyzed with HPLC in a population of 55 healthy adults (average age 41 years). TRAP was assessed for each participant with a portable aethalometer measuring black carbon (BC). Exposure measurements were collected during one typical working week. These data were used in combination with ambient levels measured at a reference site to derive subchronic BC exposure. Urinary trans,trans-muconic acid (t,t-MA), a metabolite of benzene, was used as an internal proxy of traffic exposure. DNA methylation levels were associated with short- and subchronic BC exposure. An IQR increase in BC exposure on lag 24 h (477 ng/m³), lag 48 h (491 ng/m³), lag 1 week (314 ng/m³) and subchronic exposure (618 ng/m³) were associated with a decrease in DNA methylation levels of respectively 0.0020% (??0.0040 to ??0.0001, p?=?0.047), 0.0028% (??0.0054 to ??0.0001, p?=?0.043), 0.0024% (??0.0043 to ??0.0005, p?=?0.019), and 0.025% (??0.048 to ??0.0015, p?=?0.044). In addition, an IQR increase in t,t-MA (0.135 mg/l) was associated with a 0.0021% (??0.0033 to ??0.0008, p?=?0.0019) decrease in global DNA methylation levels. Analysis of a panel of cytokines in blood samples failed to demonstrate an association between inflammatory and oxidative stress biomarkers and TRAP or DNA methylation. In a panel of healthy adults, we found negative associations between total DNA methylation and markers of TRAP exposure. Considering that change in DNA methylation concentration is a biological marker connecting environmental and lifestyle exposures and disease development trajectories, our results warrant further study.     

The Functional DNA Methylation Signatures Relevant to Altered Immune Response of Neonatal T Cells with l-Arginine Supplementation

l-Arginine is an important nutrient in the infant diet that significantly regulates the maturation of the immune system in neonates, including the maturation of CD4⁺ T cells. The biological activities of CD4⁺ T cells differ substantially between neonates and adults, and these differences may be governed by epigenetic processes. Investigating these differences and the causative processes may help understand neonatal and developmental immunity. In this study, we compared the functional DNA methylation profiles in CD4⁺ T cells of neonates and adults, focusing on the role of l-arginine supplementation. Umbilical cord blood and adult CD4⁺ T cells were cultured with/without l-arginine treatment. By comparing DNA methylation in samples without l-arginine treatment, we found that CD4⁺ T cells of neonatal cord blood generally showed higher DNA methylation than those of adults (average CpG methylation percentage 0.6305 for neonate and 0.6254 for adult, t-test p-value < 0.0001), suggesting gene silencing in neonates. By examining DNA methylation patterns of CpG dinucleotides induced by l-arginine treatment, we found that more CpG dinucleotides were hypomethylated and more genes appeared to be activated in neonatal T-cells as compared with adult. Genes activated by l-arginine stimulation of cord blood samples were more enriched regarding immune-related pathways. CpG dinucleotides at IL-13 promoter regions were hypomethylated after l-arginine stimulation. Hypomethylated CpG dinucleotides corresponded to higher IL-13 gene expression and cytokine production. Thus, DNA methylation partially accounts for the mechanism underlying differential immune function in neonates. Modulatory effects of l-arginine on DNA methylation are gene-specific. Nutritional intervention is a potential strategy to modulate immune function of neonates.     

Differential DNA Methylation in Umbilical Cord Blood of Infants Exposed to Low Levels of Arsenic in Utero

Background: There is increasing epidemiologic evidence that arsenic exposure in utero, even at low levels found throughout much of the world, is associated with adverse reproductive outcomes and may contribute to long-term health effects. Animal models, in vitro studies, and human cancer data suggest that arsenic may induce epigenetic alterations, specifically by altering patterns of DNA methylation.Objectives: In this study we aimed to identify differences in DNA methylation in cord blood samples of infants with in utero, low-level arsenic exposure.Methods: DNA methylation of cord-blood derived DNA from 134 infants involved in a prospective birth cohort in New Hampshire was profiled using the Illumina Infinium Methylation450K array. In utero arsenic exposure was estimated using maternal urine samples collected at 24–28 weeks gestation. We used a novel cell mixture deconvolution methodology for examining the association between inferred white blood cell mixtures in infant cord blood and in utero arsenic exposure; we also examined the association between methylation at individual CpG loci and arsenic exposure levels.Results: We found an association between urinary inorganic arsenic concentration and the estimated proportion of CD8⁺ T lymphocytes (1.18; 95% CI: 0.12, 2.23). Among the top 100 CpG loci with the lowest p-values based on their association with urinary arsenic levels, there was a statistically significant enrichment of these loci in CpG islands (p = 0.009). Of those in CpG islands (n = 44), most (75%) exhibited higher methylation levels in the highest exposed group compared with the lowest exposed group. Also, several CpG loci exhibited a linear dose-dependent relationship between methylation and arsenic exposure.Conclusions: Our findings suggest that in utero exposure to low levels of arsenic may affect the epigenome. Long-term follow-up is planned to determine whether the observed changes are associated with health outcomes.     

Relationship of seminal plasma antioxidants and serum male hormones with sperm chromatin status in male factor infertility

We explored the relationship between sperm chromatin integrity, hormone levels, seminal plasma total antioxidant capacity (TAC), and routine sperm parameters in men with male factor (MF, n?=?81) and non-male factor (NMF, n?=?52) infertility. Semen and blood were collected and examined from men undergoing evaluation for infertility in the Avicenna Infertility Clinic. We have examined each patient for serum hormones (LH, FSH, E2, DHEA), sperm chromatin damage, level of protamination and seminal plasma TAC. Levels of FSH, LH, sperm chromatin damage, and abnormal protamination were significantly higher in MF vs. NMF groups (p?<?0.001). Sperm chromatin damage was correlated with percentage of CMA₃- positive sperm (r?=?0.64, p?<?0.001) and with sperm concentration (r?=??0.36, p?<?0.001), motility (r?=??0.21, p?<?0.05), and morphologically normal spermatozoa (r?=??0.29, p?<?0.001). Linear regression showed sperm chromatin damage was related to percentage of CMA₃- positive sperm (p?<?0.001) in ungrouped patients. It was related to both percentage of CMA₃- positive sperm and serum DHEA in the MF group (p?<?0.001 and p?<?0.05, respectively). Sperm chromatin maturity assessed by CMA₃ test was inversely related to sperm chromatin damage assessed by the toludine blue assay. Male factor infertility associated with sperm chromatin damage may be related to sperm protamination and to serum DHEA.     

Construct Validity of the Mealtime Scan: A Secondary Data Analysis of the Making Most of Mealtimes (M3) Study

Long-term care (LTC) physical and psychosocial mealtime environments have been inconsistently assessed due to the lack of a standardized measure. The purpose of this study was to examine the construct validity of a new standardized observational measure, the Mealtime Scan (MTS), using the Making Most of Mealtimes data collected on 639 residents in 82 dining rooms in 32 LTC homes. The MTS includes physical, social, and person-centered care summary scales scored from 1 to 8. Mean ratings on these summary scales were moderate for physical (5.6 SD 0.9), social (5.0 SD 0.9), and person-centered care (PCC; 5.5 SD 0.8). Regression analyses determined which items within the MTS were associated with these summary scales: physical – music (B?=?0.27, p?=?0.04), number of staff passing food (B?=??0.11, p?=?0.03), number of residents (B?=??0.03, p?=?0.01); social – social sound (B?= 0.31 p?p?=?0.02); PCC – lighting (B?=?0.01 p?=?0.04), and total excess noise (B?=?0.05, p?相似文献   

Prenatal Exposure to Maternal Cigarette Smoking and DNA Methylation: Epigenome-Wide Association in a Discovery Sample of Adolescents and Replication in an Independent Cohort at Birth through 17 Years of Age

Background: Prenatal exposure to maternal cigarette smoking (prenatal smoke exposure) had been associated with altered DNA methylation (DNAm) at birth.Objective: We examined whether such alterations are present from birth through adolescence.Methods: We used the Infinium HumanMethylation450K BeadChip to search across 473,395 CpGs for differential DNAm associated with prenatal smoke exposure during adolescence in a discovery cohort (n = 132) and at birth, during childhood, and during adolescence in a replication cohort (n = 447).Results: In the discovery cohort, we found five CpGs in MYO1G (top-ranking CpG: cg12803068, p = 3.3 × 10^–11) and CNTNAP2 (cg25949550, p = 4.0 × 10^–9) to be differentially methylated between exposed and nonexposed individuals during adolescence. The CpGs in MYO1G and CNTNAP2 were associated, respectively, with higher and lower DNAm in exposed versus nonexposed adolescents. The same CpGs were differentially methylated at birth, during childhood, and during adolescence in the replication cohort. In both cohorts and at all developmental time points, the differential DNAm was in the same direction and of a similar magnitude, and was not altered appreciably by adjustment for current smoking by the participants or their parents. In addition, four of the five EWAS (epigenome-wide association study)–significant CpGs in the adolescent discovery cohort were also among the top sites of differential methylation in a previous birth cohort, and differential methylation of CpGs in CYP1A1, AHRR, and GFI1 observed in that study was also evident in our discovery cohort.Conclusions: Our findings suggest that modifications of DNAm associated with prenatal maternal smoking may persist in exposed offspring for many years—at least until adolescence.Citation: Lee KW, Richmond R, Hu P, French L, Shin J, Bourdon C, Reischl E, Waldenberger M, Zeilinger S, Gaunt T, McArdle W, Ring S, Woodward G, Bouchard L, Gaudet D, Davey Smith G, Relton C, Paus T, Pausova Z. 2015. Prenatal exposure to maternal cigarette smoking and DNA methylation: epigenome-wide association in a discovery sample of adolescents and replication in an independent cohort at birth through 17 years of age. Environ Health Perspect 123:193–199; http://dx.doi.org/10.1289/ehp.1408614     

Detection of DNA damage in cumulus cells using a chromatin dispersion assay

Abstract

DNA damage in cumulus cells (CCs) might be related with the developmental competence of the enclosed oocytes, however, conclusive studies are missing, partially due to the lack of a reliable, cheap, fast, and reproducible DNA damage test. We report the development of a chromatin dispersion test that allows for a fast evaluation of double strand DNA (ds-DNA) damage in CCs. The whole experiment was performed using CCs from 103 oocyte retrieval cycles evaluating the prototype D3-MAX ability (a chromatin dispersion based assay) to detect DNA breaks against in situ nick translation (ISNT) and a two tailed comet assay (TT-comet). Samples were collected from women younger than 35 years of age with a good response to stimulation. Pooled cumulus cells of MII oocytes were used. The chromatin dispersion assay results correlate with the double strand-DNA breaks values assessed by the TT-comet assay (Spearman Rho?=?0.624; p?=?0.003;), while the correlation was poor when compared to the single strand DNA (ss-DNA) breaks observed also with the TT-comet assay (Spearman Rho?=??0.141; p?=?0.554). ISNT showed a correspondence in the same cells between enzymatic incorporation of modified nucleotides and halos of chromatin dispersion. We conclude that D3-Max test detects mainly ds-DNA breaks in cumulus cells and is a reliable, fast, and easy reproducible assay suitable for routine clinical practices once the influence on oocyte quality has been established.     

Visceral adiposity and subclinical atherosclerosis in healthy young men

Abstract

Background: Atherosclerosis begins in childhood and develops silently for decades before clinical events such as myocardial infarction or stroke occur. Only few studies have evaluated the relationship between CVD risk factors and carotid artery Intimal Media Thickness (IMT) in young asymptomatic people. Aim: The aim of this study is to investigate risk factors for cardiovascular disease associated with higher Carotid Intimal Media Thickness (IMT) in healthy young subjects. Methods: A cohort of 106 healthy young men, mean age 21?±?2 years (mean?±?SD), BMI 24.4?±?2.8 (kg/m²), on military duty, participated in this cross-sectional study. Waist circumference, carotid intima–media thickness (IMT), blood pressure, and plasma concentrations of relevant metabolic parameters were measured at fasting. Smoking and habitual dietary patterns were evaluated by a semiquantitative questionnaire. Results: The population was divided into two groups on the basis of IMT values: the lowest three quartiles versus the highest quartile (cut-off value?=?0.7?mm). BMI, waist circumference, systolic (SBP), and diastolic (DBP) blood pressure were significantly higher in the group with higher IMT (p?=?0.02). All other variables, including dietary parameters and smoking, were similar in the two groups. Data analysis showed that IMT values correlated positively with SBP (r?=?0.22; p?=?0.025), DBP (r?=?0.27; p?=?0.005), waist circumference (r?=?0.29; p?=?0.002), and fat mass (r?=?0.24; p?=?0.01), and negatively with kcal/kg of body weight (r?=??0.220.22; p?=?0.022) – an indirect marker of physical activity. Based on multiple regression analysis, waist circumference and DBP were the only variables independently associated with IMT (p?=?0.029). Conclusions: In a non-selected sample of healthy young adult males, a larger waist circumference and a higher diastolic blood pressure – albeit within normal values – are the only parameters independently associated with higher IMT.     

Epigenome-Wide Study Identified Methylation Sites Associated with the Risk of Obesity

Here, we performed a genome-wide search for methylation sites that contribute to the risk of obesity. We integrated methylation quantitative trait locus (mQTL) data with BMI GWAS information through a SNP-based multiomics approach to identify genomic regions where mQTLs for a methylation site co-localize with obesity risk SNPs. We then tested whether the identified site contributed to BMI through Mendelian randomization. We identified multiple methylation sites causally contributing to the risk of obesity. We validated these findings through a replication stage. By integrating expression quantitative trait locus (eQTL) data, we noted that lower methylation at cg21178254 site upstream of CCNL1 contributes to obesity by increasing the expression of this gene. Higher methylation at cg02814054 increases the risk of obesity by lowering the expression of MAST3, whereas lower methylation at cg06028605 contributes to obesity by decreasing the expression of SLC5A11. Finally, we noted that rare variants within 2p23.3 impact obesity by making the cg01884057 site more susceptible to methylation, which consequently lowers the expression of POMC, ADCY3 and DNAJC27. In this study, we identify methylation sites associated with the risk of obesity and reveal the mechanism whereby a number of these sites exert their effects. This study provides a framework to perform an omics-wide association study for a phenotype and to understand the mechanism whereby a rare variant causes a disease.     

The Val34Leu genetic variation in the A Subunit of Coagulation Factor XIII in recurrent spontaneous abortion

The present study was carried out to assess the frequencies of factor XIII (FXIII) Val34Leu genetic variation in the patients with recurrent spontaneous abortion and healthy fertile women of Azeri Turkish origin. A total of 54 patients with recurrent spontaneous abortion and 46 healthy fertile women as controls were studied for the FXIII Val34Leu genetic variation by a RFLP-PCR method. Statistical analysis showed that patients (χ²?=?2.4, p value?=?0.292) and controls (χ²?=?1.035, p value?=?0.596) were in agreement with Hardy-Weinberg equilibrium. The Leu allele frequency was 0.18 and 0.13 in patients and controls, respectively. FXIII Leu34Leu (homozygous for 34Leu) genotype was not found in patients and controls. FXIII Val/Leu and Val/Val genotype frequencies were 19 (35.19%) and 31 (64.81%) in patients and 12 (26.09%) and 34 (73.91%) in controls, respectively. FXIII 34Leu allele and Val34Leu genotypes were more common in the case group containing individuals with unexplained RSA but the differences of FXIII Val34Leu (G/T genotype) (odds ratio?=?0.65 (0.25?<?OR?<?1.67) corresponding to 95% CI, χ²?=?0.96, p value?=?0.32) and FXIII 34Leu (T allele) (odds ratio?=?0.70 (0.30?<?OR?<?1.64) corresponding to 95% CI, χ² ₌ 0.78, p value?=?0.37) was not statistically significant. These results suggest that factor XIII Val34Leu genetic variation is not associated with recurrent spontaneous abortion.     

基于甲基化位点的肺腺癌预后预测模型的探索与建立

  目的   利用公共组学数据库挖掘并构建基于DNA甲基化位点的肺腺癌预后模型,并对模型的预测效果进行初步评价。  方法  癌症基因组图谱(the cancer genome atlas, TCGA)及基因表达谱(gene expression omnibus, GEO)数据库用于相关分析和验证,最小绝对值收敛和选择算子法(least absolute shrinkage and selection operator, LASSO) Cox回归模型用于确定与肺腺癌预后风险具有关联的甲基化位点,Cox回归用于甲基化位点与预后风险的关联性分析,Harrell's C统计量用于评价模型的预测效果。  结果  甲基化位点cg02909790和cg19378330被纳入LASSO Cox最优模型。Cox比例风险回归模型结果显示,甲基化位点组合与肺腺癌预后的关联有统计学意义(HR=8.32, 95% CI: 2.41~28.69, P < 0.001)。结合甲基化位点和临床信息建立的肺腺癌预后预测模型预测能力较好,Harrell's C为0.81(95% CI: 0.78~0.83)。  结论  基于甲基化位点cg02909790和cg19378330的肺腺癌预后模型的预测效果良好,可能是潜在的个体化肿瘤分子标志物。