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1.  A Lower Degree of PBMC L1 Methylation Is Associated with Excess Body Weight and Higher HOMA-IR in the Presence of Lower Concentrations of Plasma Folate 
PLoS ONE  2013;8(1):e54544.
Identification of associations between global DNA methylation and excess body weight (EBW) and related diseases and their modifying factors are an unmet research need that may lead to decreasing DNA methylation-associated disease risks in humans. The purpose of the current study was to evaluate the following; 1) Association between the degree of peripheral blood mononuclear cell (PBMC) L1 methylation and folate, and indicators of EBW, 2) Association between the degree of PBMC L1 methylation and folate, and insulin resistance (IR) as indicated by a higher homeostasis model assessment (HOMA-IR).
The study population consisted of 470 child-bearing age women diagnosed with abnormal pap. The degree of PBMC L1 methylation was assessed by pyrosequencing. Logistic regression models specified indicators of EBW (body mass index–BMI, body fat–BF and waist circumference–WC) or HOMA-IR as dependent variables and the degree of PBMC L1 methylation and circulating concentrations of folate as the independent predictor of primary interest.
Women with a lower degree of PBMC L1 methylation and lower plasma folate concentrations were significantly more likely to have higher BMI, % BF or WC (OR = 2.49, 95% CI:1.41–4.47, P = 0.002; OR = 2.49, 95% CI:1.40–4.51, P = 0.002 and OR = 1.98, 95%  = 1.14–3.48 P = 0.0145, respectively) and higher HOMA-IR (OR = 1.78, 95% CI:1.02–3.13, P = 0.041).
Our results demonstrated that a lower degree of PBMC L1 methylation is associated with excess body weight and higher HOMA-IR, especially in the presence of lower concentrations of plasma folate.
PMCID: PMC3554730  PMID: 23358786
2.  Physical activity and global genomic DNA methylation in a cancer-free population 
Epigenetics  2011;6(3):293-299.
Changes in DNA methylation may represent an intermediate step between the environment and human diseases. Little is known on whether behavioral risk factors may modify gene expression through DNA methylation. To assess whether DNA methylation is associated with different levels of physical activity, we measured global genomic DNA methylation using bisulfite-converted DNA and real-time PCR (MethyLight) for LINE-1 in peripheral blood of 161 participants aged 45–75 years enrolled in the North Texas Healthy Heart Study and levels of physical activity using an accelerometer (Actigraph GT1M Monitor). We found that individuals with physical activity 26–30 min/day had a significantly higher level of global genomic DNA methylation compared to those with physical activity ≤10 min/day (β = 2.52, 95% CI: 0.70, 4.35). However, the association was attenuated and became statistically insignificant after multivariate adjustment (β = 1.24, 95% CI: −0.93, 3.40). There were some suggestions of a positive association between physical activity and global genomic DNA methylation in non-Hispanics (β = 1.50, 95% CI: −0.08, 3.08) that warrants further investigation.
PMCID: PMC3092677  PMID: 21178401
DNA methylation; physical activity; peripheral blood
3.  LINE-1 hypomethylation is associated with bladder cancer risk among non-smoking Chinese 
Reduced levels of global DNA methylation, assessed in peripheral blood, have been associated with bladder cancer risk in European and American populations. Similar data are lacking in Asian populations where genetic differences, lifestyle factors, and different environmental exposures may affect DNA methylation and its risk relationship with bladder cancer. The association between global DNA methylation measured at long interspersed nuclear element (LINE-1) repeat regions through bisulfite pyrosequencing in lymphocyte DNA and bladder cancer risk was examined in a case-control study of 510 bladder cancer patients and 528 healthy control subjects in Shanghai, China. In an initial analysis restricted to control subjects, LINE-1 methylation was elevated among men, those who frequently consumed cruciferous vegetables, and those with a null genotype for either glutathione S-transferase M1 (GSTM1) or GSTT1. In contrast, reduced LINE-1 methylation was found in current smokers with a high cytochrome P450 1A2 (CYP1A2) phenotype index. In a case-control analysis, there was no significant association of LINE-1 methylation with case status, although reduced LINE-1 methylation was associated with increased risk of bladder cancer among never smokers (P for trend = 0.03); analysis by tertile revealed odds ratios (ORs) of 1.91 (lowest tertile; 95% CI = 1.17–3.13) and 1.34 (middle tertile; 95% CI = 0.79–2.28) when compared to the highest tertile. This association was strongest among nonsmokers null for either the GSTM1 or GSTT1 genotype (P for trend = 0.006). Further research is needed to understand the relationships between methyl group availability and LINE-1 methylation in relation to bladder cancer risk.
PMCID: PMC3208798  PMID: 21445976
4.  White blood cell global methylation and IL-6 promoter methylation in association with diet and lifestyle risk factors in a cancer-free population 
Epigenetics  2012;7(6):606-614.
Altered levels of global DNA methylation and gene silencing through methylation of promoter regions can impact cancer risk, but little is known about their environmental determinants. We examined the association between lifestyle factors and levels of global genomic methylation and IL-6 promoter methylation in white blood cell DNA of 165 cancer-free subjects, 18–78 years old, enrolled in the COMIR (Commuting Mode and Inflammatory Response) study, New York, 2009–2010. Besides self-administrated questionnaires on diet and physical activity, we measured weight and height, white blood cell (WBC) counts, plasma levels of high sensitivity C-reactive protein (hs-CRP), and genomic (LINE-1) and gene-specific methylation (IL-6) by pyrosequencing in peripheral blood WBC. Mean levels of LINE-1 and IL-6 promoter methylation were 78.2% and 57.1%, respectively. In multivariate linear regression models adjusting for age, gender, race/ethnicity, body mass index, diet, physical activity, WBC counts and CRP, only dietary folate intake from fortified foods was positively associated with LINE-1 methylation. Levels of IL-6 promoter methylation were not significantly correlated with age, gender, race/ethnicity, body mass index, physical activity or diet, including overall dietary patterns and individual food groups and nutrients. There were no apparent associations between levels of methylation and inflammation markers such as WBC counts and hs-CRP. Overall, among several lifestyle factors examined in association with DNA methylation, only dietary folate intake from fortification was associated with LINE-1 methylation. The long-term consequence of folate fortification on DNA methylation needs to be further evaluated in longitudinal settings.
PMCID: PMC3398989  PMID: 22531363
DNA Methylation; cancer; diet; lifestyle factors
5.  Obesity, body composition, and prostate cancer 
BMC Cancer  2012;12:23.
Established risk factors for prostate cancer have not translated to effective prevention or adjuvant care strategies. Several epidemiologic studies suggest greater body adiposity may be a modifiable risk factor for high-grade (Gleason 7, Gleason 8-10) prostate cancer and prostate cancer mortality. However, BMI only approximates body adiposity, and may be confounded by centralized fat deposition or lean body mass in older men. Our objective was to use bioelectric impedance analysis (BIA) to measure body composition and determine the association between prostate cancer and total body fat mass (FM) fat-free mass (FFM), and percent body fat (%BF), and which body composition measure mediated the association between BMI or waist circumference (WC) with prostate cancer.
The study used a multi-centered recruitment protocol targeting men scheduled for prostate biopsy. Men without prostate cancer at biopsy served as controls (n = 1057). Prostate cancer cases were classified as having Gleason 6 (n = 402), Gleason 7 (n = 272), or Gleason 8-10 (n = 135) cancer. BIA and body size measures were ascertained by trained staff prior to diagnosis, and clinical and comorbidity status were determined by chart review. Analyses utilized multivariable linear and logistic regression.
Body size and composition measures were not significantly associated with low-grade (Gleason 6) prostate cancer. In contrast, BMI, WC, FM, and FFM were associated with an increased risk of Gleason 7 and Gleason 8-10 prostate cancer. Furthermore, BMI and WC were no longer associated with Gleason 8-10 (ORBMI = 1.039 (1.000, 1.081), ORWC = 1.016 (0.999, 1.033), continuous scales) with control for total body FFM (ORBMI = 0.998 (0.946, 1.052), ORWC = 0.995 (0.974, 1.017)). Furthermore, increasing FFM remained significantly associated with Gleason 7 (ORFFM = 1.030 (1.008, 1.052)) and Gleason 8-10 (ORFFM = 1.044 (1.014, 1.074)) after controlling for FM.
Our results suggest that associations between BMI and WC with high-grade prostate cancer are mediated through the measurement of total body FFM. It is unlikely that FFM causes prostate cancer, but instead provides a marker of testosterone or IGF1 activities involved with retaining lean mass as men age.
PMCID: PMC3292483  PMID: 22257467
6.  Implications of LINE1 Methylation for Bladder Cancer Risk in Women 
Epigenetic alterations including changes to cellular DNA methylation levels contribute to carcinogenesis and may serve as powerful biomarkers of the disease. This investigation sought to determine whether hypomethylation at the long interspersed nuclear elements (LINE1), reflective of the level of global DNA methylation, in peripheral blood-derived DNA is associated with increased risk of bladder cancer.
Experimental Design
LINE1 methylation was measured from blood-derived DNA obtained from participants of a population-based incident case control study of bladder cancer in New Hampshire. Bisulfite-modified DNA was pyrosequenced to determine LINE1 methylation status; a total of 285 cases and 465 controls were evaluated for methylation.
Being in the lowest LINE1 methylation decile was associated with a 1.8-fold increased risk of bladder cancer (95% CI, 1.12-2.90) in models controlling for gender, age and smoking, and the association was stronger in women than in men (ORs = 2.48, 95% CI 1.19-5.17 in women and 1.47, 95% CI 0.79-2.74 in men). Amongst controls, women were more likely to have lower LINE1 methylation than men (p-value 0.04), and levels of arsenic in the 90th percentile were associated with reduced LINE1 methylation (p-value 0.04).
LINE1 hypomethylation may be an important biomarker of bladder cancer risk, especially amongst women.
PMCID: PMC2831156  PMID: 20179218
Bladder Cancer; Epidemiology; Gender Differences
7.  Aerobic performance and body composition changes during military service 
To examine the association between aerobic performance and body composition changes by body mass index (BMI).
6–12 months’ follow-up during military service.
Conscripts entering military service in 2005 in Sodankylä Jaeger Brigade (Finland).
945 men (19 years, SD 1 years).
Main outcome measures
Height, weight, waist circumference, BMI, and aerobic performance (Cooper test) were recorded. Body composition was measured by bioelectrical impedance analysis (BIA). The measured parameters were fat mass (FM), fat free mass (FFM), and visceral fat area (VFA). All the measurements were performed at the beginning and end of service.
On average, the military training period improved the running distance by 6.8% (169 m, p < 0.001) and the improvements were more pronounced in overweight (223.9 m/9.5%, p < 0.001) and obese (273.3 m/13.6 %, p < 0.001) conscripts. A strong inverse correlation between aerobic performance and body composition changes was observed, especially for weight (r = –0.305, p < 0.001) and VFA (r = –0.465, p < 0.001). A significant association between aerobic performance and changes in weight (p < 0.001), waist circumference (p < 0.001), FM (p < 0.001), and VFA (p < 0.001) by BMI was detected. The associated decrease in weight, waist circumference, FM, and VFA with improved aerobic performance was more substantial between overweight and obese compared with normal-weight subjects.
Favourable changes in body composition are associated with improved aerobic performance during a physical training period such as military service. These findings are pronounced among overweight and obese men and can be applied at the population level in reducing obesity and co-morbidities.
PMCID: PMC3378011  PMID: 22643154
Bioelectrical impedance assessment; Cooper test; fat; military conscripts
8.  Global DNA methylation levels in girls with and without a family history of breast cancer 
Epigenetics  2011;6(1):29-33.
Lower levels of global DNA methylation in white blood cell (WBC) DNA have been associated with adult cancers. It is unknown whether individuals with a family history of cancer also have lower levels of global DNA methylation early in life. We examined global DNA methylation in WBC (measured in three repetitive elements, LINE1, Sat2 and Alu, by MethyLight and in LINE1 by pyrosequencing) in 51 girls aged 6–17 years. Compared to girls without a family history of breast cancer, methylation levels were lower for all assays in girls with a family history of breast cancer and statistically significantly lower for Alu and LINE1 pyrosequencing. After adjusting for age, body mass index (BMI) and Tanner stage, only methylation in Alu was associated with family history of breast cancer. If these findings are replicated in larger studies, they suggest that lower levels of global WBC DNA methylation observed later in life in adults with cancer may also be present early in life in children with a family history of cancer.
PMCID: PMC3052913  PMID: 20930546
Alu; DNA global methylation; early life exposure; epigenetics; LINE1; methylight; pyrosequencing; Sat2
9.  LINE-1 Methylation Levels in Leukocyte DNA and Risk of Renal Cell Cancer 
PLoS ONE  2011;6(11):e27361.
Leukocyte global DNA methylation levels are currently being considered as biomarkers of cancer susceptibility and have been associated with risk of several cancers. In this study, we aimed to examine the association between long interspersed nuclear elements (LINE-1) methylation levels, as a biomarker of global DNA methylation in blood cell DNA, and renal cell cancer risk.
Experimental Design
LINE-1 methylation of bisulfite-converted genomic DNA isolated from leukocytes was quantified by pyrosequencing measured in triplicate, and averaged across 4 CpG sites. A total of 328 RCC cases and 654 controls frequency-matched(2∶1) on age(±5years), sex and study center, from a large case-control study conducted in Central and Eastern Europe were evaluated.
LINE-1 methylation levels were significantly higher in RCC cases with a median of 81.97% (interquartile range[IQR]: 80.84–83.47) compared to 81.67% (IQR: 80.35–83.03) among controls (p = 0.003, Wilcoxon). Compared to the lowest LINE-1 methylation quartile(Q1), the adjusted ORs for increasing methylation quartiles were as follows: OR(Q2) = 1.84(1.20−2.81), OR(Q3) = 1.72(1.11−2.65) and OR(Q4) = 2.06(1.34−3.17), with a p-trend = 0.004. The association was stronger among current smokers (p-trend<0.001) than former or never smokers (p-interaction = 0.03). To eliminate the possibility of selection bias among controls, the relationship between LINE-1 methylation and smoking was evaluated and confirmed in a case-only analysis, as well.
Higher levels of LINE-1 methylation appear to be positively associated with RCC risk, particularly among current smokers. Further investigations using both post- and pre-diagnostic genomic DNA is warranted to confirm findings and will be necessary to determine whether the observed differences occur prior to, or as a result of carcinogenesis.
PMCID: PMC3208631  PMID: 22076155
10.  Serum Glycated Albumin Is Inversely Influenced by Fat Mass and Visceral Adipose Tissue in Chinese with Normal Glucose Tolerance 
PLoS ONE  2012;7(11):e51098.
Recent studies have revealed that body mass index (BMI) inversely influenced serum glycated albumin (GA), which may cause an underestimation of GA-monitored short-term hyperglycemic control.
This study was to investigate the association between anthropometric variables (BMI and waist circumference (W)) and accurate adiposity variables (percentage of body fat (%fat), fat mass, free fat mass (FFM), subcutaneous fat area (SFA), and visceral fat area (VFA)) with serum GA.
A total of 2563 subjects (1037 men, 593 premenopausal women, and 933 postmenopausal women) with normal glucose tolerance underwent bioelectrical impedance body fat content measurement and magnetic resonance imaging. Serum GA and absolute value of GA (aGA) were measured by enzymatic assay.
Compared to the BMI <25.0 kg/m2 group, the BMI ≥25.0 kg/m2 group had significantly higher fasting plasma glucose, glycated hemoglobin A1c, and body fat parameters including W, %fat, fat mass, FFM, SFA, and VFA, but significantly lower aGA, and GA in all the three sex- and menopause-stratified groups (all P<0.05). GA decreased with the increment of fat mass for all three groups (all P for trend <0.001). In the same BMI category, men and postmenopausal women with elevated %fat (men, ≥25%; women, ≥35%) still had significantly lower GA than those with normal %fat (men, <25%; women, <35%) (all P<0.05). Multiple stepwise regression showed that %fat, fat mass, and VFA were independently associated with GA.
Serum GA was inversely influenced by fat mass and visceral adipose tissue in Chinese with normal glucose tolerance.
PMCID: PMC3510195  PMID: 23209844
11.  Body fatness and sex steroid hormone concentrations in US men – Results from NHANES III 
Cancer causes & control : CCC  2011;22(8):10.1007/s10552-011-9790-z.
Obesity is associated with a variety of chronic diseases, including cancer, which may partly be explained by its influence on sex steroid hormone concentrations. Whether different measures of obesity, i.e., body mass index (BMI), waist circumference, and percent body fat were differentially associated with circulating levels of sex steroid hormones was examined in 1,265 men, aged 20 to 90+ years, attending the morning examination session of the Third National Health and Nutrition Examination Survey (NHANES III).
Methods and Methods
Serum hormones were measured by immunoassay. Weight, height, and waist circumference were measured by trained staff. Percent body fat was estimated from bioelectrical impedance. Multivariate linear regression was used to estimate associations between body fatness measures and hormone levels.
Total and free testosterone and sex hormone binding globulin concentrations decreased, whereas total and free estradiol increased with increasing BMI, waist circumference, and percent body fat (all P-trend <0.05). The magnitude of change in these hormones was similar for a one quartile increase in each body fatness measure.
Measured BMI, waist circumference, and percent body fat led to similar inferences about their association with hormone levels in men.
PMCID: PMC3818569  PMID: 21678033
NHANES III; testosterone; estradiol; obesity
12.  Global DNA methylation levels in white blood cell DNA from sisters discordant for breast cancer from the New York site of the Breast Cancer Family Registry 
Epigenetics  2012;7(8):868-874.
Lower global DNA methylation is associated with genomic instability and it is one of the epigenetic mechanisms relevant to carcinogenesis. Emerging evidence for several cancers suggests that lower overall levels of global DNA methylation in blood are associated with different cancer types, although less is known about breast cancer. We examined global DNA methylation levels using a sibling design in 273 sisters affected with breast cancer and 335 unaffected sisters from the New York site of the Breast Cancer Family Registry. We measured global DNA methylation in total white blood cell (WBC) and granulocyte DNA by two different methods, the [3H]-methyl acceptance assay and the luminometric methylation assay (LUMA). Global methylation levels were only modestly correlated between sisters discordant for breast cancer (Spearman correlation coefficients ranged from -0.08 to 0.24 depending on assay and DNA source). Using conditional logistic regression models, women in the quartile with the lowest DNA methylation levels (as measured by the [3H]-methyl acceptance assay) had a 1.8-fold (95% CI = 1.0–3.3) higher relative association with breast cancer than women in the quartile with the highest DNA methylation levels. When we examined the association on a continuous scale, we also observed a positive association (odds ratio, OR = 1.3, 95% CI = 1.0–1.7, for a one unit change in the natural logarithm of the DPM/μg of DNA). We observed no association between measures by the LUMA assay and breast cancer risk. If replicated in prospective studies, this study suggests that global DNA methylation levels measured in WBC may be a potential biomarker of breast cancer risk even within families at higher risk of cancer.
PMCID: PMC3427282  PMID: 22705975
blood; breast cancer; epigenetics; global DNA methylation; global methylation; LUMA; luminometric methylation assay; methyl acceptance assay; white blood cell; [3H]-methyl acceptance assay
13.  Body composition and arsenic metabolism: a cross-sectional analysis in the Strong Heart Study 
Environmental Health  2013;12:107.
The objective of this study was to evaluate the association between measures of body composition and patterns of urine arsenic metabolites in the 1989–1991 baseline visit of the Strong Heart Study, a cardiovascular disease cohort of adults recruited from rural communities in Arizona, Oklahoma, North Dakota and South Dakota.
We evaluated 3,663 Strong Heart Study participants with urine arsenic species above the limit of detection and no missing data on body mass index, % body fat and fat free mass measured by bioelectrical impedance, waist circumference and other variables. We summarized urine arsenic species patterns as the relative contribution of inorganic (iAs), methylarsonate (MMA) and dimethylarsinate (DMA) species to their sum. We modeled the associations of % arsenic species biomarkers with body mass index, % body fat, fat free mass, and waist circumference categories in unadjusted regression models and in models including all measures of body composition. We also considered adjustment for arsenic exposure and demographics.
Increasing body mass index was associated with higher mean % DMA and lower mean % MMA before and after adjustment for sociodemographic variables, arsenic exposure, and for other measures of body composition. In unadjusted linear regression models, % DMA was 2.4 (2.1, 2.6) % higher per increase in body mass index category (< 25, ≥25 & <30, ≥30 & <35, ≥35 kg/m2), and % MMA was 1.6 (1.4, 1.7) % lower. Similar patterns were observed for % body fat, fat free mass, and waist circumference measures in unadjusted models and in models adjusted for potential confounders, but the associations were largely attenuated or disappeared when adjusted for body mass index.
Measures of body size, especially body mass index, are associated with arsenic metabolism biomarkers. The association may be related to adiposity, fat free mass or body size. Future epidemiologic studies of arsenic should consider body mass index as a potential modifier for arsenic-related health effects.
PMCID: PMC3883520  PMID: 24321145
American Indians; Arsenic; Arsenic metabolism; Arsenic species; Obesity; Body mass index; Strong Heart Study
14.  Comparison of Various Anthropometric and Body Fat Indices in Identifying Cardiometabolic Disturbances in Chinese Men and Women 
PLoS ONE  2013;8(8):e70893.
Although many adiposity indices may be used to predict obesity-related health risks, uncertainty remains over which of them performs best.
This study compared the predictive capability of direct and indirect adiposity measures in identifying people at higher risk of metabolic abnormalities.
This population-based cross-sectional study recruited 2780 women and 1160 men. Body weight and height, waist circumference (WC), and hip circumference (HC) were measured and body mass index (BMI), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) were calculated. Body fat (and percentage of fat) over the whole body and the trunk were determined by bioelectrical impedance analysis (BIA). Blood pressure, fasting lipid profiles, and glucose and urine acid levels were assessed.
In women, the ROC and the multivariate logistic regression analyses both showed that WHtR consistently had the best performance in identifying hypertension, dyslipidemia, hyperuricemia, diabetes/IFG, and metabolic syndrome (MetS). In men, the ROC analysis showed that WHtR was the best predictor of hypertension, WHtR and WC were equally good predictors of dyslipidemia and MetS, and WHtR was the second-best predictor of hyperuricemia and diabetes/IFG. The multivariate logistic regression also found WHtR to be superior in discriminating between MetS, diabetes/IFG, and dyslipidemia while BMI performed better in predicting hypertension and hyperuricemia in men. The BIA-derived indices were the second-worst predictors for all of the endpoints, and HC was the worst.
WHtR was the best predictor of various metabolic abnormalities. BMI may be used as an alternative measure of obesity for identifying hypertension in both sexes.
PMCID: PMC3741370  PMID: 23951031
15.  Promoter methylation of serotonin transporter gene is associated with obesity measures: a monozygotic twin study 
Epigenetic mechanisms are increasingly being recognized as an important factor for obesity. The serotonin transporter gene (SLC6A4) has a critical role in regulating food intake, body weight and energy balance. This study examines the potential association between SLC6A4 promoter methylation and obesity measures in a monozygotic (MZ) twin sample.
We studied 84 MZ twin pairs drawn from the Vietnam Era Twin Registry. Obesity measures include body mass index (BMI), body weight, waist circumference (WC) and waist-hip ratio (WHR). The SLC6A4 promoter methylation profile in peripheral blood leukocytes was quantified by bisulfite pyrosequencing. The association between methylation variation and obesity parameters was examined by mixed-model regression and matched pair analysis, adjusting for age, smoking, alcohol consumption, physical activity and total daily energy intake. Multiple testing was controlled using the adjusted false discovery rate (q-value).
Mean methylation level was positively correlated with BMI (r=0.29; P=0.0002), body weight (r=0.31; P<0.0001) and WC (r=0.20; P=0.009), but not WHR. Intra-pair differences in mean methylation were significantly correlated with intra-pair differences in BMI, body weight and WC, but not WHR. On average, a 1% increase in mean methylation was associated with 0.33 kg m−2 increase in BMI (95% CI: 0.02–0.65; P=0.03), 1.16 kg increase in body weight (95% CI, 0.16–2.16; P=0.02) and 0.78 cm increase in WC (95% CI, 0.05–1.50; P=0.03) after controlling for potential confounders.
SLC6A4 promoter hypermethylation is significantly associated with an increased prevalence of obesity within a MZ twin study.
PMCID: PMC3539149  PMID: 22290534
DNA methylation; serotonin transporter gene; SLC6A4; monozygotic twins
16.  LINE-1 hypomethylation is inversely associated with microsatellite instability and CpG island methylator phenotype (CIMP) in colorectal cancer 
The CpG island methylator phenotype (CIMP) with widespread promoter CpG island methylation is a phenotype in colorectal cancer, associated with microsatellite instability (MSI) and BRAF mutation. Genome-wide hypomethylation may also play an important role in genomic instability. However, the relation between global DNA methylation level and methylation in individual CpG islands remains uncertain. Utilizing 869 population-based colorectal cancers, we measured LINE-1 (long interspersed nucleotide element-1) methylation level by Pyrosequencing, which correlates with global DNA methylation level. We quantified DNA methylation in 8 CIMP-specific promoters (CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1) by real-time PCR (MethyLight technology). LINE-1 methylation levels in tumors were approximately normally distributed (mean 61.4%, median 62.3%, standard deviation 9.6%). Among the 869 tumors, 128 (15%) were classified as CIMP-high (≥6/8 methylated promoters). The mean LINE-1 methylation level was higher in CIMP-high tumors (65.1%, p<0.0001) than non-CIMP-high tumors (60.7%), and higher in MSI-high tumors (64.7%, p<0.0001) than non-MSI-high tumors (60.7%). When tumors were stratified by MSI/CIMP status, compared to non-MSI-high non-CIMP-high tumors (mean LINE-1 methylation level 60.4%), the mean LINE-1 methylation level was higher in MSI-high CIMP-high (64.8%, p<0.0001), MSI-high non-CIMP-high (64.6%, p=0.03) and non-MSI-high CIMP-high tumors (66.1%, p=0.0003). In addition, 18q loss of heterozygosity in non-MSI-high tumors was correlated with LINE-1 hypomethylation (p=0.004). In conclusion, both CIMP-high and MSI-high are inversely associated with LINE-1 hypomethylation, suggesting that CIMP/MSI and genomic hypomethylation may represent different pathways to colorectal cancer. Our data also support a possible link between global hypomethylation and chromosomal instability.
PMCID: PMC2630175  PMID: 18366060
colon cancer; methylation; epigenomics; CIMP; LINE-1
17.  Global DNA methylation levels in white blood cells as a biomarker for hepatocellular carcinoma risk: a nested case–control study 
Carcinogenesis  2012;33(7):1340-1345.
Global DNA hypomethylation is associated with genomic instability and human cancer and blood DNAs collected at the time of cancer diagnosis have been used to examine the relationship between global methylation and cancer risk. To test the hypothesis that global hypomethylation is associated with increased risk of hepatocellular carcinoma (HCC), we conducted a prospective case–control study nested within a community-based cohort with 16 years of follow-up. We measured methylation levels in Satellite 2 (Sat2) by MethyLight and LINE-1 by pyrosequencing using baseline white blood cell DNA from 305 HCC cases and 1254 matched controls. We found that Sat2 hypomethylation was associated with HCC risk [odds ratio (OR) per unit decrease in natural log Sat2 methylation = 1.77, 95% confidence interval (CI) = 1.06–2.95]. The association was significant among individuals diagnosed with HCC before age 62 (OR per unit decrease in natural log Sat2 methylation = 2.47, 95% CI = 1.06–5.73) but not after (OR = 1.67, 95% CI = 0.84–3.32). We did not observe an association of LINE-1 with HCC overall risk by age at diagnosis. Among carriers of hepatitis B virus surface antigen (HBsAg), with each 1U decrease in natural log Sat2 methylation level, the OR for HCC increased by 2.19 (95% CI = 1.00–4.89). LINE-1 hypomethylation was associated with about a 2-fold increased risk of HCC, with ORs (95% CI) of 2.39 (1.06–5.39), 2.09 (0.91–4.77) and 2.28 (0.95–5.51, P trend = 0.14) for HBsAg carriers in the third, second and lowest quartile of LINE-1 methylation, respectively compared with carriers in the fourth. These results suggest that global hypomethylation may be a useful biomarker of HCC susceptibility.
PMCID: PMC3499052  PMID: 22581841
18.  Blood leukocyte DNA hypomethylation and gastric cancer risk in a high-risk Polish population 
Global hypomethylation has been shown to increase genome instability potentially leading to increased cancer risk. We determined whether global methylation in blood leukocyte DNA was associated with gastric cancer in a population-based study on 302 gastric cancer cases and 421 age- and sex-matched controls in Warsaw, Poland, between 1994 and 1996. Using PCR-pyrosequencing, we analyzed methylation levels of Alu and LINE-1, 2 CG-rich repetitive elements, to measure global methylation levels. Gastric cancer risk was highest among those with lowest level of methylation in either Alu (OR = 1.3, 95% CI = 0.9–1.9) or LINE-1 (OR = 1.4, 95% CI = 0.9–2.0) relative to those with the highest levels, although the trends were not statistically significant. For Alu, the association was stronger among those aged 70 or older (OR = 2.6, 95% CI = 1.3–5.5, p for interaction = 0.02). We did not observe meaningful differences in the associations by other risk factors and polymorphisms examined. For LINE-1, the association tended to be stronger among individuals with a family history of cancer (OR = 3.1, 95% CI = 1.4–7.0, p for interaction = 0.01), current alcohol drinkers (OR = 1.9, 95% CI = 1.0–3.6, p for interaction = 0.05), current smokers (OR = 2.3, 95% CI = 1.1–4.6, p for interaction = 0.02), those who rarely or never consumed fruit (OR = 3.1, 95% CI = 1.2–8.1, p for interaction = 0.03), CC carriers for the MTRR Ex5+123C>T polymorphism (OR = 2.3, 95% CI = 1.2–4.4, p for interaction = 0.01) and TT carriers for the MTRR Ex15+572T>C polymorphism (OR = 1.7, 95% CI = 1.0–2.8, p for interaction = 0.06). The association was not different by sex, Helicobacter pylori infection, intake of folate, vitamin B6 and total protein and the remaining polymorphisms examined. Our results indicate that interactions between blood leukocyte DNA hypomethylation and host characteristics may determine gastric cancer risk.
PMCID: PMC3009461  PMID: 20099281
gastric cancer; methylation; global hypomethylation; gastric cancer risk
19.  LINE-1 hypomethylation in gastric cancer, detected by bisulfite pyrosequencing, is associated with poor prognosis 
Gastric Cancer  2012;16:480-487.
Genome-wide DNA hypomethylation plays an important role in genomic instability and carcinogenesis. DNA methylation in the long interspersed nucleotide element-1, L1 (LINE-1) repetitive element is a good indicator of the global DNA methylation level. In some types of human neoplasms, LINE-1 methylation level is attracting interest as a predictive marker for patient prognosis. However, the prognostic significance of LINE-1 hypomethylation in gastric cancer remains unclear.
Using 203 resected gastric cancer specimens, we quantified LINE-1 methylation using bisulfite-pyrosequencing technology. A Cox proportional hazards model was used to calculate the hazard ratio (HR), adjusted for the clinical and pathological variables.
Gastric cancers showed significantly lower LINE-1 methylation levels compared to matched normal gastric mucosa (p < 0.0001; n = 74). Tumoral LINE-1 methylation range was 11.6–97.5 on a 0–100 scale (n = 203; mean 71.4, median 74.4, standard deviation 12.9). LINE-1 hypomethylation was significantly associated with shorter overall survival [log-rank p = 0.029; univariate HR 2.01, 95 % confidence interval (CI) 1.09–3.99, p = 0.023; stage-matched HR 1.88, 95 % CI 1.02–3.74, p = 0.041; multivariate HR 1.98, 95 % CI 1.04–4.04, p = 0.036]. No significant effect modification was observed by any of the covariates in survival analysis (all p interaction >0.25).
LINE-1 hypomethylation in gastric cancer is associated with shorter survival, suggesting that it has potential for use as a prognostic biomarker.
PMCID: PMC3824342  PMID: 23179365
LINE-1 elements; Gastric cancer; Methylation; Epigenetics; Prognosis
20.  BMI vs. body composition and radiographically-defined osteoarthritis of the knee in women: a 4-year follow-up study 
To elucidate the role of body mass index (BMI) and knee osteoarthritis (OAK) by evaluating measures of body composition including fat mass and skeletal muscle mass (SMM).
Data is from 541 women enrolled in the Michigan Bone Health Study, a longitudinal, population-based study. At visits in 1998 and 2002, radiographs were taken of both knees and were evaluated for the presence of OAK (≥ 2 on the Kellgren and Lawrence (K-L) scale). Joint space width (JSW) was measured with electronic calipers. Fat mass and SMM were determined using bioelectrical impedance analysis.
In 2002, the prevalence of OAK was 11% in this population of women, whose mean age was 47 years. Fat mass, lean mass, SMM, waist circumference and BMI was greater in women with OAK compared to those without OAK. In multiple variable analyses adjusted for age, fat mass and SMM explained OAK prevalence and increasing OAK severity better than models with BMI; further SMM explained more variation than did fat mass. SMM was positively associated with level of left and right medial JSW while there was no consistent association of JSW and BMI or fat mass.
Fat mass and SMM were associated with K-L OAK score and the amount of joint space, with more variation explained by SMM. SMM was highly associated with JSW. Therefore, though obesity, frequently characterized with BMI, is a frequently reported risk factor for OAK, this mis-attribution may mean that interventions that focus on weight loss as treatment for OA should be aware that this may negatively impact muscle mass.
PMCID: PMC2311420  PMID: 17884608
osteoarthritis; body mass index; body composition; fat mass; skeletal muscle mass
21.  Is bioelectrical impedance accurate for use in large epidemiological studies? 
Nutrition Journal  2008;7:26.
Percentage of body fat is strongly associated with the risk of several chronic diseases but its accurate measurement is difficult. Bioelectrical impedance analysis (BIA) is a relatively simple, quick and non-invasive technique, to measure body composition. It measures body fat accurately in controlled clinical conditions but its performance in the field is inconsistent. In large epidemiologic studies simpler surrogate techniques such as body mass index (BMI), waist circumference, and waist-hip ratio are frequently used instead of BIA to measure body fatness. We reviewed the rationale, theory, and technique of recently developed systems such as foot (or hand)-to-foot BIA measurement, and the elements that could influence its results in large epidemiologic studies. BIA results are influenced by factors such as the environment, ethnicity, phase of menstrual cycle, and underlying medical conditions. We concluded that BIA measurements validated for specific ethnic groups, populations and conditions can accurately measure body fat in those populations, but not others and suggest that for large epdiemiological studies with diverse populations BIA may not be the appropriate choice for body composition measurement unless specific calibration equations are developed for different groups participating in the study.
PMCID: PMC2543039  PMID: 18778488
22.  Regional Anthropometry Changes in Antiretroviral-Naïve Persons Initiating a Zidovudine-Containing Regimen in Mbarara, Uganda 
Lipodystrophy is commonly reported in Africa after antiretroviral therapy (ART) is initiated, but few studies have objectively measured changes in body composition. Body composition was determined in 76 HIV-infected participants from Mbarara, Uganda after starting a thymidine-analog regimen, and annual change was determined using repeated measures analysis. We measured skinfolds (tricep, thigh, subscapular, and abdomen), circumferences (arm, hip, thigh, waist), and total lean and fat mass (using bioelectric impedance analysis). A cross-sectional sample of 49 HIV-uninfected participants was studied for comparison. At baseline, most body composition measures were lower in HIV-infected than uninfected participants, but waist circumference was similar. After 12 months on ART, there was little difference in body composition measures between HIV-infected and uninfected participants; median waist circumference appeared higher in HIV-infected participants (79 vs. 75 cm; p = 0.090). Among HIV-infected participants, increases were observed in total lean and fat mass, circumference, and skinfold measures; only the increase in tricep skinfold did not reach statistical significance (+1.05 mm; 95% confidence interval: −0.24, 2.34; p = 0.11). Regional anthropometry in peripheral and central body sites increased over 12 months after ART initiation in HIV-infected persons from southwestern Uganda, suggesting a restoration to health. Gains in the tricep skinfold, a reliable marker of subcutaneous fat, appeared blunted, which could indicate an inhibitory effect of zidovudine on peripheral subcutaneous fat recovery.
PMCID: PMC3159125  PMID: 21128866
23.  The Prognostic Significance of Whole Blood Global and Specific DNA Methylation Levels in Gastric Adenocarcinoma 
PLoS ONE  2010;5(12):e15585.
Epigenetics, particularly DNA methylation, has recently been elucidated as important in gastric cancer (GC) initiation and progression. We investigated the clinical and prognostic importance of whole blood global and site-specific DNA methylation in GC.
Genomic DNA was extracted from the peripheral blood of 105 Omani GC patients at diagnosis. DNA methylation was quantified by pyrosequencing of global DNA and specific gene promoter regions at 5 CpG sites for CDH1, 7 CpG sites for p16, 4 CpG sites for p53, and 3 CpG sites for RUNX3. DNA methylation levels in patients were categorized into low, medium, and high tertiles. Associations between methylation level category and clinicopathological features were evaluated using χ2 tests. Survival analyses were carried out using the Kaplan-Meier method and log rank test. A backward conditional Cox proportional hazards regression model was used to identify independent predictors of survival.
Older GC patients had increased methylation levels at specific CpG sites within the CDH1, p53, and RUNX-3 promoters. Male gender was significantly associated with reduced global and increased site-specific DNA methylation levels in CDH1, p16, and p53 promoters. Global DNA low methylation level was associated with better survival on univariate analysis. Patients with high and medium methylation vs. low methylation levels across p16 promoter CpG sites, site 2 in particular, had better survival. Multivariate analysis showed that global DNA hypermethylation was a significant independent predictor of worse survival (hazard ratio (HR) = 2.0, 95% CI: 1.1–3.8; p = 0.02) and high methylation mean values across p16 promoter sites 1–7 were associated with better survival with HR of 0.3 (95% CI, 0.1–0.8; p = 0.02) respectively.
Analysis of global and site-specific DNA methylation in peripheral blood by pyrosequencing provides quantitative DNA methylation values that may serve as important prognostic indicators.
PMCID: PMC3009731  PMID: 21203466
24.  Repetitive element DNA methylation levels in white blood cell DNA from sisters discordant for breast cancer from the New York site of the Breast Cancer Family Registry 
Carcinogenesis  2012;33(10):1946-1952.
Global decreases in DNA methylation, particularly in repetitive elements, have been associated with genomic instability and human cancer. Emerging, though limited, data suggest that in white blood cell (WBC) DNA levels of methylation, overall or in repetitive elements, may be associated with cancer risk. We measured methylation levels of three repetitive elements [Satellite 2 (Sat2)], long interspersed nuclear element-1 (LINE-1) and Alu) by MethyLight, and LINE-1 by pyrosequencing in a total of 282 breast cancer cases and 347 unaffected sisters from the New York site of the Breast Cancer Family Registry (BCFR) using DNA from both granulocytes and total WBC. We found that methylation levels in all markers were correlated between sisters (Spearman correlation coefficients ranged from 0.17 to 0.55). Sat2 methylation was statistically significantly associated with increased breast cancer risk [odds ratio (OR) = 2.09, 95% confidence interval (CI) = 1.09–4.03; for each unit decrease in the natural log of the methylation level, OR = 2.12, 95% CI = 0.88–5.11 for the lowest quartile compared with the highest quartile]. These associations were only observed in total WBC but not granulocyte DNA. There was no association between breast cancer and LINE-1 and Alu methylation. If replicated in larger prospective studies, these findings support that selected markers of epigenetic changes measured in WBC, such as Sat2, may be potential biomarkers of breast cancer risk.
PMCID: PMC3499042  PMID: 22678115
25.  Influence of DNMT Genotype on Global and Site Specific DNA Methylation Patterns in Neonates and Pregnant Women 
PLoS ONE  2013;8(10):e76506.
This study examines the relationship between common genetic variation within DNA methyltransferase genes and inter-individual variation in DNA methylation. Eleven polymorphisms spanning DNMT1 and DNMT3B were genotyped. Global and gene specific (IGF2, IGFBP3, ZNT5) DNA methylation was quantified by LUMA and bisulfite Pyrosequencing assays, respectively, in neonatal cord blood and in maternal peripheral blood. Associations between maternal genotype and maternal methylation (n ≈ 333), neonatal genotype and neonatal methylation (n ≈ 454), and maternal genotype and neonatal methylation (n ≈ 137) were assessed. The findings of this study provide some support to the hypothesis that genetic variation in DNA methylating enzymes influence DNA methylation at global and gene-specific levels; however observations were not robust to correction for multiple testing. More comprehensive analysis of the influence of genetic variation on global and site specific DNA methylation is warranted.
PMCID: PMC3788139  PMID: 24098518

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