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Author(s): van Otterdijk, Sanne D; Binder, Alexandra M; Szarc Vel Szic, Katarzyna; Schwald, Julia; Michels, Karin B | Abstract: IntroductionThe prevalence of type 2 diabetes (T2D) and the metabolic syndrome (MetS) is increasing and several studies suggested an involvement of DNA methylation in the development of these metabolic diseases. This study was designed to investigate if differential DNA methylation in blood can function as a biomarker for T2D and/or MetS.MethodsPyrosequencing analyses were performed for the candidate genes KCNJ11, PPARγ, PDK4, KCNQ1, SCD1, PDX1, FTO and PEG3 in peripheral blood leukocytes (PBLs) from 25 patients diagnosed with only T2D, 9 patients diagnosed with T2D and MetS and 11 control subjects without any metabolic disorders.ResultsNo significant differences in gene-specific methylation between patients and controls were observed, although a trend towards significance was observed for PEG3. Differential methylation was observed between the groups in 4 out of the 42 single CpG loci located in the promoters regions of the genes FTO, KCNJ11, PPARγ and PDK4. A trend towards a positive correlation was observed for PEG3 methylation with HDL cholesterol levels.DiscussionAltered levels of DNA methylation in PBLs of specific loci might serve as a biomarker for T2D or MetS, although further investigation is required.

Background Maternal smoking has been linked to lower birth weight and higher risk of childhood obesity. However, it is unknown whether grand-maternal smoking during pregnancy is associated with grandchildren birth weight and body mass index (BMI) trajectories. Methods We investigated associations of smoking during pregnancy with birth weight, risks of overweight and BMI trajectories among 46,858 mother-child dyads and 6,583 grandmother-mother-child triads of three cohort studies of related individuals. Smoking during pregnancy was reported by mothers, and anthropometric data were provided by participants in each cohort. Results Compared to grandchildren of non-smoking women, grandchildren of women who smoked more than 14 cigarettes per day throughout pregnancy were 70 g (95% CI: 12, 129 g; P for trend = 0.01) heavier at birth, and 18% (95% CI: 4%, 34%; P for trend = 0.01) more likely to become overweight. The mean BMI of grandchildren of women who smoked during pregnancy was 0.45 kg/m2 (95% CI: 0.14, 0.75 kg/m2; P for trend = 0.006) higher through adolescence and young adulthood than that of grandchildren of non-smoking mothers. Conclusions Grandmothers' smoking during pregnancy was associated with higher birth weight, higher risk of overweight, and higher BMI through adolescence and young adulthood.

BACKGROUNDIn the absence of clinical trial data, large post-marketing observational studies are essential to evaluate the safety and effectiveness of medications during pregnancy. We identified a cohort of pregnancies ending in live birth within the 2000-2007 Medicaid Analytic eXtract (MAX). Herein, we provide a blueprint to guide investigators who wish to create similar cohorts from healthcare utilization data and we describe the limitations in detail.METHODSAmong females ages 12-55, we identified pregnancies using delivery-related codes from healthcare utilization claims. We linked women with pregnancies to their offspring by state, Medicaid Case Number (family identifier) and delivery/birth dates. Then we removed inaccurate linkages and duplicate records and implemented cohort eligibility criteria (i.e., continuous and appropriate enrollment type, no private insurance, no restricted benefits) for claim information completeness.RESULTSFrom 13,460,273 deliveries and 22,408,810 child observations, 6,107,572 pregnancies ending in live birth were available after linkage, cleaning, and removal of duplicate records. The percentage of linked deliveries varied greatly by state, from 0 to 96%. The cohort size was reduced to 1,248,875 pregnancies after requiring maternal eligibility criteria throughout pregnancy and to 1,173,280 pregnancies after further applying infant eligibility criteria. Ninety-one percent of women were dispensed at least one medication during pregnancy.CONCLUSIONSMother-infant linkage is feasible and yields a large pregnancy cohort, although the size decreases with increasing eligibility requirements. MAX is a useful resource for studying medications in pregnancy and a spectrum of maternal and infant outcomes within the indigent population of women and their infants enrolled in Medicaid. It may also be used to study maternal characteristics, the impact of Medicaid policy, and healthcare utilization during pregnancy. However, careful attention to the limitations of these data is necessary to reduce biases.

There is growing interest in identifying surrogate tissues to identify epimutations in cancer patients since primary target tissues are often difficult to obtain. Methylation patterns at imprinted loci are established during gametogenesis and post fertilization and their alterations have been associated with elevated risk of cancer. Methylation at several imprinted differentially methylated regions (GRB10 ICR, H19 ICR, KvDMR, SNRPN/SNURF ICR, IGF2 DMR0, and IGF2 DMR2) were analyzed in DNA from leukocytes and mammary tissue (normal, benign diseases, or malignant tumors) from 87 women with and without breast cancer (average age of cancer patients: 53; range: 31–77). Correlations between genomic variants and DNA methylation at the studied loci could not be assessed, making it impossible to exclude such effects. Methylation levels observed in leukocyte and mammary tissue DNA were close to the 50% expected for monoallellic methylation. While no correlation was observed between leukocyte and mammary tissue DNA methylation for most of the analyzed imprinted genes, Spearman's correlations were statistically significant for IGF2 DMR0 and IGF2 DMR2, although absolute methylation levels differed. Leukocyte DNA methylation levels of selected imprinted genes may therefore serve as surrogate markers of DNA methylation in cancer tissue.

Low birthweight, premature birth, intrauterine growth retardation, and maternal malnutrition have been related to an increased risk of cardiovascular disease, type 2 diabetes mellitus, obesity, and neuropsychiatric disorders later in life. Conversely, high birthweight has been linked to future risk of cancer. Global DNA methylation estimated by the methylation of repetitive sequences in the genome is an indicator of susceptibility to chronic diseases. We used data and biospecimens from an epigenetic birth cohort to explore the association between trajectories of fetal and maternal weight and LINE-1 methylation in 319 mother-child dyads. Newborns with low or high birthweight had significantly lower LINE-1 methylation levels in their cord blood compared to normal weight infants after adjusting for gestational age, sex of the child, maternal age at delivery, and maternal smoking during pregnancy (p = 0.007 and p = 0.036, respectively), but the magnitude of the difference was small. Infants born prematurely also had lower LINE-1 methylation levels in cord blood compared to term infants, and this difference, though small, was statistically significant (p = 0.004). We did not find important associations between maternal prepregnancy BMI or gestational weight gain and global methylation of the cord blood or fetal placental tissue. In conclusion, we found significant differences in cord blood LINE-1 methylation among newborns with low and high birthweight as well as among prematurely born infants. Future studies may elucidate whether chromosomal instabilities or other functional consequences of these changes contribute to the increased risk of chronic diseases among individuals with these characteristics.