Harold Snieder

Obesity related methylation changes in DNA of peripheral blood leukocytes

BackgroundDespite evidence linking obesity to impaired immune function, little is known about the specific mechanisms. Because of emerging evidence that immune responses are epigenetically regulated, we hypothesized that DNA methylation changes are involved in obesity induced immune dysfunction and aimed to identify these changes.MethodWe conducted a genome wide methylation analysis on seven obese cases and seven lean controls aged 14 to 18 years from extreme ends of the obesity distribution and performed further validation of six CpG sites from six genes in 46 obese cases and 46 lean controls aged 14 to 30 years.ResultsIn comparison with the lean controls, we observed one CpG site in the UBASH3A gene showing higher methylation levels and one CpG site in the TRIM3 gene showing lower methylation levels in the obese cases in both the genome wide step (P = 5 × 10-6 and P = 2 × 10-5 for the UBASH3A and the TRIM3 gene respectively) and the validation step (P = 0.008 and P = 0.001 for the UBASH3A and the TRIM3 gene respectively).ConclusionsOur results provide evidence that obesity is associated with methylation changes in blood leukocyte DNA. Further studies are warranted to determine the causal direction of this relationship as well as whether such methylation changes can lead to immune dysfunction.See commentary: http://www.biomedcentral.com/1741-7015/8/88/abstract

Heritability of Blood Pressure and Hemodynamics in African- and European-American Youth

Abstract— Hypertension prevalence is much higher in African‐Americans (AAs) than in European‐Americans (EAs). It is unknown whether this difference is related to potential ethnic differences in the relative contribution of genes and environment to population variation in blood pressure and underlying hemodynamics. We studied 308 EA and 226 AA twin pairs, including monozygotic and dizygotic twins, of the same as well as the opposite sex (mean±SD age, 14.7±3.1 years). Supine resting systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure, and heart rate (HR) were measured by a Dinamap instrument and hemodynamics (stroke volume, cardiac index, and total peripheral resistance [TPR] index) by impedance cardiography. Ethnic and sex effects on genetic and environmental contributions to resting blood pressure and hemodynamics were estimated by genetic model fitting. For most measures, the best‐fitting model showed no differences in heritability between AAs and EAs or between males and females, with heritabilities of 0.50 for cardiac index, of 0.64 for HR, and of SBP, pulse pressure, and stroke volume in between. Heritability of DBP was 0.45 in EAs and 0.58 in AAs with no effect of sex. For TPR index in EAs, 46% of the variance could be attributed to familial effects, but no significant distinction could be made between shared environmental and genetic factors. Heritability of TPR index in AAs was 0.51. Adjustment for obesity yielded virtually identical heritabilities. In summary, relative influences of genetic and environmental factors on blood pressure and hemodynamics in AA and EA youth are similar and independent of (genes for) obesity.

Association between birth weight and adult blood pressure in twins: historical cohort study

Abstract Objectives: To evaluate the associations in twins between within pair differences in birth weight and subsequent blood pressures as adults thereby removing the impact of potential parental confounding variables. Design: Historical cohort study. Setting: St Thomass UK adult twin register, June 1992 to September 1995. Participants: 492 pairs of female twins (mean age 54 years). Main outcome measures: Mean within pair differences in adult blood pressure in each of four strata of within pair differences in birth weight (0, 1-500 g, 501-1000 g, >1000 g). Differences in blood pressure were analysed before and after adjustment for potential confounders between adult twins, after exclusion of those twin pairs including at least one twin taking antihypertensive drugs, and by zygosity. Results: Reported mean birth weights of heavier and lighter twins were 2.51 (SD 0.61)v 2.12 (0.59) kg respectively. A graded inverse relation between strata of within pair differences in birth weight and differences in adult blood pressure was apparent, with an adjusted blood pressure range of 8.7/5.1 mm Hg across the four strata (test for trend: systolic, P=0.05; diastolic, P=0.09). After excluding those women taking antihypertensive drugs the significance of the association was similar (systolic, P=0.04; diastolic, P=0.10). When differences in blood pressure were stratified for zygosity similar but non-significant trends were apparent. Conclusion: It would seem that birth weight is inversely associated with adult blood pressure and that this association is independent of parental confounding variables probably including, in view of the findings in monozygotic twins, genetic factors. The observed blood pressure differences are likely to result from retarded intrauterine growth due to placental dysfunction rather than inadequate maternal nutrition. Key messages Among adult twins, blood pressures tend to be lower among those twins who were heavier at birth Strata of within pair birthweight differences of twins show a graded inverse relation with adult blood pressure differences Monozygotic and dizygotic twins show a similar inverse association between birthweight differences and adult blood pressure differences The inverse association between birth weight and adult blood pressure is independent of parental confounding variables

Leukocyte Telomere Length in Healthy Caucasian and African-American Adolescents: Relationships with Race, Sex, Adiposity, Adipokines, and Physical Activity

OBJECTIVEnTo examine the relationships of race, sex, adiposity, adipokines, and physical activity to telomere length in adolescents.nnnSTUDY DESIGNnLeukocyte telomere length (T/S ratio) was assessed cross-sectionally in 667 adolescents (aged 14-18 years; 48% African-Americans; 51% girls) using a quantitative polymerase chain reaction method. Generalized estimating equations analyses were performed.nnnRESULTSnTelomere length was greater in the African-American adolescents than in the Caucasian adolescents (age- and sex-adjusted T/S ratio ± SE, 1.32 ± 0.01 vs 1.27 ± 0.01: P = .014) and greater in girls than in boys (age- and race-adjusted T/S ratio ± SE, 1.31 ± 0.01 vs 1.27 ± 0.01; P = .007). None of the adiposity or adipokine measures explained a significant proportion of the variance in telomere length. Vigorous physical activity was positively associated with telomere length (adjusted R(2) = 0.019; P = .009) and accounted for 1.9% of the total variance only in girls.nnnCONCLUSIONSnThis study, conducted in a biracial adolescent cohort, demonstrated that (1) race and sex differences in telomere length have already emerged during adolescence; (2) adiposity and adipokines are not associated with telomere length at this age; and (3) the antiaging effect of vigorous physical activity may begin in youth, especially in girls.

FTO variant rs9939609 is associated with body mass index and waist circumference, but not with energy intake or physical activity in European- and African-American youth

BackgroundGenome-wide association studies found common variants in the fat mass and obesity-associated (FTO) gene associated with adiposity in Caucasians and Asians but the association was not confirmed in African populations. Association of FTO variants with insulin resistance and energy intake showed inconsistent results in previous studies. This study aimed to assess the influence of FTO variant rs9939609 on adiposity, insulin resistance, energy intake and physical activity in European - (EA) and African-American (AA) youth.MethodsWe conducted a cross-sectional study in EA and AA youths. One thousand, nine hundred and seventy-eight youths (48.2% EAs, 47.1% male, mean age 16.5 years) had measures of anthropometry. Percent body fat (%BF) was measured by dual-energy X-ray absorptiometry, visceral adipose tissue (VAT) and subcutaneous abdominal adipose tissue (SAAT) by magnetic resonance imaging. Energy intake and physical activity were based on self report from up to 7 24-hour recalls. Physical activity was also measured by accelerometry.ResultsFTO rs9939609 was significantly associated with body mass index (BMI) (P = 0.01), weight (P = 0.03) and waist circumference (P = 0.04), with per-allele effects of 0.4 kg/m2, 1.3 kg and 0.8 cm, respectively. No significant association was found between rs9939609 and %BF, VAT, SAAT or insulin resistance (P > 0.05), or between rs9939609 and energy intake or vigorous physical activity (P > 0.05). No significant interactions of rs9939609 with ethnicity, gender, energy intake or physical activity were observed (P > 0.05).ConclusionsThe FTO variant rs9939609 is modestly associated with BMI and waist circumference, but not with energy intake or physical activity. Moreover, these effects were similar for EAs and AAs. Improved understanding of the effect of the FTO variant will offer new insights into the etiology of excess adiposity.

Activation markers of coagulation and fibrinolysis in twins: heritability of the prethrombotic state

BACKGROUNDnActivation markers of coagulation and fibrinolysis are increased in individuals at risk of coronary-artery disease and other thrombotic disorders--a condition defined as the prethrombotic state. We aimed to find out the extent to which the prethrombotic state is determined by genetic factors.nnnMETHODSnWe analysed concentrations of prothrombin, prothrombin fragment 1+2, thrombin-antithrombin complex, crosslinked fibrin degradation product D-dimer, and thrombin-activatable fibrinolysis inhibitor by ELISA in 118 monozygotic and 112 dizygotic unselected female twins aged 21-73 years from the St Thomas UK Adult Twin Registry. We used quantitative genetic-model fitting to estimate heritability.nnnFINDINGSnWe found significant heritabilities in concentrations of the activation markers in plasma. Genetic factors contributed 45, 40, and 65% of the variation in concentrations of fragment 1+2, thrombin-antithrombin complex, and D-dimer, respectively. Age was important only in fragment 1+2 concentrations, in which it accounted for 12% of the variation. The remaining variation could be attributed to unique environmental factors. Variation in concentrations of precursor prothrombin in plasma was determined by 57% heritability, and that of zymogen thrombin-activatable fibrinolysis inhibitor showed a very strong genetic component (82%).nnnINTERPRETATIONnThe activation mechanisms of the coagulation and fibrinolytic systems, and therefore the prethrombotic state, are controlled to a substantial degree by genetic factors. Genes influencing activation of haemostasis are likely to be an important component of the overall thrombotic tendency in the general population.

Determination of Twin Zygosity: A Comparison of DNA with Various Questionnaire Indices

This study examined cross-validation and test-retest reliability of questions and questionnaire indices commonly used for twin zygosity classification. Mothers of 58 monozygotic (MZ) and 52 dizygotic (DZ) same sex twin pairs were interviewed by telephone to answer questions regarding the similarity of their twins (mean age = 14.6 +/- 2.8 years). A logistic regression equation correctly classified 91% of both MZ and DZ twin pairs in our sample using 7 of the 12 zygosity questions. The internal consistency for the total questionnaire (Cronbachs alpha) was 0.88. The median two month temporal stability estimate for the individual questions was r = .56 and r = .79 for the test total. For the cross-validation, zygosity classification indices taken from 9 previous studies were applied to our sample and compared to classification according to DNA microsatellite analyses (agreement range = 44 to 100%). The accuracy of the classification indices was significantly lower than the original studies for 62% of the comparisons. If zygosity determination with DNA markers or blood group typing for all subjects is not feasible, rather than using classification indices based on other studies, an optimal classification scheme can be achieved by using a zygosity questionnaire of which the reliability and validity of the questions is established in a random subsample of the same twin cohort.

Gender differences in the genetic factors responsible for variation in bone density and ultrasound.

Although genetic factors are thought to explain a large proportion of the variation in bone density in women, few studies have been conducted in men. Therefore, it is unclear whether the individual differences in bone strength between men and women are a reflection of gender differences in the relative influence of genetic and environmental factors on bone density variance. The aim of this study was to determine if there were gender differences in the genetic components of variance for bone density and ultrasound. In addition, the study aimed to explore the hypothesis that there are unique gender‐specific genetic determinants of these traits. Bone mineral density (BMD) of the hip, distal forearm, and lumbar spine were measured by dual‐energy X‐ray absorptiometry (DXA) as well as quantitative ultrasound (QUS) at the calcaneus in healthy female twin pairs (286 identical [MZ] and 265 nonidentical [DZ]), male twin pairs (72 MZ and 65 DZ), and 82 opposite‐sex (OS) pairs aged between 18 and 80 years. For hip BMD, distal forearm, and QUS measurements, the differences between MZ correlations and like‐sex DZ correlations were similar for both sexes, suggesting little difference in the component of total variance explained by genetic factors between male and female twin pairs. However, correlations between OS twin pairs were lower than that of like‐sex twin pairs, suggesting the possibility of unique gender‐specific genetic effects. At the forearm, model fitting suggested a small gender difference in the magnitude of genetic variance as well as the presence of a unique gender‐specific genetic variance component. Hip, lumbar spine, and QUS measurements were better explained by models that assumed no gender differences in genetic variance between the sexes, but the study had insufficient power to detect small differences in the genetic components of variance. The results of this study suggest that the proportion of bone strength variance explained by genetic factors is similar for men and women. However, at some regions there is evidence to suggest a gender‐specific genetic component to the overall genetic variance.

Growth of Left Ventricular Mass in African American and European American Youth

Increased left ventricular mass has been established as a strong risk factor for cardiovascular morbidity and mortality. To evaluate growth of left ventricular mass from childhood into early adulthood and its possible sociodemographic, anthropometric, and hemodynamic moderators, individual growth curves across age of left ventricular mass were created for 687 African American and European American males and females with a maximum of 10 annual assessments (age, 8.2 to 27.5 years). African Americans and males had significantly greater left ventricular mass (P <0.001) than did European Americans and females, respectively. Males also showed a larger rate of change in left ventricle mass than did girls (P <0.001). The ethnicity and gender effects on left ventricular mass only became apparent in early adolescence, and they persisted when controlling for socioeconomic status and anthropometric and hemodynamic variables. Body mass index and height were the strongest anthropometric predictors, and pulse pressure was the strongest hemodynamic predictor of left ventricular mass. Although significant, the contribution of pulse pressure to the prediction of left ventricular mass was small, once body mass index and height were entered into the model. The results of the present study suggest that increased left ventricular mass in boys and African Americans has its origin in late childhood. Apart from these ethnicity and gender effects, individual differences in cardiac growth can mainly be explained by body growth and increases in general adiposity.

Dissecting the genetic architecture of the cardiovascular and renal stress response.

We review the evidence for a genetic basis of the cardiovascular and renal stress response. A bio-behavioral model of stress-induced hypertension is presented that explains how repeated exposure to stress in combination with genetic susceptibility might lead to the development of hypertension. In this model, we focus on three underlying physiological systems that mediate the stress response of the heart, vasculature and kidney: the sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system (RAAS) and the endothelial system (ES). We then review the evidence for a genetic influence on cardiovascular reactivity to psychological stress and stress-induced sodium retention using data from twin and family studies and a limited number of candidate gene studies. Finally, by describing the underlying physiological systems of our model and their genetic underpinning we emphasize the importance of inclusion of genetic measurements in any future studies testing the reactivity hypothesis.