11. |
- Kiekens, Wouter, et al.
(author)
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Explaining Health Disparities between Heterosexual and LGB Adolescents by Integrating the Minority Stress and Psychological Mediation Frameworks : Findings from the TRAILS Study
- 2020
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In: Journal of Youth and Adolescence. - : Springer Science and Business Media LLC. - 0047-2891 .- 1573-6601. ; 49, s. 1767-1782
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Journal article (peer-reviewed)abstract
- Lesbian, gay, and bisexual (LGB) adolescents experience elevated levels of internalizing problems and use more substances than heterosexual adolescents. The minority stress and psychological mediation framework are complementary theoretical frameworks that were developed to explain these disparities. However, limited empirical research has integrated both frameworks to study health disparities between heterosexual and LGB adolescents. This study attempts such an integration, using data from the first five waves (participant age 11-22) of the TRacking Adolescents' Individual Lives Survey (TRAILS), a cohort study of Dutch adolescents (N = 1738; 151 LGB; 54.8% girls). It was tested whether an LGB identity was linked to internalizing problems and substance use through a serial mediation process, in which sexual identity would be associated with peer victimization and negative relationships with parents (first set of mediators, in keeping with the minority stress framework), which in turn would be associated with fear of negative social evaluation and a lack of social support (second set of mediators, in keeping with the psychological mediation framework), and eventually increasing the risk for internalizing problems and elevated levels of substance use. Moreover, it was tested whether the link between minority stress and substance use was mediated by peers' substance use levels, as hypothesized by the psychological mediation framework. Compared to heterosexual participants, LGB participants reported more internalizing problems, smoked more cigarettes, and used more marijuana, but did not consume more alcohol. The relation between sexual identity and internalizing problems was mediated by peer victimization and parental rejection, which is in line with the minority stress framework. No statistically significant support was found for the psychological mediation framework. These findings provide a better understanding of the pathways through which sexual identity disparities in mental wellbeing and substance use come about.
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12. |
- Liu, C, et al.
(author)
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A DNA methylation biomarker of alcohol consumption.
- 2018
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In: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 23, s. 422-433
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Journal article (peer-reviewed)abstract
- The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10(-7). Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10(-7). In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.
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13. |
- Meyer, Saskia, et al.
(author)
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New insights in Type I and II CD20 antibody mechanisms-of-action with a panel of novel CD20 antibodies
- 2018
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In: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 180:6, s. 808-820
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Journal article (peer-reviewed)abstract
- Based on their mechanisms-of-action, CD20 monoclonal antibodies (mAbs) are grouped into Type I [complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC)] and Type II [programmed cell death (PCD) and ADCC] mAbs. We generated 17 new hybridomas producing CD20 mAbs of different isotypes and determined unique heavy and light chain sequence pairs for 13 of them. We studied their epitope binding, binding kinetics and structural properties and investigated their predictive value for effector functions, i.e. PCD, CDC and ADCC. Peptide mapping and CD20 mutant screens revealed that 10 out of these 11 new mAbs have an overlapping epitope with the prototypic Type I mAb rituximab, albeit that distinct amino acids of the CD20 molecule contributed differently. Binding kinetics did not correlate with the striking differences in CDC activity among the mIgG2c mAbs. Interestingly, chimerization of mAb m1 resulted in a mAb displaying both Type I and II characteristics. PCD induction was lost upon introduction of a mutation in the framework of the heavy chain affecting the elbow angle, supporting that structural changes within this region can affect functional activities of CD20 mAbs. Together, these new CD20 mAbs provide further insights in the properties dictating the functional efficacy of CD20 mAbs.
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14. |
- Pfeiffer, L., et al.
(author)
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DNA methylation of lipid-related genes affects blood lipid levels
- 2015
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In: Circ Cardiovasc Genet. ; 8:2, s. 334-42
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Journal article (peer-reviewed)abstract
- BACKGROUND: Epigenetic mechanisms might be involved in the regulation of interindividual lipid level variability and thus may contribute to the cardiovascular risk profile. The aim of this study was to investigate the association between genome-wide DNA methylation and blood lipid levels high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and total cholesterol. Observed DNA methylation changes were also further analyzed to examine their relationship with previous hospitalized myocardial infarction. METHODS AND RESULTS: Genome-wide DNA methylation patterns were determined in whole blood samples of 1776 subjects of the Cooperative Health Research in the Region of Augsburg F4 cohort using the Infinium HumanMethylation450 BeadChip (Illumina). Ten novel lipid-related CpG sites annotated to various genes including ABCG1, MIR33B/SREBF1, and TNIP1 were identified. CpG cg06500161, located in ABCG1, was associated in opposite directions with both high-density lipoprotein cholesterol (beta coefficient=-0.049; P=8.26E-17) and triglyceride levels (beta=0.070; P=1.21E-27). Eight associations were confirmed by replication in the Cooperative Health Research in the Region of Augsburg F3 study (n=499) and in the Invecchiare in Chianti, Aging in the Chianti Area study (n=472). Associations between triglyceride levels and SREBF1 and ABCG1 were also found in adipose tissue of the Multiple Tissue Human Expression Resource cohort (n=634). Expression analysis revealed an association between ABCG1 methylation and lipid levels that might be partly mediated by ABCG1 expression. DNA methylation of ABCG1 might also play a role in previous hospitalized myocardial infarction (odds ratio, 1.15; 95% confidence interval=1.06-1.25). CONCLUSIONS: Epigenetic modifications of the newly identified loci might regulate disturbed blood lipid levels and thus contribute to the development of complex lipid-related diseases.
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