The influence of the CYP2D6*4 polymorphism on drug response and disease susceptibility

This thesis is about the role of CYP2D6, a drug-metabolizing enzyme, in today’s pharmacotherapy. Cytochrome P450 2D6 (CYP2D6) is an important member of a large family of enzymes with the name cytochrome P450 which is abundantly present in most non-monocellular living organisms. Its history probably goes back for millions of years, when animals developed detoxifying enzymes as a defence mechanism against plant stress metabolites. Evolutionary pressure led to more and more diversity in these P450 genes. Nowadays, this genetic variation in CYP2D6 plays an important role in explaining variability in drug response. In this introduction, the variability in drug response will be discussed, followed by genetic variation, pharmacokinetics and pharmacodynamics, the cytochrome P450 enzyme family, the possible infl uence of CYP2D6 on drug response and adverse reactions to drugs, disease susceptibility, and aims and scope of this thesis

Comparison of SARS-CoV-2-Specific Antibodies in Human Milk after mRNA-Based COVID-19 Vaccination and Infection

SARS-CoV-2-specific antibodies are secreted into human milk of infected or vaccinated lactating women and might provide protection to the breastfed infant against COVID-19. Differences in antibody response after these types of exposure are unknown. In this longitudinal cohort study, we compared the antibody response in human milk following SARS-CoV-2 vaccination or infection. We analyzed 448 human milk samples of 28 lactating women vaccinated with the SARS-CoV-2 vaccine BNT162b2 as well as 82 human milk samples of 18 lactating women with a prior SARS-CoV-2 infection. The levels of SARS-CoV-2-specific IgA in human milk were determined over a period of 70 days both after vaccination and infection. The amount of SARS-CoV-2-specific IgA in human milk was similar after SARS-CoV-2 vaccination and infection. After infection, the variability in IgA levels was higher than after vaccination. Two participants with detectable IgA prior to vaccination were analyzed separately and showed higher IgA levels following vaccination compared to both groups. In conclusion, breastfed infants of mothers who have been vaccinated with the BNT162b2 vaccine receive human milk with similar amounts of SARS-CoV-2-specific antibodies compared to infants of previously infected mothers

Association of Systemic Lupus Erythematosus Clinical Features with European Population Genetic Substructure

Systemic Lupus Erythematosus (SLE) is an autoimmune disease with a very varied spectrum of clinical manifestations that could be partly determined by genetic factors. We aimed to determine the relationship between prevalence of 11 clinical features and age of disease onset with European population genetic substructure. Data from 1413 patients of European ancestry recruited in nine countries was tested for association with genotypes of top ancestry informative markers. This analysis was done with logistic regression between phenotypes and genotypes or principal components extracted from them. We used a genetic additive model and adjusted for gender and disease duration. Three clinical features showed association with ancestry informative markers: autoantibody production defined as immunologic disorder (P = 6.8×10(-4)), oral ulcers (P = 6.9×10(-4)) and photosensitivity (P = 0.002). Immunologic disorder was associated with genotypes more common in Southern European ancestries, whereas the opposite trend was observed for photosensitivity. Oral ulcers were specifically more common in patients of Spanish and Portuguese self-reported ancestry. These results should be taken into account in future research and suggest new hypotheses and possible underlying mechanisms to be investigated. A first hypothesis linking photosensitivity with variation in skin pigmentation is suggested

The Central Paratethys during Oligocene as an ancient counterpart of the present-day Black Sea: Unique records from the coccolith limestones

Four isochronous Oligocene coccolith limestone horizons from the Carpathians were examined in order to reconstruct paleoceanographic conditions in the Central Paratethys. The dominance of small and size-uniform pyrite framboids, the occurrence of low-diversity dinoflagellate cysts and coccolithophorids and the presence of biomarker molecule 28,30-dinorhopane indicate that the water column was stratified with the upper water column being relatively well oxygenated, but the bottom water being anoxic. The latter is confirmed by the fine and consistent horizontal laminations in various parts of the basin, scarcity of benthic organisms and their trace fossils. The limestones exhibit typical marine δ13C values, but are significantly depleted in 18O and enriched in 87Sr relative to contemporaneous ocean water. These isotopic compositions result from a decreased salinity of the surface waters caused by an increased riverine input. This is confirmed by the lack or impoverishment of planktonic foraminifers, presence to abundance of goniodomid dinoflagellate cysts and massive occurrence of low-diversity nannoplankton assemblages, which indicates decreased salinities as low as 17‰ and high productivity in the upper water column. These observations indicate that the limestones were formed during periods when connection of the Central Paratethys with the global ocean was limited, which impeded water exchangecausing the development of low-salinity conditions of surface water and bottom-water anoxia. During the deposition of the oldest Tylawa horizon, primary productivity was enhanced and chemocline was positioned exceptionally high in the water column. Moreover, decreased δ13C values in both carbonates and organic matter of this horizon suggest that widespread methane venting took place in the basin during NP23. All these data show that during the Oligocene the Central Paratethys experienced similar conditions to those of the current Black Sea, which can be used as a modern analogue, especially for the Tylawa horizon. Therefore, the Tylawa horizon can be perceived as a potential effect of future post-depositional processes of coccolith marls analogous to those having been deposited in the Black Sea for 2.7 kyr