BackgroundGlioblastoma patients are at high risk of developing venous thromboembolism (VTE). Tumor-intrinsic features are considered to play a role, but the underlying pathophysiological mechanisms... Show moreBackgroundGlioblastoma patients are at high risk of developing venous thromboembolism (VTE). Tumor-intrinsic features are considered to play a role, but the underlying pathophysiological mechanisms remain incompletely understood.ObjectivesTo identify tumor-expressed genes and signaling pathways that associate with glioblastoma-related VTE by using next generation RNA-sequencing (RNA-Seq).MethodsThe tumor gene expression profile of 23 glioblastoma patients with VTE and 23 glioblastoma patients without VTE was compared using an unpaired analysis. Ingenuity Pathway Analysis (IPA) core analysis was performed on the top 50 differentially expressed genes to explore associated functions and pathways. Based on full RNA-Seq data, molecular glioblastoma subtypes were determined by performing cluster analysis.ResultsOf the 19,327 genes, 1246 (6.4 %) were differentially expressed between glioblastoma patients with and without VTE (unadjusted P < 0.05). The most highly overexpressed gene was GLI1, a classical target gene in the Sonic Hedgehog (Shh) signaling pathway (log2 fold change: 3.7; unadjusted P < 0.0001, adjusted P = 0.219). In line, Shh signaling was among the top canonical pathways and processes associated with VTE. The proportion of patients with the proneural/neural glioblastoma subtype was higher among those with VTE than controls.ConclusionShh signaling may be involved in the development of glioblastoma-related VTE. Show less
Guimaraes, T.A.C. de; Georgiou, M.; Robson, A.G.; Fujinami, K.; Vincent, A.; Nasser, F.; ... ; Michaelides, M. 2023
Background/aims To investigate genotype-phenotype associations in patients with KCNV2 retinopathy.Methods Review of clinical notes, best-corrected visual acuity (BCVA), molecular variants,... Show moreBackground/aims To investigate genotype-phenotype associations in patients with KCNV2 retinopathy.Methods Review of clinical notes, best-corrected visual acuity (BCVA), molecular variants, electroretinography (ERG) and retinal imaging. Subjects were grouped according to the combination of KCNV2 variants-two loss-of-function (TLOF), two missense (TM) or one of each (MLOF)-and parameters were compared.Results Ninety-two patients were included. The mean age of onset (mean +/- SD) in TLOF (n=55), TM (n=23) and MLOF (n=14) groups was 3.51 +/- 0.58, 4.07 +/- 2.76 and 5.54 +/- 3.38 years, respectively. The mean LogMAR BCVA ( +/- SD) at baseline in TLOF, TM and MLOF groups was 0.89 +/- 0.25, 0.67 +/- 0.38 and 0.81 +/- 0.35 for right, and 0.88 +/- 0.26, 0.69 +/- 0.33 and 0.78 +/- 0.33 for left eyes, respectively. The difference in BCVA between groups at baseline was significant in right (p=0.03) and left eyes (p=0.035). Mean outer nuclear layer thickness ( +/- SD) at baseline in TLOF, MLOF and TM groups was 37.07 +/- 15.20 mu m, 40.67 +/- 12.53 and 40.38 +/- 18.67, respectively, which was not significantly different (p=0.85). The mean ellipsoid zone width (EZW) loss ( +/- SD) was 2051 mu m ( +/- 1318) for patients in the TLOF, and 1314 mu m ( +/- 965) for MLOF. Only one patient in the TM group had EZW loss at presentation. There was considerable overlap in ERG findings, although the largest DA 10 ERG b-waves were associated with TLOF and the smallest with TM variants.Conclusions Patients with missense alterations had better BCVA and greater structural integrity. This is important for patient prognostication and counselling, as well as stratification for future gene therapy trials. Show less
Bos, T.A.; Piers, S.R.D.; Wessels, M.W.; Houweling, A.C.; Bökenkamp, R.; Bootsma, M.; ... ; European Reference Network Rare 2023
BackgroundThe arrhythmogenic cardiomyopathy (ACM) phenotype, with life-threatening ventricular arrhythmias and heart failure, varies according to genetic aetiology. We aimed to characterise the... Show moreBackgroundThe arrhythmogenic cardiomyopathy (ACM) phenotype, with life-threatening ventricular arrhythmias and heart failure, varies according to genetic aetiology. We aimed to characterise the phenotype associated with the variant c.1211dup (p.Val406Serfs*4) in the plakophilin-2 gene (PKP2) and compare it with previously reported Dutch PKP2 founder variants.MethodsClinical data were collected retrospectively from medical records of 106 PKP2 c.1211dup heterozygous carriers. Using data from the Netherlands ACM Registry, c.1211dup was compared with 3 other truncating PKP2 variants (c.235C > T (p.Arg79*), c.397C > T (p.Gln133*) and c.2489+1G > A (p.?)).ResultsOf the 106 carriers, 47 (44%) were diagnosed with ACM, at a mean age of 41 years. By the end of follow-up, 29 (27%) had experienced sustained ventricular arrhythmias and 12 (11%) had developed heart failure, with male carriers showing significantly higher risks than females on these endpoints (p < 0.05). Based on available cardiac magnetic resonance imaging and echocardiographic data, 46% of the carriers showed either right ventricular dilatation and/or dysfunction, whereas a substantial minority (37%) had some form of left ventricular involvement. Both geographical distribution of carriers and haplotype analysis suggested PKP2 c.1211dup to be a founder variant originating from the South-Western coast of the Netherlands. Finally, a Cox proportional hazards model suggested significant differences in ventricular arrhythmia-free survival between 4 PKP2 founder variants, including c.1211dup.ConclusionsThe PKP2 c.1211dup variant is a Dutch founder variant associated with a typical right-dominant ACM phenotype, but also left ventricular involvement, and a possibly more severe phenotype than other Dutch PKP2 founder variants. Show less
In the first part of this thesis we focus on the genetic determinants of lipid metabolism as atherogenic dyslipidemia is major component of cardiometabolic disease and consequently of CVD. In the... Show moreIn the first part of this thesis we focus on the genetic determinants of lipid metabolism as atherogenic dyslipidemia is major component of cardiometabolic disease and consequently of CVD. In the second part of the thesis, we study the age-related changes of cardiometabolic risk factors over the life course across four generations. In this thesis, we aimed to gain new insights into the underlying pathophysiology of cardiometabolic disease and the long-term and cumulative exposure of its risk factors over the life course, thereby facilitating the search for preventive and curative strategies of cardiometabolic disease. In the first part of this thesis, we focused on the genetic determinants of lipid metabolism during both fasting and postprandial states. In the second part, we studied the age-related changes of cardiometabolic risk factors, in particular of body weight, overweight and obesity, over the life course across four generations. An important finding of the thesis is that obesity has worsened in the younger generations, reaching almost double the prevalence of older generations. However, after midlife the levels of obesity levelled off, which could be a reason why the adverse shift in obesity was not associated with unfavourable changes in cardiometabolic risk factors. We also found out that some genes effect body weight differently at different ages, which suggests that gene-environment interactions play an important role in body weight and consequently in obesity. Show less
Kapteijn, M.Y.; Kaptein, F.H.J.; Stals, M.A.M.; Klaase, E.E.; Eijk, R. van; Ruano, D.; ... ; Garcia-Ortiz, I. 2023
Background and objectives: Patients with glioblastoma have a high risk of developing venous thromboembolism (VTE). However, the role of underlying genetic risk factors remains largely unknown.... Show moreBackground and objectives: Patients with glioblastoma have a high risk of developing venous thromboembolism (VTE). However, the role of underlying genetic risk factors remains largely unknown. Therefore, the aim of this study was to discover whether genetic aberrations in glioblastoma associate with VTE risk.Methods: In this cohort study, all consecutive patients diagnosed with glioblastoma in two Dutch hospitals be-tween February 2017 and August 2020 were included. Targeted DNA next-generation sequencing of all glio-blastomas was performed for diagnostic purposes and included mutational status of the genes ATRX, BRAF, CIC, FUBP1, H3F3A, IDH1, IDH2, PIK3CA, PTEN and TP53 and amplification/gain or deletion of BRAF, CDKN2A, EGFR, NOTCH1 and PTEN. The primary outcome was VTE within three months before glioblastoma diagnosis until two years after. Cumulative incidences were determined using competing risk analysis adjusting for mor-tality. Univariable Cox regression analysis was performed to determine hazard ratios.Results: From 324 patients with glioblastoma, 25 were diagnosed with VTE. Patients with a CDKN2A deletion had a 12-month adjusted cumulative incidence of VTE of 12.5 % (95%CI: 7.3-19.3) compared with 5.4 % (95%CI: 2.6-9.6) in patients with CDKN2A wildtype (p = 0.020), corresponding to a HR of 2.53 (95%CI: 1.12-5.73, p = 0.026). No significant associations were found between any of the other investigated genes and VTE.Conclusion: This study suggests a potential role for CDKN2A deletion in glioblastoma-related VTE. Therefore, once independently validated, CDKN2A mutational status may be a promising predictor to identify glioblastoma patients at high risk for VTE, who may benefit from thromboprophylaxis. Show less
This thesis addresses the repair of DNA double-strand breaks (DSBs) that arise in different contexts, both artificially inflicted DNA damage and spontaneously arising breaks. We have found that the... Show moreThis thesis addresses the repair of DNA double-strand breaks (DSBs) that arise in different contexts, both artificially inflicted DNA damage and spontaneously arising breaks. We have found that the (mutational) repair outcome of a DSB depends on the context in which it occurs. When cells are not replicating, DSBs are repaired via non-homologous end-joining (NHEJ). NHEJ efficiency can be affected by defective RNA processing. In replicating cells, the preferable mechanism for DSB repair is homologous recombination (HR). When canonical HR cannot be executed, because the repair template is not available (at G4-induced breaks, for example) or when not all HR factors are present (in BRCA1 deficient situations), alternative annealing is needed. This is carried out via polymerase theta-mediated end-joining (TMEJ), or when homologous nucleotides are available, via HELQ-1 mediated annealing of these homologous stretches. Finally, we have found that large tandem duplications can arise when break ends cannot anneal properly after the extension step in HR. Show less
Aims: In a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was... Show moreAims: In a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was conducted to test this pharmacogenetic hypothesis. Methods and results: dal-GenE was a double-blind trial in patients with an acute coronary syndrome within 1-3 months and the AA genotype at variant rs1967309 in the ADCY9 gene. A total of 6147 patients were randomly assigned to receive dalcetrapib 600 mg or placebo daily. The primary endpoint was the time from randomization to first occurrence of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke. After a median follow-up of 39.9 months, the primary endpoint occurred in 292 (9.5%) of 3071 patients in the dalcetrapib group and 327 (10.6%) of 3076 patients in the placebo group [hazard ratio 0.88; 95% confidence interval (CI) 0.75-1.03; P= 0.12]. The hazard ratios for the components of the primary endpoint were 0.79 (95% CI 0.65-0.96) for myocardial infarction, 0.92 (95% CI 0.64-1.33) for stroke, 1.21 (95% CI 0.91-1.60) for death from cardiovascular causes, and 2.33 (95% CI 0.60-9.02) for resuscitated cardiac arrest. In a pre-specified on-treatment sensitivity analysis, the primary endpoint event rate was 7.8% (236/3015) in the dalcetrapib group and 9.3% (282/3031) in the placebo group (hazard ratio 0.83; 95% CI 0.70-0.98). Conclusion: Dalcetrapib did not significantly reduce the risk of occurrence of the primary endpoint of ischaemic cardiovascular events at end of study. A new trial would be needed to test the pharmacogenetic hypothesis that dalcetrapib improves the prognosis of patients with the AA genotype.[GRAPHICS]. Show less
Pharmacogenomics (PGx) is widely recognized as an important aspect in personalizedMedicine. By analyzing and interpreting one’s genetic profile dose and drug adjustmentscan be made. In this way,... Show morePharmacogenomics (PGx) is widely recognized as an important aspect in personalizedMedicine. By analyzing and interpreting one’s genetic profile dose and drug adjustmentscan be made. In this way, one can strive to improve the safety and efficacy of drugtreatments. Nonetheless, not all genetic variability in drug response can be explained withcurrent PGx. In this thesis we explore the role of additional genetic factors which can explain this missing heritability. Firstly, rare and novel variants which are unaccounted for in routine PGx panels might play a role. Secondly, the complexity of pharmacogenes can result in an inability tounravel the genetic make-up of these genes. Thirdly, haplotype phasing is generally nottaken into account in PGx. Fourthly, all genetic variants are currently summarized intoone of four metabolic categories: poor metabolizers (PM), intermediate metabolizers(IM), normal metabolizers (NM) (previously EM) and ultra-rapid metabolizers (UM).However, enzyme activity is not a matter of ‘on’ or ‘off ’, but is more of a continuous scale.Finally, the effect of a genetic variant on drug metabolism shows substrate specific effects.This substrate specificity can result in erroneous extrapolation of variant effects to theentire range of substrates. The development of novel technologies to determine one’sgenetic make-up is evolving rapidly, thereby providing opportunities for the field of PGxto address these issues. In this thesis we show that by using long-read sequencing or trio-based sequencing more information can be obtained which can lead to a better understanding of the (rare) variants and can help with haplotype phasing. Moreover, we have shown that by combining long-read sequencing with artificial intelligence a substantial increase in explained variability can be achieved. Show less
Objective: To evaluate the long-term ipsi- and contralateral hearing of patients with a unilateral enlarged vestibular aqueduct (EVA). Study design: Multicenter retrospective cohort study. Setting:... Show moreObjective: To evaluate the long-term ipsi- and contralateral hearing of patients with a unilateral enlarged vestibular aqueduct (EVA). Study design: Multicenter retrospective cohort study. Setting: Three tertiary otology and audiology referral centers. Patients and diagnostic interventions: A total of 34 children with a unilateral enlarged vestibular aqueduct as identified on CT and/or MR imaging were evaluated with pure tone and speech perception audiometry. Mean outcome measures: Radiologic measurements of the vestibular aqueduct, ipsi- and contralateral hearing loss, ipsi- and contralateral hearing loss progression over time and DNA test results. Results: All patients in this cohort with unilateral EVA presented with hearing loss. Hearing loss was progressive in 38% of the ipsilateral ears. In 29% of the children, hearing loss was also found in the contralateral ear without EVA. In 90%, the contralateral hearing was stable, with a mean follow up of 4.2 years. We found a significant correlation between the severity of the hearing loss and the size of the EVA. A genetic diagnosis associated with EVA and/or SNHL was found in only 7%. Conclusion: About a third of the children with unilateral EVA are at risk of developing hearing loss in the contralateral ear. This indicates that at least in some patients with a unilateral EVA, a bilateral pathogenic process underlies the hearing loss, in contrary to what the imaging results suggest. These findings are important for counseling of EVA patients and their parents and have implications for follow up. Show less
Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure.Methods and results The consortium... Show moreAims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure.Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model.Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction. Show less
Abu Hamdeh, S.; Tenovuo, O.; Peul, W.; Marklund, N. 2021
Background To date, there is neither any pharmacological treatment with efficacy in traumatic brain injury (TBI) nor any method to halt the disease progress. This is due to an incomplete... Show moreBackground To date, there is neither any pharmacological treatment with efficacy in traumatic brain injury (TBI) nor any method to halt the disease progress. This is due to an incomplete understanding of the vast complexity of the biological cascades and failure to appreciate the diversity of secondary injury mechanisms in TBI. In recent years, techniques for high-throughput characterization and quantification of biological molecules that include genomics, proteomics, and metabolomics have evolved and referred to as omics. Methods In this narrative review, we highlight how omics technology can be applied to potentiate diagnostics and prognostication as well as to advance our understanding of injury mechanisms in TBI. Results The omics platforms provide possibilities to study function, dynamics, and alterations of molecular pathways of normal and TBI disease states. Through advanced bioinformatics, large datasets of molecular information from small biological samples can be analyzed in detail and provide valuable knowledge of pathophysiological mechanisms, to include in prognostic modeling when connected to clinically relevant data. In such a complex disease as TBI, omics enables broad categories of studies from gene compositions associated with susceptibility to secondary injury or poor outcome, to potential alterations in metabolites following TBI. Conclusion The field of omics in TBI research is rapidly evolving. The recent data and novel methods reviewed herein may form the basis for improved precision medicine approaches, development of pharmacological approaches, and individualization of therapeutic efforts by implementing mathematical "big data" predictive modeling in the near future. Show less
This thesis aimed to provide insight in the etiology, predictors, and outcomes of aggression and antisocial behavior in children and adolescents. The first part of this thesis focused on more... Show moreThis thesis aimed to provide insight in the etiology, predictors, and outcomes of aggression and antisocial behavior in children and adolescents. The first part of this thesis focused on more conventional prediction of outcomes and continuation of aggression and antisocial behavior on the basis of the following constructs: parental psychopathology (Chapter 2), anxiety and depression (Chapter 3), and Oppositional Defiant Disorder symptoms (Chapter 4). Next, the second part of this thesis focused on novel biological markers of aggression, consisting of a review on the genetics of aggression (Chapter 5) and an empirical study on the metabolomics of aggression (Chapter 6). Chapter 7 provides a summary and general discussion of the thesis' contents. Show less
Background and Aims: Inflammatory bowel disease [IBD] phenotypes are very heterogeneous between patients, and current clinical and molecular classifications do not accurately predict the course... Show moreBackground and Aims: Inflammatory bowel disease [IBD] phenotypes are very heterogeneous between patients, and current clinical and molecular classifications do not accurately predict the course that IBD will take over time. Genetic determinants of disease phenotypes remain largely unknown but could aid drug development and allow for personalised management. We used genetic risk scores [GRS] to disentangle the genetic contributions to IBD phenotypes.Methods: Clinical characteristics and imputed genome-wide genetic array data of patients with IBD were obtained from two independent cohorts [cohort A, n= 1097; cohort B, n= 2156]. Genetic risk scoring [GRS] was used to assess genetic aetiology shared across traits and IBD phenotypes. Significant GRS-phenotype (false-discovery rate [FDR] corrected p<0.05) associations identified in cohort A were put forward for replication in cohort B.Results: Crohn's disease [CD] GRS were associated with fibrostenotic CD [R-2= 7.4%, FDR = 0.02] and ileocaecal resection [R-2 = 4.1%, FDR = 1.6E-03], and this remained significant after correcting for previously identified clinical and genetic risk factors. Ulcerative colitis [UC] GRS [R-2 = 7.1%, FDR = 0.02] and primary sclerosing cholangitis [PSC] GRS [R-2 . 3.6%, FDR = 0.03] were associated with colonic CD, and these two associations were largely driven by genetic variation in MHC. We also observed pleiotropy between PSC genetic risk and smoking behaviour [R-2 = 1.7%, FDR = 0.04].Conclusions: Patients with a higher genetic burden of CD are more likely to develop fibrostenotic disease and undergo ileocaecal resection, whereas colonic CD shares genetic aetiology with PSC and UC that is largely driven by variation in MHC. These results further our understanding of specific IBD phenotypes. Show less
Ghatan, S.; Costantini, A.; Li, R.; Bruin, C. de; Appelman-Dijkstra, N.M.; Winter, E.M.; ... ; Medina-Gomez, C. 2021
Purpose of Review Fractures are frequently encountered in paediatric practice. Although recurrent fractures in children usually unveil a monogenic syndrome, paediatric fracture risk could be shaped... Show morePurpose of Review Fractures are frequently encountered in paediatric practice. Although recurrent fractures in children usually unveil a monogenic syndrome, paediatric fracture risk could be shaped by the individual genetic background influencing the acquisition of bone mineral density, and therefore, the skeletal fragility as shown in adults. Here, we examine paediatric fractures from the perspective of monogenic and complex trait genetics.Recent Findings Large-scale genome-wide studies in children have identified similar to 44 genetic loci associated with fracture or bone traits whereas similar to 35 monogenic diseases characterized by paediatric fractures have been described.Genetic variation can predispose to paediatric fractures through monogenic risk variants with a large effect and polygenic risk involving many variants of small effects. Studying genetic factors influencing peak bone attainment might help in identifying individuals at higher risk of developing early-onset osteoporosis and discovering drug targets to be used as bone restorative pharmacotherapies to prevent, or even reverse, bone loss later in life. Show less
Boer, I. de; Terwindt, G.M.; Maagdenberg, A.M.J.M. van den 2020
Migraine is a common brain disorder with a large genetic component. Of the two main migraine types, migraine with aura and migraine without aura, the genetic underpinning in the former is least... Show moreMigraine is a common brain disorder with a large genetic component. Of the two main migraine types, migraine with aura and migraine without aura, the genetic underpinning in the former is least understood. Given the evidence from epidemiological studies in cohorts and families that the genetic contribution is highest in migraine with aura, this seems paradoxical. Various genetic approaches have been applied to identify genetic factors that confer risk for migraine. Initially, so-called candidate gene associations studies (CGAS) have been performed that test DNA variants in genes prioritized based on presumed a priori knowledge of migraine pathophysiology. More recently, genome-wide association studies (GWAS) tested variants in any gene in an hypothesis-free manner. Whereas GWAS in migraine without aura, or the more general diagnosis migraine have already identified dozens of gene variants, the specific hunt for gene variants in migraine with aura has been disappointing. The only GWAS specifically investigating migraine with aura yielded only one single associated single nucleotide polymorphism (SNP), near MTDH and PGCP, with genome-wide significance. However, interrogation of all genotyped SNPs, so beyond this one significant hit, was more successful and led to the notion that migraine with aura and migraine without aura are genetically more alike than different. Until now, most relevant genetic discoveries related to migraine with aura came from investigating monogenetic syndromes with migraine aura as a prominent phenotype (i.e. FHM, CADASIL and FASPS). This review will highlight the genetic findings relevant to migraine with aura. Show less
This thesis describes the genetic and prokaryotic diversity of giant barrel sponges. Although it was originally believed that the giant barrel sponges in the AtlanticOcean and the Indo-Pacific... Show moreThis thesis describes the genetic and prokaryotic diversity of giant barrel sponges. Although it was originally believed that the giant barrel sponges in the AtlanticOcean and the Indo-Pacific Ocean were two different species, our analyses showed thatthere are several species in both ocean basins. Even more remarkable, is that each species is most closely related to a species in the other ocean basin. According to our analysis, there are threegiant barrel sponge species in the Atlantic Ocean, and, at least, six in the Indo-Pacific Ocean. Sponges house a large and diverse community of microorganisms. It is generally believed thatthese microorganisms play a central role in the physiological processes in the host. It appears that the region in which a giant barrel sponge occursmainly determines the composition of their microbial community. However, if you lookat a smaller scale within a region, for example within one reef or around an island suchas Curaçao, it appears that not only is the geographical location important, but the hostspecies to which an individual belongs also plays an important role. Show less
Houwink, E.J.F.; Hortensius, O.R.; K. van boven; Sollie, A.; Numans, M.E. 2019
This thesis examines how both genetic and more conventional epidemiological endeavors may complement research into effects of statin therapy. These include a pharmacogenetic GWAS meta-analysis... Show moreThis thesis examines how both genetic and more conventional epidemiological endeavors may complement research into effects of statin therapy. These include a pharmacogenetic GWAS meta-analysis on statin-induced HDL-C response by the Genomic Investigation of consortium, which identified CETP as a loci of interest, and two-sample Mendelian randomization studies utilizing summary level data from the GIST and other GWAS consortia on fasted blood lipids and type 2 diabetes. We additionally examine the issue of survival bias in Mendelian randomization studies. Finally, we show that intra-individual lipid variability associates with worse neurocognitive outcomes in older individuals at high risk for vascular disease, discuss its interplay with lipid-lowering treatment, and describe the literature regarding genetic factors of possible interest. Show less
Streptomyces are multicellular, Gram-positive bacteria in the phylum of actinobacteria which produce a high amount of bioactive natural products of which the expression is tightly coordinated with... Show moreStreptomyces are multicellular, Gram-positive bacteria in the phylum of actinobacteria which produce a high amount of bioactive natural products of which the expression is tightly coordinated with the life cycle. This thesis shows the identification of S. roseifaciens, a novel species with an uncommon, verticillate spore morphology and a unique household of SsgA-like proteins. Analyses of the peptidoglycan composition show that S. coelicolor show a pattern of 3-3 cross-linking befitting a tip-growing organism and change in composition between vegetative mycelium and spores. Kitasatosporae carry meso-DAP in the peptidoglycan of vegetative mycelium and LL-DAP in the peptidoglycan of spores. In line with this difference, the peptidoglycan architecture of these two growth stages undergoes such radical changes that they would seem to be from different species. S. coelicolor is naturally vancomycin resistant, but the addition of D-alanine and disruption in a single gene increases vancomycin sensitivity by a thousandfold. A knockout mutant of the alanine racemase, alr, requires exogenous addition of D-alanine. The Alr crystal structure of S. coelicolor and the D-cycloserine producer S. lavendulae were compared as to look for possible mechanisms for D-cycloserine resistance. Show less
