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HRAS belongs to the RAS genes superfamily. RAS genes are important players in several human tumors and the single-nucleotide polymorphism rs12628 has been shown to contribute to the risk of bladder, colon, gastrointestinal, oral, and thyroid carcinoma. We hypothesized that this SNP may affect the risk of cutaneous melanoma as well. HRAS gene contains a polymorphic region (rs112587690), a repeated hexanucleotide -GGGCCT- located in intron 1. Three alleles of this region, P1, P2, and P3, have been identified that contain two, three, and four repeats of the hexanucleotide, respectively. We investigated the clinical impact of these polymorphisms in a case–control study. A total of 141 melanoma patients and 118 healthy donors from the North America Caucasian population were screened for rs12628 and rs112587690 polymorphisms. Genotypes were assessed by capillary sequencing or fragment analysis, respectively, and rs12628 CC and rs112587690 P1P1 genotypes significantly associated with increased melanoma risk (OR = 3.83, p = 0.003; OR = 11.3, p = 0.033, respectively), while rs112587690 P1P3 frequency resulted significantly higher in the control group (OR = 0.5, p = 0.017). These results suggest that rs12628 C homozygosis may be considered a potential risk factor for melanoma development in the North American population possibly through the linkage to rs112587690.
A bis(squaraine) dye equipped with alkyl and oligoethyleneglycol chains was synthesized by connecting two dicyanomethylene substituted squaraine dyes with a phenylene spacer unit. The aggregation behavior of this bis(squaraine) was investigated in non-polar toluene/tetrachloroethane (98:2) solvent mixture, which revealed competing cooperative self-assembly pathways into two supramolecular polymorphs with entirely different packing structures and UV/Vis/NIR absorption properties. The self-assembly pathway can be controlled by the cooling rate from a heated solution of the monomers. For both polymorphs, quasi-equilibrium conditions between monomers and the respective aggregates can be established to derive thermodynamic parameters and insights into the self-assembly mechanisms. AFM measurements revealed a nanosheet structure with a height of 2 nm for the thermodynamically more stable polymorph and a tubular nanorod structure with a helical pitch of 13 nm and a diameter of 5 nm for the kinetically favored polymorph. Together with wide angle X-ray scattering measurements, packing models were derived: the thermodynamic polymorph consists of brick-work type nanosheets that exhibit red-shifted absorption bands as typical for J-aggregates, while the nanorod polymorph consists of eight supramolecular polymer strands of the bis(squaraine) intertwined to form a chimney-type tubular structure. The absorption of this aggregate covers a large spectral range from 550 to 875 nm, which cannot be rationalized by the conventional exciton theory. By applying the Essential States Model and considering intermolecular charge transfer, the aggregate spectrum was adequately reproduced, revealing that the broad absorption spectrum is due to pronounced donor-acceptor overlap within the bis(squaraine) nanorods. The latter is also responsible for the pronounced bathochromic shift observed for the nanosheet structure as a result of the slip-stacked arranged squaraine chromophores.
In mehreren klinischen und außerklinischen Populationen werden die allelischen Variationen der Monoaminoxidase-A mit aggressivem, ängstlichem und abhängigem Verhalten in Verbindung gebracht. In unserer Studie haben wir den Einfluss von Allelvariationen der Monoaminoxidase-A auf aggressivitätsassoziierte Persönlichkeitsmerkmale und die Erkrankungswahrscheinlichkeit für Probanden mit Persönlichkeitsstörungen untersucht. Die Hypothese ist, dass ein geschlechtsspezifischer Zusammenhang zwischen der Allelvariation mit konsekutiv geringerer Enzymaktivität und Cluster-B-Persönlichkeitsstörungen nach DSM-VI, antisozialen Persönlichkeitsstörungen, sowie den Persönlichkeitsmerkmalen „Suche nach neuen Erfahrungen“ (TPQ), Neurotizismus, Verträglichkeit und Gewissenhaftigkeit bestehen könnte (NEO-PI-R). Der Genotyp des MAOA-Polymorphismus MAO-LPR wurde an 566 Patienten mit Persönlichkeitsstörungen und an 281 Probanden einer gesunden Kontrollgruppe untersucht. Der MAOA-LPR-Genotyp zeigt eine signifikante Korrelation mit Cluster-B-Persönlichkeitsstörungen nach DSM-IV (chi2=7.77, p=0.005, df=1). Dabei sind 26% der Probanden mit einer Persönlichkeitsstörung aus dem B-Cluster homo- oder hemizygot für den MAOA-Genotyp, der zur Ausprägung einer Variante mit geringer Enzymaktivität führt. Im Vergleich weisen dagegen nur 16.4% der Probanden aus der Kontrollgruppe diesen Genotyp auf. Zusammenhänge zwischen Allelvariationen der MAOA-Aktivität und Persönlichkeitsmerkmalen, die mit impulsivem und aggressivem Verhalten in Verbindung gebracht werden, erweisen sich als unbeständig. Eine Korrelation mit Cluster-C-Persönlichkeitsstörungen kann nicht nachgewiesen werden. Unsere Ergebnisse zeigen einen Zusammenhang zwischen Hemi- und Homzygotität der MAOA-LPR-Variante mit konsekutiv geringer Enzymaktivität und Cluster-B-Persönlichkeitsstörungen. Für den Einfluss der mit geringerer MAOA-Aktivität einhergehenden Variationen des Genotyps auf Aggression, Impulsivität und gewalttätiges Verhalten beim Menschen gibt es Hinweise (Shih et al. 1999). Immer häufiger werden Beweise für ein Zusammenwirken von genetischen Determinanten und Umwelteinflüssen gefunden. Unsere Erkenntnisse unterstützen weiterhin die These, dass die genetische Determination der MAOA-Aktivität auch in bestimmtem Maße zur Ausprägung des Gleichgewichts zwischen hyper- (impulsiv-aggressiv) und hyporeaktivem (ängstlich-depressiv) Verhalten beiträgt.
Chronisch nierenkranke Menschen weisen im Vergleich zur gesunden Allgemeinbevölkerung eine stark erhöhte Prävalenz für kardiovaskuläre Erkrankungen auf. Die jährliche kardiovaskuläre Mortalität ist nach statistischer Korrektur des Mortalitätsrisikos für Alter, Geschlecht und Diabetes mellitus um 10 bis 20fach höher als in der gesunden Bevölkerung. Chronische Inflammationsprozesse spielen eine zentrale Rolle in der Atherogenese und stehen in enger Assoziation zum erhöhten kardiovaskulären Risiko sowie zur erhöhten kardiovaskulären Mortalität. Akutphaseproteinen - insbesondere dem C-reaktiven Protein - kommen als Marker chronischer Inflammationsprozesse in der Prädiktion kardiovaskulärer Ereignisse eine besondere Bedeutung zu. Bisherige Studien führen zum Ergebnis einer 35 – 40 %igen Heritabilität des CRP-Baselinespiegels und weisen Interleukin-6 als zentralen Regulator der CRP-Genexpression bzw. der Akutphase-Reaktion aus. Unter Berücksichtigung der genannten wissenschaftlichen Erkenntnisse resultierte die Aufgabenstellung dieser Arbeit in der Untersuchung des Interleukin-6 –174 G->C Poly-morphismus hinsichtlich seines vorstellbaren Einflusses auf die Akutphase-Reaktion in einem chronisch nierenkranken, nicht dialysepflichtigen Patientenkollektiv (n = 224). Die Genotypisierung erfolgte durch Heteroduplexanalyse. In der Zusammenschau lassen die erzielten Resultate aus der Sicht eines kodominanten bzw. dominant-rezessiven Modells den Schluss zu, dass der Interleukin-6 –174 G->C Polymorphismus keinen signifikanten Einfluss auf die Modulation der Akutphase-Reaktion sowie auf ein erhöhtes kardiovaskuläres Risiko nimmt. Ein signifikanter Zusammenhang konnte allerdings zwischen bestehender koronarer Herzkrankheit bzw. peripherer arterieller Verschlusskrankheit und erhöhten CRP-, Fibrinogen-, Kreatinin-, Harnstoff-Spiegeln bzw. erniedrigter Kreatininclearance nachgewiesen werden.
Many polymorphisms are linked to alternative reproductive strategies. In animals, this is particularly common in males. Ant queens are an important exception. The case of ant queen size dimorphisms has not been studied in sufficient detail, and thus this thesis aimed at elucidating causes and consequences of the different size of small (microgynous) and large (macrogynous)ant queens using the North American ant species Leptothorax rugatulus as a model system. Employing neutral genetic markers, no evidence for a taxonomically relevant separation of the gene pools of macrogynes and microgynes was found. Queens in polygynous colonies were highly related to each other, supporting the hypothesis that colonies with more than one queen commonly arise by secondary polygyny, i.e. by the adoption of daughter queens into their natal colonies. These results and conclusions are also true for the newly discovered queen size polymorphism in Leptothorax cf. andrei. Several lines of evidence favor the view that macrogynes predominantly found their colonies independently, while microgynes are specialized for dependent colony founding by readoption. Under natural conditions, mother and daughter size are highly correlated and this is also true for laboratory colonies. However, the size of developing queens is influenced by queens present in the colony. Comparing populations across the distribution range, it turns out that queen morphology (head width and ovariole number) is more differentiated among populations than worker morphology (coloration, multivariate size and shape), colony characteristics (queen and worker number per colony) or neutral genetic variation. Northern and southern populations differed consistently which indicates the possibility of two different species. The queen size dimorphism in L. rugatulus did neither influence the sex ratio produced by a colony, nor its ratio of workers to gynes. However, the sex ratio covaried strongly across populations with the average number of queens per colony in accordance with sex ratio theory. At the colony level, sex ratio could not be explained by current theory and a hypothesis at the colony-level was suggested. Furthermore, queen body size has no significant influence on the amount of reproductive skew among queens. Generally, the skew in L. rugatulus is low, and supports incomplete control models, rather than the classic skew models. In eight of fourteen mixed or microgynous colonies, the relative contributions of individual queens to workers, gynes and males were significantly different. This was mainly due to the fact that relative body size was negatively correlated with the ratio of gynes to workers produced. This supports the kin conflict over caste determination hypothesis which views microgyny as a selfish reproductive tactic.
Association of Autoimmune Addison's Disease with Alleles of STAT4 and GATA3 in European Cohorts
(2014)
Background: Gene variants known to contribute to Autoimmune Addison's disease (AAD) susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for.
Aim: To investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts.
Methods: A sequential association study design was employed with genotyping using Sequenom iPlex technology. In phase one, 85 SNPs in 19 genes were genotyped in UK and Norwegian AAD cohorts (691 AAD, 715 controls). In phase two, 21 SNPs in 11 genes were genotyped in German, Swedish, Italian and Polish cohorts (1264 AAD, 1221 controls). In phase three, to explore association of GATA3 polymorphisms with AAD and to determine if this association extended to other autoimmune conditions, 15 SNPs in GATA3 were studied in UK and Norwegian AAD cohorts, 1195 type 1 diabetes patients from Norway, 650 rheumatoid arthritis patients from New Zealand and in 283 UK Graves' disease patients. Meta-analysis was used to compare genotype frequencies between the participating centres, allowing for heterogeneity.
Results: We report significant association with alleles of two STAT4 markers in AAD cohorts (rs4274624: P = 0.00016; rs10931481: P = 0.0007). In addition, nominal association of AAD with alleles at GATA3 was found in 3 patient cohorts and supported by meta-analysis. Association of AAD with CYP27B1 alleles was also confirmed, which replicates previous published data. Finally, nominal association was found at SNPs in both the NF-kappa B1 and IL23A genes in the UK and Italian cohorts respectively.
Conclusions: Variants in the STAT4 gene, previously associated with other autoimmune conditions, confer susceptibility to AAD. Additionally, we report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis.
Neuro-immune alterations in the peripheral and central nervous system play a role in the pathophysiology of chronic pain, and non-coding RNAs – and microRNAs (miRNAs) in particular – regulate both immune and neuronal processes. Specifically, miRNAs control macromolecular complexes in neurons, glia and immune cells and regulate signals used for neuro-immune communication in the pain pathway. Therefore, miRNAs may be hypothesized as critically important master switches modulating chronic pain. In particular, understanding the concerted function of miRNA in the regulation of nociception and endogenous analgesia and defining the importance of miRNAs in the circuitries and cognitive, emotional and behavioral components involved in pain is expected to shed new light on the enigmatic pathophysiology of neuropathic pain, migraine and complex regional pain syndrome. Specific miRNAs may evolve as new druggable molecular targets for pain prevention and relief. Furthermore, predisposing miRNA expression patterns and inter-individual variations and polymorphisms in miRNAs and/or their binding sites may serve as biomarkers for pain and help to predict individual risks for certain types of pain and responsiveness to analgesic drugs. miRNA-based diagnostics are expected to develop into hands-on tools that allow better patient stratification, improved mechanism-based treatment, and targeted prevention strategies for high risk individuals.
The olfactory system of leafcutting ants: neuroanatomy and the correlation to social organization
(2009)
In leaf-cutting ants (genera Atta and Acromyrmex), the worker caste exhibits a pronounced size-polymorphism, and division of labor is largely dependent on worker size (alloethism). Behavioral studies have shown a rich diversity of olfactory-guided behaviors, and the olfactory system seems to be highly developed and very sensitive. To allow fine-tuned behavioral responses to different tasks, adaptations within the olfactory system of different sized workers are expected. In a recent study, two different phenotypes of the antennal lobe of Atta vollenweideri workers were found: MG- and RG-phenotype (with and without a macroglomerulus, MG). The existence of the macroglomerulus is correlated to the body size of workers, with small workers showing the RG-phenotype and large workers showing the MG-phenotype. In the MG, the information about the releaser component of the trail-pheromone is processed. In the first part of my PhD-project, I focus on quantifying behavioral differences between different sized workers in Atta vollenweideri. The study analyzes the trail following behavior; which can be generally performed by all workers. An artificial trail consisting of the releaser component of the trail-pheromone in decreasing concentration was used to test the trail-following performance of individual workers. The trail-following performance of the polymorphic workers is depended of the existence of the MG in the antennal lobe. Workers possessing the MG-phenotype were significantly better in following a decreasing trail then workers showing the RG-phenotype. In the second part I address the question if there are more structural differences, besides the MG, in the olfactory system of different sized workers. Therefore I analyze whether the glomerular numbers are related to worker size. The antennal lobes of small workers contain ~390 glomeruli (low-number; LN-phenotype), and in large workers I found a substantially higher number of ~440 glomeruli (high-number; HN-phenotype). All LN-phenotype workers and some of the small HN-phenotype workers do not possess an MG (LN-RG-phenotype and HN-RG-phenotype) at all, whereas the remaining majority of HN-phenotype workers do possess an MG (HN-MG-phenotype). Mass-stainings of antennal olfactory receptor neurons revealed that the sensory tracts divide the antennal lobe into six clusters of glomeruli (T1-T6). In the T4-cluster ~50 glomeruli are missing in the LN-phenotype workers. Selective staining of single sensilla and their associated receptor neurons showed that T4-glomeruli are innervated by receptor neurons from the main type of olfactory sensilla, the Sensilla trichodea curvata which are also projecting to glomeruli in all other clusters. The other type of olfactory sensilla, the Sensilla basiconica, exclusively innervates T6-glomeruli. Quantitative analyses revealed a correlation between the number of Sensilla basiconica and the volume of T6 glomeruli in different sized workers. The results of both behavioral and neuroanatomical studies in Atta vollenweideri suggest that developmental plasticity of antennal-lobe phenotypes promotes differences in olfactory-guided behavior which may underlie task specialization within ant colonies. The last part of my project focuses on the evolutionary origin of the macroglomerulus and the number of glomeruli in the antennal lobe. I compared the number, volumes and position of the glomeruli of the antennal lobe of 25 different species from all three major Attini groups (lower, higher and leaf-cutting Attini). The antennal lobes of all investigated Attini comprise a high number of glomeruli (257-630). The highest number was found in Apterostigma cf. mayri. This species is at a basal position within the Attini phylogeny, and a high number of glomeruli might have been advantageous in the evolution of the advanced olfactory systems of this Taxa. The macroglomerulus can be found in all investigated leaf-cutting Attini, but in none of the lower and higher Attini species. It is found only in large workers, and is located close to the entrance of the antennal nerve in all investigated species. The results indicate that the presence of a macroglomerulus in large workers of leaf-cutting Attini is a derived overexpression of a trait in the polymorphic leaf-cutting species. It presumably represents an olfactory adaptation to elaborate foraging and mass recruitment systems, and adds to the complexity of division of labor and social organization known for this group.
Background
Although 5-HTTLPR has been shown to influence the risk of life stress-induced depression in the majority of studies, others have produced contradictory results, possibly due to weak effects and/or sample heterogeneity.
Methods
In the present study we investigated how age, type and intensity of life-stressors modulate the effect of 5-HTTLPR on depression and anxiety in a European population cohort of over 2300 subjects. Recent negative life events (RLE), childhood adversity (CHA), lifetime depression, Brief Symptoms Inventory (BSI) depression and anxiety scores were determined in each subject. Besides traditional statistical analysis we calculated Bayesian effect strength and relevance of 5-HTTLPR genotypes in specified models.
Results
The short (s) low expressing allele showed association with increased risk of depression related phenotypes, but all nominally significant effects would turn to non-significant after correction for multiple testing in the traditional analysis. Bayesian effect strength and relevance analysis, however, confirmed the role of 5-HTTLPR. Regarding current (BSI) and lifetime depression 5-HTTLPR-by-RLE interactions were confirmed. Main effect, with other words direct association, was supported with BSI anxiety. With more frequent RLE the prevalence or symptoms of depression increased in ss carriers. Although CHA failed to show an interaction with 5-HTTLPR, in young subjects CHA sensitized towards the depression promoting effect of even mild RLE. Furthermore, the direct association of anxiety with the s allele was driven by young (\(\leq\)30) individuals.
Limitations
Our study is cross-sectional and applies self-report questionnaires.
Conclusions
Albeit 5-HTTLPR has only weak/moderate effects, the s allele is directly associated with anxiety and modulates development of depression in homogeneous subgroups.
Mit Hilfe von Assoziationsstudien wurde im Rahmen der vorliegenden Arbeit versucht, die Rolle verschiedener Kandidatengene (vesikulärer Monoamintransporter VMAT2, Dopamintransporter DAT, Brain Derived Neurotrophic Factor BDNF) bei Persönlichkeitsmerkmalen und psychiatrischen Erkrankungen näher zu beleuchten. C. Robert Cloninger postuliert in seiner biosozialen Persönlichkeitstheorie eine genetische Grundlage von Temperamentfaktoren, die im dopaminergen, serotoninergen und noradrenergen Transmittersystem zu finden sei. Im Rahmen der vorliegenden Arbeit wurde daher untersucht, ob Gene in Schlüsselpositionen monoaminerger Transmittersysteme - das Gen des vesikulären Monoamintransporters und des Dopamintransporters - die Ausprägung von Persönlichkeitsfaktoren beeinflussen. Außerdem wurde nach einer Assoziation von Genvarianten des vesikulären Monoamintransporters mit suizidalem Verhalten und der Panikstörung geforscht. Weiterhin flossen Ergebnisse zum Dopaminrezeptor D4 und zum Brain Derived Neurotrophic Factor ein. In dieser Arbeit konnte ein Zusammenwirken von Genvarianten des vesikulären Monoamintransporters und des Dopaminrezeptors D4 auf die Ausprägung der Persönlichkeitsdimension TPQ-Novelty Seeking (F2,244 = 3,851, p = 0,023) gezeigt werden. Auch ergab sich, dass die Gene des Dopamintransporters und des Brain Derived Neurotrophic Factors die Dimensionen TPQ-Harm Avoidance (F1,266 = 6,868, p = 0,009) und NEO-PI-R-Neurotizismus (F1,266 = 6,027, p = 0,015) modulieren. Letztgenannte Ergebnisse weisen deutlich darauf hin, dass mehrere Gene bei der Ausprägung von Persönlichkeitsdimensionen interagieren, die mit ängstlichem und depressivem Verhalten in Verbindung stehen. Da Persönlichkeitszüge die Entstehung von suizidalem Verhalten und die Entwicklung von Angsterkrankungen beeinflussen und weil diese Verhaltensabnormitäten entscheidend durch monoaminerge Prozesse modifiziert werden, wurde auch nach einer Assoziation von Varianten des vesikulären Monoamintransporters mit dem Suizid und der Panikstörung gesucht. In beiden Fällen fielen die Ergebnisse negativ aus. Eine mögliche Erklärung dafür ist, dass der vesikuläre Monoamintransporter ursächlich nicht in Zusammenhang mit suizidalem Verhalten und der Panikstörung steht. Möglicherweise spielt jedoch nur der hier untersuchte allelische Marker keine Rolle. Andere polymorphe Regionen dieses Gens könnten dagegen die Entwicklung solcher Verhaltensabnormitäten begünstigen. Auch können Einschränkungen, die durch das Studiendesign bedingt waren, für die hier beschriebenen Resultate verantwortlich sein. Die Bereitschaft zu suizidalem Verhalten wird - nach zahlreichen Studienergebnissen - ganz entscheidend von Prozessen im serotoninergen System geprägt. Bei der Ausbildung der Panikstörung wirken verschiedene monoaminerge Neurotransmitter, wie Noradrenalin, Dopamin und Serotonin zusammen. So scheint der vesikuläre Monoamintransporter, der zu all diesen Überträgerstoffen eine Affinität besitzt, nach wie vor in diesem Zusammenhang ein interessantes Kandidatengen. Zukünftig sind Untersuchungen in Form von familienbasierten Studien oder Zwillings-Adoptionsstudien nötig, um weiterführende Erkenntnisse zur genetischen Grundlage von suizidalem Verhalten und der Panikstörung zu gewinnen. TPQ: Tridimensional Personality Questionnaire; Cloninger, 1987 NEO-PI-R: NEO-Persönlichkeitsinventar, revidiert; Costa, McCrae, 1992