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- Kindberg, Elin, 1981-
(författare)
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Host genetic risk factors to viral diseases - a double-edged sword : Studies of norovirus and tick-borne encephalitis virus
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- It is today well known that the outcome of a certain infection depends on factors of both the host and the pathogen. Studies of host genetic susceptibility to infectious diseases aim to increase the understanding of why some individuals are more susceptible than others, to a certain infection. Knowledge of genetic susceptibility to a viral disease may be used in development of new therapeutic means, and also to recognize individuals who are at increased risk of severe symptoms if infected with a pathogen. It seems however that a risk factor for one disease may play a protective role in another situation; like a double-edged sword.In this thesis I have studied genetic factors affecting susceptibility to norovirus (NoV) and factors affecting the risk of developing tick-borne encephalitis (TBE) after infection with TBE virus (TBEV). NoV is the cause of the “winter vomiting disease”, affecting millions of people every year, and causing up to 200,000 fatalities among children in developing countries, each year. It is today recognized that the secretor status of an individual, i.e. the ability to express ABO blood groups and related antigens, in secretions and on mucosa, affect the risk of being infected by NoV. By studying authentic NoV outbreaks in Denmark, Spain and Sweden and by comparing the secretor status of affected and unaffected individuals we were able to confirm that secretor status have indeed great impact on susceptibility to some NoV strains, but also that there are strains circulating, which infect individuals regardless of secretor status.TBEV is endemic in many parts of Europe and Asia but studies have shown that 70-95% of all infections are asymptomatic or sub-clinical. Some individuals do however develop TBE, a severe disease including meningitis or encephalitis with or without myelitis. Also, many patients suffer from long-time sequelae and TBEV infections may in worst case be fatal. The reason for difference in disease outcome is not known and we have chosen to study if genetic factors affecting the immune response may play a role in disease outcome. To do this we used a prospectively collected Lithuanian material with samples from patients with TBE, AME (aseptic meningoencephalitis) and matched healthy controls. So far we have found that a deletion in chemokine receptor 5 (CCR5), a gene encoding a receptor involved in cell migration, is a risk factor for developing disease. We have also data showing that toll-like receptor 3 (TLR3), a receptor recognizing double stranded RNA (dsRNA), which is a product of TBEV replication, may instead of being protective increase the risk of TBE.
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| 2. |
- Tillmar, Andreas, 1980-
(författare)
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Populations and Statistics in Forensic Genetics
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- DNA has become a powerful forensic tool for solving cases such as linking a suspect to a crime scene, resolving biological relationship issues and identifying disaster victims. Traditionally, DNA investigations mainly involve two steps; the establishment of DNA profiles from biological samples and the interpreta-tion of the evidential weight given by theses DNA profiles. This thesis deals with the latter, with focus on models for assessing the weight of evidence and the study of parameters affecting these probability figures.In order to calculate the correct representative weight of DNA evidence, prior knowledge about the DNA markers for a relevant population sample is required. Important properties that should be studied are, for example, how frequently certain DNA-variants (i.e. alleles) occur in the population, the differences in such frequencies between subpopulations, expected inheritance patterns of the DNA markers within a family and the forensic efficiency of the DNA markers in casework.In this thesis we aimed to study important population genetic parameters that influence the weight of evidence given by a DNA-analysis, as well as models for proper consideration of such parameters when calculating the weight of evi-dence in relationship testing.We have established a Swedish frequency database for mitochondrial DNA haplotypes and a haplotype frequency database for markers located on the X-chromosome. Furthermore, mtDNA haplotype frequencies were used to study the genetic variation within Sweden, and between Swedish and other European populations. No genetic substructure was found in Sweden, but strong similari-ties with other western European populations were observed.Genetic properties such as linkage and linkage disequilibrium could be im-portant when using X-chromosomal markers in relationship testing. This was true for the set of markers that we studied. In order to account for this, we pro-posed a model for how to take linkage and linkage disequilibrium into account when calculating the weight of evidence provided by X-chromosomal analysis.Finally, we investigated the risk of erroneous decisions when using DNA in-vestigations for family reunification. We showed that the risk is increased due to uncertainties regarding population allele frequencies, consanguinity and compet-ing close relationship between the tested individuals. Additional information and the use of a refined model for the alternative hypotheses reduced the risk of making erroneous decisions.In summary, as a result of the work on this thesis, we can use mitochondrial DNA and X-chromosome markers in order to resolve complex relationship in-vestigations. Moreover, the reliability of likelihood estimates has been increased by the development of models and the study of relevant parameters affecting probability calculations.
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| 3. |
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| 4. |
- Zackrisson, Anna-Lena, 1968-
(författare)
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Pharmacogenetics from a Forensic Perspective : CYP2D6 and CYP2C19 genotype distributions in autopsy cases
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In Sweden about 550 individuals die every year due to drug intoxication. A challenge for the forensic toxicologist is to determine whether or not the analytical results can explain intoxication as a cause of death. The most common drugs found among intoxication cases are psychiatric drugs and analgesics. Many of these drugs are metabolised by CYP-enzymes such as CYP2D6 and CYP2C19. Genetic variations, polymorphisms, in the genes coding for these enzymes can lead to an inactive enzyme resulting in poor metabolism, which can lead to adverse drug reactions, even with fatal outcome. The CYP2D6 gene can be multiplied, which can lead to an ultra-rapid metabolism if the alleles are active. Another polymorphism, in the CYP2C19 gene, can also lead to an ultra-rapid metabolism. This increased metabolism can result in insufficient drug plasma concentration and, with that, failed treatment. Alternately, if the drug is a pro-drug and has to be activated by these enzymes, it can lead to a high amount of active metabolites. There is a large inter-individual variation of these polymorphisms and also a large variation between different populations. Additional information about an individual’s pharmacogenetics may possibly facilitate the interpretation of the postmortem result and contribute to solve the “toxicological puzzle”.The general aim of this thesis was to study if genetic variation in the drug metabolising enzymes, CYP2D6 and CYP2C19 can contribute to fatal intoxication. Reliable and rapid SNP and CNV assays suitable for forensic samples using PCR and pyrosequencing were developed for CYP2D6 and genotype frequencies in a Swedish population were shown to be in concordance with earlier published data. SNP assays were established for polymorphisms in the CYP2C19 gene.Genotype distributions in fatal intoxication cases were compared with Swedish blood donors and significant difference between the materials were established. The allele CYP2D6*4 was found to be less frequent among the intoxication cases, as compared with the blood donors. No differences in CYP2C19 genotype frequencies were found between the materials. These findings are the opposite of our hypothesis that we expected to find an increased number of individuals carrying genetic variations, leading to poor metabolism among fatal intoxication cases. However, we are convinced that information concerning an individual’s genotype can be of importance in specific intoxication cases. Further studies are required to illuminate this question. Two further autopsy materials were studied; suicide cases (intoxications excluded) and natural death cases. A significant increased number of individuals carrying more than two active CYP2D6 alleles among the suicide cases were found compared to natural death cases. Furthermore, we found some significant differences between the materials when the individuals in each material were grouped according to how many active CYP2D6 alleles they carry in combination with the CYP2C19 genotype, which was divided into six subgroups. We do not currently have any explanation for the differences between the materials.
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| 5. |
- Kawasaki, Aki, 1963-
(författare)
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Selective wavelength pupillometry to evaluate outer and inner retinal photoreception
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- PurposeIntrinsically photosensitive retinal ganglion cells (ipRGCs) express a unique photopigment called melanopsin. Capable of direct phototransduction, the ipRGCs are also influenced by rods and cones via synaptic inputs. Thus, the photoinput that mediates the pupil light reflex derives from both outer (rods and cones) and inner (melanopsin-mediated) retinal photoreception. This thesis has aimed to develop a pupillometric test that provides quantitative information about the functional status of outer and inner retinal photoreception in healthy eyes and in eyes with retinal degeneration. In addition to regulating the pupil light reflex, the ipRGCs signal light information for the circadian rhythm, thus, these two non-visual physiologic responses to inner retinal photoreception were examined simultaneously.MethodsPupil responses to a long and short wavelength light over a range of intensities (under conditions of light, mesopic and dark adaptation) were recorded using a customized infrared computerized pupillometer. Results were compared for two groups: patients with retinitis pigmentosa and controls. The response function threshold intensity and a half-max intensity was determined from the rod-weighted and cone-weighted pupil responses and correlated to extent of visual loss. The pupil response to light offset was assessed as a measure of direct melanopsin activation. Lastly, pupil responses to red and blue light at equal photo flux were recorded hourly during a 24-hour period and correlated to salivary melatonin concentrations in healthy subjects.ResultsIn normal eyes, the blue light evoked greater pupil responses compared to equiluminant red light. With increasing intensity, pupil contraction became more sustained which was most apparent with the brightest blue light. In patients with retinitis pigmentosa, the pupil responses mediated predominantly by rod and cone activation were significantly reduced compared to controls, (p<0.001) and the relative decrease in their contribution resulted in a greater influence of melanopsin on the post-stimulus response. Even at endstage retinal degeneration, pupil responses that derived predominantly from residual cone activity were detectable. The threshold intensity of the rod-mediated, but not cone-mediated, pupil response was also significantly reduced (p=0.006) in patients and the half-maximal intensity of rods correlated with severity of visual loss (r2=0.7 and p=0.02). In healthy controls, the melanopsin-mediated pupil response demonstrated a circadian modulation whereas the cone-mediated pupil response did not.ConclusionEarly and progressive loss of rod function in mild-moderate stages of retinitis pigmentosa is detectable and quantifiable as a progressive loss of pupillary sensitivity to extremely dim blue lights obtained under conditions of dark adaptation. In advanced stages of retinal degeneration, chromatic pupillometry is more sensitive than standard electroretinography for detecting residual levels of rod and especially cone activity. In addition, selective wavelength pupillometry can assess non-visual light-dependent functions. The timing of the post-stimulus pupil response to blue light is in phase with melatonin secretion, suggesting a circadian regulation of this pupil parameter.
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| 6. |
- Ekström, Curt, 1944-
(författare)
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Studies on the Epidemiology of Open-angle Glaucoma
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Glaucoma is a common disease in the elderly population. Open-angle glaucoma (OAG) is the predominant form of glaucoma. Chronic simple glaucoma and capsular glaucoma, characterized by the occurrence of pseudoexfoliation in the anterior eye segment, are the most frequent types of OAG. The purpose of the present thesis was to study the epidemiology of OAG in the municipality of Tierp, whose population has a high exposure to pseudoexfoliation.In a case-finding study, the prevalence of known cases of OAG by December 31, 1983 was estimated to 1.4% in people ≥45 years of age. Sixty-three percent of all cases had capsular glaucoma. Patients with advanced glaucoma were older, had had the disease for longer, had higher mean initial intraocular pressure, and had more extensive visual field defects at the time of diagnosis.A population survey of people 65–74 years of age was conducted in 1984–86. The prevalence of OAG was 5.3%. Pseudoexfoliation was found in 17%, being more common in females. Pseudoexfoliation was associated with OAG only in people previously diagnosed with the disease (odds ratio = 16). In cases detected at the survey, an intraocular pressure ≥20 mmHg was a serious risk factor of having OAG (odds ratio = 9.7).In a 5-year follow-up study of participants in the population survey, increased intraocular pressure and pseudoexfoliation were recognized as independent risk factors for the development of OAG (standardized risk ratios = 3.4 and 9.8, respectively). Interaction between increased intraocular pressure and pseudoexfoliation was indicated. By May 2006, the incidence of OAG was estimated to 7.1 per 1,000 person-years. The incidence of capsular glaucoma was more than twice that of chronic simple glaucoma.The prevalence and incidence of OAG was higher than that reported from other studies conducted on Caucasian populations. The probable explanation for this finding is exposure to pseudoexfoliation.
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| 7. |
- Åström, Siv, 1947-
(författare)
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Long-term follow-up of pseudoexfoliation, intraocular pressure and glaucoma : epidemiological studies in northern Sweden
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Purpose An age-cohort was studied with long-term follow-up. The population was born in 1915, living in the municipality of Skellefteå in 1981. The purpose was to investigate the prevalence and incidence of pseudoexfoliation (PEX), its influence on intraocular pressure (IOP) and development of open-angle glaucoma (OAG). Another purpose was to estimate the value of screening for glaucoma by comparing the screened group within the cohort with the remaining unscreened group.Methods In 1981, 339 (40%) of the 856 individuals in the cohort underwent an eye examination. This screened group was re-examined at seven-year intervals until 2002. At each visit the presence of PEX was registered, IOP was measured and the presence of glaucoma was assessed. After the 21-year follow-up period, glaucoma cases were also searched for in the medical records of the remaining unscreened individuals in the cohort. Proportions of glaucoma were compared between the two groups.Results The prevalence of PEX was 23% (95% confidence interval (CI): 20-26%) at the age of 66 and increased to 61% (CI: 50-71%) at the age of 87. The annual incidence of PEX was 1.8% (CI: 1.3-2.4%). The prevalence of OAG increased from 2.1% (CI: 0.8-4.3%) at the age of 66 years to 25 % (CI: 16-35%) at 87 years. The overall annual incidence of OAG was 0.9% (CI: 0.6-1.3%) and for OAG with PEX 2.1% (CI: 1.2-3.3%). PEX increased the risk of developing glaucoma at least four-fold. The incidence of diagnosed OAG in women was higher in the screened group than in the unscreened group (incidence rate ratio (IRR)=1.94, p=0.035). A corresponding difference could not be verified for men (p=0.58). The mean, agedependent, increase in IOP during the 21-year observation period was 0.05 mmHg/year.Conclusion The prevalence of PEX in this study population was the highest reported, and it increased with age. The presence of PEX increased the risk of developing OAG four times. In this study a higher proportion of OAG was revealed by screening among women but not among men. The age-related IOP increase was clinically insignificant.
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