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- Do, Ron, et al.
(författare)
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Common variants associated with plasma triglycerides and risk for coronary artery disease
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1345-
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Tidskriftsartikel (refereegranskat)abstract
- Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
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| 3. |
- Eriksson, Niclas, 1978-
(författare)
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On the Prediction of Warfarin Dose
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Warfarin is one of the most widely used anticoagulants in the world. Treatment is complicated by a large inter-individual variation in the dose needed to reach adequate levels of anticoagulation i.e. INR 2.0 – 3.0. The objective of this thesis was to evaluate which factors, mainly genetic but also non-genetic, that affect the response to warfarin in terms of required maintenance dose, efficacy and safety with special focus on warfarin dose prediction.Through candidate gene and genome-wide studies, we have shown that the genes CYP2C9 and VKORC1 are the major determinants of warfarin maintenance dose. By combining the SNPs CYP2C9 *2, CYP2C9 *3 and VKORC1 rs9923231 with the clinical factors age, height, weight, ethnicity, amiodarone and use of inducers (carbamazepine, phenytoin or rifampicin) into a prediction model (the IWPC model) we can explain 43 % to 51 % of the variation in warfarin maintenance dose. Patients requiring doses < 29 mg/week and doses ≥ 49 mg/week benefitted the most from pharmacogenetic dosing. Further, we have shown that the difference across ethnicities in percent variance explained by VKORC1 was largely accounted for by the allele frequency of rs9923231. Other novel genes affecting maintenance dose (NEDD4 and DDHD1), as well as the replicated CYP4F2 gene, have small effects on dose predictions and are not likely to be cost-effective, unless inexpensive genotyping is available.Three types of prediction models for warfarin dosing exist: maintenance dose models, loading dose models and dose revision models. The combination of these three models is currently being used in the warfarin treatment arm of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) study. Other clinical trials aiming to prove the clinical validity and utility of pharmacogenetic dosing are also underway.The future of pharmacogenetic warfarin dosing relies on results from these ongoing studies, the availability of inexpensive genotyping and the cost-effectiveness of pharmacogenetic driven warfarin dosing compared with new oral anticoagulant drugs.
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| 4. |
- Heikkilä, Katriina, et al.
(författare)
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Work stress and risk of cancer: meta-analysis of 5700 incident cancer events in 116 000 European men and women
- 2013
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Ingår i: The BMJ. - : BMJ. - 1756-1833. ; 345:f165
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Tidskriftsartikel (refereegranskat)abstract
- Objective To investigate whether work related stress, measured and defined as job strain, is associated with the overall risk of cancer and the risk of colorectal, lung, breast, or prostate cancers.Design Meta-analysis of pooled prospective individual participant data from 12 European cohort studies including 116 056 men and women aged 17-70 who were free from cancer at study baseline and were followed-up for a median of 12 years. Work stress was measured and defined as job strain, which was self reported at baseline. Incident cancers (all n=5765, colorectal cancer n=522, lung cancer n=374, breast cancer n=1010, prostate cancer n=865) were ascertained from cancer, hospital admission, and death registers. Data were analysed in each study with Cox regression and the study specific estimates pooled in meta-analyses. Models were adjusted for age, sex, socioeconomic position, body mass index (BMI), smoking, and alcohol intakeResults A harmonised measure of work stress, high job strain, was not associated with overall risk of cancer (hazard ratio 0.97, 95% confidence interval 0.90 to 1.04) in the multivariable adjusted analyses. Similarly, no association was observed between job strain and the risk of colorectal (1.16, 0.90 to 1.48), lung (1.17, 0.88 to 1.54), breast (0.97, 0.82 to 1.14), or prostate (0.86, 0.68 to 1.09) cancers. There was no clear evidence for an association between the categories of job strain and the risk of cancer.Conclusions These findings suggest that work related stress, measured and defined as job strain, at baseline is unlikely to be an important risk factor for colorectal, lung, breast, or prostate cancers.
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| 6. |
- Karlsson, Lars, 1981-
(författare)
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The Incentive to Abate : The Swedish Pulp and Paper Industry and the 1969 Environment Protection Act
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Swedish Environment Protection Act (SEPA) was implemented in 1969 and constituted the first comprehensive Swedish regulation of industry-induced environmental externalities. In keeping with a longstanding corporatist tradition, Swedish policymakers aimed to establish a cooperative climate with industrial producers and instructed the regulatory authorities to strive to reach consensual agreements with affected firms. Despite such accommodations, the environmental adaptation of Swedish industrial production proceeded at a greater pace, during the 1970’s and 1980’s, than in most comparable countries, many of which had implemented seemingly more stringent environmental regulations than had Sweden.This thesis seeks to identify the firm level incentives behind this process, by examining the economic impact of the SEPA upon one of the more pollution-intensive branches of Swedish industrial production, the pulp and paper industry. Guided by previous research, an hypothesis is proposed in which the implementation of the SEPA came to aid the structural rationalization of this industry during the 1970’s and 1980’s, by inducing the exit of marginal, small-scale pulp and paper mills, thereby relaxing the prevailing competition over wood resources and available market space and creating more room for expansion within the surviving mills. As larger firms tend to operate larger mills, the hypothesized effects are suggested to have benefited large-scale producers within the industry, at the expense of their smaller rivals. The findings of the thesis show that the economic effects of the SEPA were more severe for small as compared to large-scale mills and that regulatory requirements for pollution abatement did contribute to the shutdown of several small-scale mills during the 1970’s and 1980’s. No conclusive evidence could, however, be found for the validity of the thesis’ hypothesis as a whole, as these shutdowns were not predominantly administered by small-scale firms, as predicted by the hypothesis. Rather, the vast majority of these shutdowns were accounted for by some of the largest firms within the industry. Some tentative evidence was found, however, that the implementation of the SEPA may have benefitted certain large-scale producers within the industry, by facilitating acquisitions of smaller firms with valuable assets.
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| 7. |
- Magnusson, Kristina, et al.
(författare)
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Specific Uptake of an Amyloid-beta Protofibril-Binding Antibody-Tracer in A beta PP Transgenic Mouse Brain
- 2013
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 37:1, s. 29-40
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Tidskriftsartikel (refereegranskat)abstract
- Evidence suggests that amyloid-beta (A beta) protofibrils/oligomers are pathogenic agents in Alzheimer's disease (AD). Unfortunately, techniques enabling quantitative estimates of these species in patients or patient samples are still rather limited. Here we describe the in vitro and ex vivo characteristics of a new antibody-based radioactive ligand, [I-125]mAb158, which binds to A beta protofibrils with high affinity. [I-125]mAb158 was specifically taken up in brain of transgenic mice expressing amyloid-beta protein precursor (A beta PP) as shown ex vivo. This was in contrast to [I-125]mAb-Ly128 which does not bind to A beta. The uptake of intraperitoneally-administered [I-125]mAb158 into the brain was age- and time-dependent, and saturable in A beta PP transgenic mice with modest A beta deposition. Brain uptake was also found in young A beta PP transgenic mice that were devoid of A beta deposits, suggesting that [I-125]mAb158 targets soluble A beta protofibrils. The radioligand was diffusely located in the parenchyma, sometimes around senile plaques and only occasionally colocalized with cerebral amyloid angiopathy. A refined iodine-124-labeled version of mAb158 with much improved blood-brain barrier passage and a shorter plasma half-life might be useful for PET imaging of A beta protofibrils.
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