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Medicine, Denmark

Wadt K.A.W.,Rigshospitalet | Aoude L.G.,QIMR Berghofer Medical Research Institute | Golmard L.,University Pierre and Marie Curie | Hansen T.V.O.,Center for Genomic Medicine | And 3 more authors.
Familial Cancer | Year: 2015

Known melanoma predisposition genes only account for around 40 % of high-density melanoma families. Other rare mutations are likely to play a role in melanoma predisposition. RAD51B plays an important role in DNA repair through homologous recombination, and inactivation of RAD51B has been implicated in tumorigenesis. Thus RAD51B is a good candidate melanoma susceptibility gene, and previously, a germline splicing mutation in RAD51B has been identified in a family with early-onset breast cancer. In order to find genetic variants associated with melanoma predisposition, whole-exome sequencing was carried out on blood samples from a three-case cutaneous melanoma family. We identified a novel germline RAD51B nonsense mutation, and we demonstrate reduced expression of RAD51B in melanoma cells indicating inactivation of RAD51B. This is only the second report of a germline truncating RAD51B mutation. While this case report is consistent with melanoma being part of the RAD51B cancer spectrum further population-based screening of large case–control sample series will be needed to definitively establish if this is the case. © 2015, Springer Science+Business Media Dordrecht. Source

Chin K.,Kyoto University | Takegami M.,Kyoto University | Takegami M.,Japan National Cardiovascular Center Research Institute | Takahashi K.-I.,Red Cross | And 9 more authors.
Chest | Year: 2013

Background: Dyslipidemia is often comorbid with obstructive sleep apnea (OSA), but few populationbased studies have investigated their relationship. Short sleep duration is associated with hypertension and diabetes; however, its association with dyslipidemia is not well known. We investigated relationships among OSA, sleep duration, and the lipid profile in a community-based study. Methods: We measured the respiratory disturbance index (RDI) and sleep duration by a type 3 portable device and actigraph in 275 men in a Japanese company. Fasting blood parameters were obtained from periodic inspection data. Results: According to Japanese criteria, 143 subjects had dyslipidemia. Percent sleep time of oxygen saturation as measured by pulse oximetry (SpO2) <90% and prevalence of severe OSA were greater and sleep duration and mean SpO2 during sleep were lower in subjects with dyslipidemia than in those without. Univariate analysis showed that the RDI was positively correlated with serum triglyceride (TG) levels (ρ = 0.20, P < .01), and sleep duration was negatively correlated with serum total cholesterol (TC) levels (γ = -0.13, P = .03) and serum low-density lipoprotein cholesterol levels (γ = -0.12, P = .04). Stepwise multiple regression analysis revealed that TG was correlated with RDI (β = 0.14, P = .02), BMI (β = 0.20, P < .01), and alcohol intake (β = 0.20, P < .01), and that TC was correlated with sleep duration (β = -0.13, P = .03), age (β = 0.15, P = .02), and waist/hip ratio (β = 0.15, P = .02). Conclusions: Short sleep duration was associated with TC levels and RDI was positively associated with TG levels among working-aged men in an urban Japanese company. Correcting the status of OSA and/or short sleep duration might improve the lipid profile and cardiovascular consequences. © 2013 American College of Chest Physicians. Source

Gorlova O.,Dartmouth College | Fedorov A.,University of Toledo | Logothetis C.,University of Houston | Amos C.,Dartmouth College | And 2 more authors.
BMC Evolutionary Biology | Year: 2014

Background: The existence of introns in eukaryotic genes is believed to provide an evolutionary advantage by increasing protein diversity through exon shuffling and alternative splicing. However, this eukaryotic feature is associated with the necessity of exclusion of intronic sequences, which requires considerable energy expenditure and can lead to splicing errors. The relationship between intronic burden and evolution is poorly understood. The goal of this study was to analyze the relationship between the intronic burden and the level of evolutionary conservation of the gene. Results: We found a positive correlation between the level of evolutionary conservation of a gene and its intronic burden. The level of evolutionary conservation was estimated using the conservation index (CI). The CI value was determined on the basis of the most distant ortholog of the human protein sequence and ranged from 0 (the gene was unique to the human genome) to 9 (an ortholog of the human gene was detected in plants). In multivariable model, both the number of introns and total intron size remained significant predictors of CI. We also found that the number of alternative splice variants was positively correlated with CI.The expression level of a gene was negatively correlated with the number of introns and total size of intronic region. Genes with a greater intronic burden had lower density of missense and nonsense mutations in the coding regions of the gene, which suggests that they are under a stronger pressure from purifying selection. Conclusions: We identified a positive association between intronic burden and CI. One of the possible explanations of this is the idea of a cost-benefits balance. Evolutionarily conserved (functionally important) genes can "afford" the negative consequences of maintaining multiple introns because these consequences are outweighed by the benefit of maintaining the gene. Evolutionarily conserved and functionally important genes may use introns to create novel splice variants to tune the gene function to developmental stage and tissue type. © 2014 Gorlova et al.; licensee BioMed Central Ltd. Source

Pedersen T.X.,Rigshospitalet | Pedersen T.X.,Copenhagen University | Madsen M.,Copenhagen University | Junker N.,Copenhagen University | And 6 more authors.
Cardiovascular Research | Year: 2013

AimsUraemia is a strong risk factor for cardiovascular disease. Osteopontin (OPN) is highly expressed in aortas of uraemic apolipoprotein E knockout (E KO) mice. OPN affects key atherogenic processes, i.e. inflammation and phenotypic modulation of smooth muscle cells (SMCs). We explored the role of OPN on vascular pathology in uraemic mice.Methods and resultsUraemia was induced by 5/6 nephrectomy in E KO and in OPN and E double KO mice (E/OPN KO). In E KO mice, uraemia increased the relative surface plaque area in the aortic arch (from 28 ± 2% [n = 15], to 37 ± 3% [n = 20] of the aortic arch area, P < 0.05). A positive correlation was observed between plasma OPN and aortic atherosclerosis in uraemic E KO mice (r2 = 0.48, P = 0.001). In contrast, aortic atherosclerosis was not increased by uraemia in E/OPN KO mice. OPN deficiency in haematopoietic cells (including macrophages) did not affect development of uraemic atherosclerosis, even though OPN-deficient foam cells had decreased inflammatory capacity. Gene expression analyses indicated that uraemia de-differentiates SMCs in the arterial wall. This effect was dampened in whole-body OPN-deficient mice.ConclusionThe data suggest that OPN promotes development of uraemic atherosclerosis possibly by changing the phenotype of vascular smooth muscle cells. © 2013 Published on behalf of the European Society of Cardiology. All rights reserved. Source

Andersen S.B.,Technical University of Denmark | Andersen S.B.,University of Oxford | Marvig R.L.,RigshospitaletCopenhagen | Marvig R.L.,Center for Genomic Medicine | And 3 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Laboratory experiments show that social interactions between bacterial cells can drive evolutionary change at the population level, but significant challenges limit attempts to assess the relevance of these findings to natural populations, where selection pressures are unknown. We have increasingly sophisticated methods for monitoring phenotypic and genotypic dynamics in bacteria causing infectious disease, but in contrast, we lack evidence-based adaptive explanations for those changes. Evolutionary change during infection is often interpreted as host adaptation, but this assumption neglects to consider social dynamics shown to drive evolutionary change in vitro. We provide evidence to show that long-term behavioral dynamics observed in a pathogen are driven by selection to outcompete neighboring conspecific cells through social interactions. We find that Pseudomonas aeruginosa bacteria, causing lung infections in patients with cystic fibrosis, lose cooperative iron acquisition by siderophore production during infection. This loss could be caused by changes in iron availability in the lung, but surprisingly, we find that cells retain the ability to take up siderophores produced by conspecifics, even after they have lost the ability to synthesize siderophores. Only when cooperative producers are lost from the population is the receptor for uptake lost. This finding highlights the potential pitfalls of interpreting loss of function in pathogenic bacterial populations as evidence for trait redundancy in the host environment. More generally, we provide an example of how sequence analysis can be used to generate testable hypotheses about selection driving long-term phenotypic changes of pathogenic bacteria in situ. Source

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