| 1. |
- Bramsen, Jesper B., et al.
(författare)
-
A screen of chemical modifications identifies position-specific modification by UNA to most potently reduce siRNA off-target effects
- 2010
-
Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 38:17, s. 5761-5773
-
Tidskriftsartikel (refereegranskat)abstract
- Small interfering RNAs (siRNAs) are now established as the preferred tool to inhibit gene function in mammalian cells yet trigger unintended gene silencing due to their inherent miRNA-like behavior. Such off-target effects are primarily mediated by the sequence-specific interaction between the siRNA seed regions (position 2-8 of either siRNA strand counting from the 5'-end) and complementary sequences in the 3'UTR of (off-) targets. It was previously shown that chemical modification of siRNAs can reduce off-targeting but only very few modifications have been tested leaving more to be identified. Here we developed a luciferase reporter-based assay suitable to monitor siRNA off-targeting in a high throughput manner using stable cell lines. We investigated the impact of chemically modifying single nucleotide positions within the siRNA seed on siRNA function and off-targeting using 10 different types of chemical modifications, three different target sequences and three siRNA concentrations. We found several differently modified siRNAs to exercise reduced off-targeting yet incorporation of the strongly destabilizing unlocked nucleic acid (UNA) modification into position 7 of the siRNA most potently reduced off-targeting for all tested sequences. Notably, such position-specific destabilization of siRNA-target interactions did not significantly reduce siRNA potency and is therefore well suited for future siRNA designs especially for applications in vivo where siRNA concentrations, expectedly, will be low.
|
|
| 2. |
- Strickertsson, Jesper A. B., et al.
(författare)
-
Interferon-gamma inhibits ghrelin expression and secretion via a somatostatin-mediated mechanism
- 2011
-
Ingår i: World Journal of Gastroenterology. - 1007-9327. ; 17:26, s. 3117-3125
-
Tidskriftsartikel (refereegranskat)abstract
- AIM: To investigate if and how the proinflammatory cytokine interferon gamma (IFN gamma) affects ghrelin expression in mice. METHODS: The plasma concentration of ghrelin, and gastric ghrelin and somatostatin expression, were examined in wild-type mice and mice infected with Helicobacter pylori (H. pylon). Furthermore, ghrelin expression was examined in two achlorhydric mouse models with varying degrees of gastritis due to bacterial overgrowth. To study the effect of IFN gamma alone, mice were given a subcutaneous infusion of IFN gamma for 7 d. Finally, the influence of IFN gamma, and somatostatin on the ghrelin promoter was characterized. RESULTS: H. pylori infection was associated with a 50% reduction in ghrelin expression and plasma concentration. Suppression of ghrelin expression was inversely correlated with gastric inflammation in achlorhdyric mouse models. Subcutaneous infusion of IFN gamma suppressed fundic ghrelin mRNA expression and plasma ghrelin concentrations. Finally, we showed that the ghrelin promoter operates under the control of somatostatin but not under that of IFN gamma. CONCLUSION: Gastric infection and inflammation is associated with increased IFN gamma expression and reduced ghrelin expression. IFN gamma does not directly control ghrelin expression but inhibits it indirectly via somatostatin. (C) 2011 Baishideng. All rights reserved.
|
|
| 3. |
- Borgquist, Rasmus, et al.
(författare)
-
The diagnostic performance of imaging methods in ARVC using the 2010 Task Force criteria.
- 2014
-
Ingår i: European heart journal cardiovascular Imaging. - : Oxford University Press (OUP). - 2047-2412 .- 2047-2404. ; 15:11, s. 1219-1225
-
Tidskriftsartikel (refereegranskat)abstract
- This study evaluates the agreement between echocardiographic and cardiac magnetic resonance (CMR) imaging data, and the impact a discrepancy between the two may have on the clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC).
|
|
| 4. |
- Dahl-Jensen, D., et al.
(författare)
-
Eemian interglacial reconstructed from a Greenland folded ice core
- 2013
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 493:7433, s. 489-494
-
Tidskriftsartikel (refereegranskat)abstract
- Efforts to extract a Greenland ice core with a complete record of the Eemian interglacial (130,000 to 115,000 years ago) have until now been unsuccessful. The response of the Greenland ice sheet to the warmer-than-present climate of the Eemian has thus remained unclear. Here we present the new North Greenland Eemian Ice Drilling ('NEEM') ice core and show only a modest ice-sheet response to the strong warming in the early Eemian. We reconstructed the Eemian record from folded ice using globally homogeneous parameters known from dated Greenland and Antarctic ice-core records. On the basis of water stable isotopes, NEEM surface temperatures after the onset of the Eemian (126,000 years ago) peaked at 8 +/- 4 degrees Celsius above the mean of the past millennium, followed by a gradual cooling that was probably driven by the decreasing summer insolation. Between 128,000 and 122,000 years ago, the thickness of the northwest Greenland ice sheet decreased by 400 +/- 250 metres, reaching surface elevations 122,000 years ago of 130 +/- 300 metres lower than the present. Extensive surface melt occurred at the NEEM site during the Eemian, a phenomenon witnessed when melt layers formed again at NEEM during the exceptional heat of July 2012. With additional warming, surface melt might become more common in the future.
|
|
| 5. |
- Garde, Anne Helene, et al.
(författare)
-
Month-to-month variation in sleep among healthy, Scandinavian daytime workers
- 2014
-
Ingår i: Scandinavian Journal of Clinical & Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 74:6, s. 527-535
-
Tidskriftsartikel (refereegranskat)abstract
- Background. The overall purpose of the present study was to attain more insight in month-to-month variation of sleep duration and quality in order to improve design and interpretation of, e.g. epidemiological studies using sleep as outcome. Methods. The study design entailed monthly self-reports from 38 (26 women/12 men) daytime workers, who completed the Karolinska Sleep Diary (KSD) once a month during one year. A subgroup (n = 16) also wore actigraphs on one day every month during a year. Self-reports of bedtime, time of awakening, sleep duration, individual sleep characteristics, disturbed sleep index (DSI, 4 items) and awakening index (AWI, 3 items) were analyzed together with actigraphy-derived measures. Hours of daylight were used to test for circa-annual variation in statistical models adjusted for intake of hypnotics and alcohol, gender, age and within-person variability. Results. Hours of daylight were found to be associated to self-reported bedtime (p = 0.032) and DSI (p = 0.030), thereby indicating a circa-annual variation. Bedtime was delayed by 1.8 min (95% CI: 0.6-2.9 min) per 1 hour increase in length of daylight. Sleep was slightly more disturbed during the winter. Conclusion. Only circa-annual variation in self-reports of bedtime and DSI were observed in a healthy daytime working population, and the effects were small. Therefore potential bias due to circa-annuality in the studied parameters appears to be of limited concern in adult daytime working populations.
|
|
| 6. |
- Hansen, Jesper, et al.
(författare)
-
Diversity fluctuations and biogeography of Ordovician brachiopod faunas in northeastern Spitsbergen
- 2010
-
Ingår i: Bulletin of Geosciences. - : Czech Geological Survey. - 1214-1119 .- 1802-8225. ; 85:3, s. 497-504
-
Tidskriftsartikel (refereegranskat)abstract
- Investigations of Lower and Middle Ordovician brachiopods in northeastern Spitsbergen have revealed strong ties to faunas in North America and Greenland at the generic level, although the fauna appears mostly endemic at the species level. During the early Palaeozoic, the archipelago of Svalbard, including Spitsbergen, was located at equatorial latitudes along the northeastern margin of Laurentia. The northeastern part of Spitsbergen experienced significant sea level changes, changing from very shallow water in the Tremadocian to deep water in the Floian and slowly back to shallow- water carbonate environments in the Middle Ordovician. The Tremadocian and early Floian brachiopod fauna was of low diversity with a high proportion of cosmopolitan warm-water related rhynchonelliform genera. In the late Floian there was an abrupt diversification event, taking place against the background of the increasing isolation of Laurentia, leading to a diverse, mostly endemic fauna. This diverse fauna remained into the Middle Ordovician. A similar diversification event has been recorded in North America, but here it occurs later, in the Dapingian. The diachroneity of brachiopod diversification within different parts of a continent has previously been shown for South China, suggesting that it may be a common phenomenon. In contrast to the mostly endemic Middle Ordovician rhynchonelliform genera, the linguliform brachiopods included many genera with a wide distribution. This difference is attributed to their different dispersal strategies.
|
|
| 7. |
|
|
| 8. |
- Hansen, Jesper, et al.
(författare)
-
Taxonomy and biostratigraphy of Ordovician brachiopods from northeastern Ny Friesland, Spitsbergen
- 2011
-
Ingår i: Zootaxa. - 1175-5326 .- 1175-5334. ; :3076, s. 1-122
-
Tidskriftsartikel (refereegranskat)abstract
- We describe Early and Middle Ordovician brachiopod faunas from northeastern Spitsbergen and discuss their biostratigraphical and palaeoecological implications. We recognise 60 species and 41 genera representing both linguliform and rhynchonelliform brachiopods. These include one new genus, the obolid Lenticulella with the type species Lenticulella amphora (Krause & Rowell, 1975), and 23 new species: Ectenoglossa? oviforma, Elliptoglossa vulgaris, Rosobolus? elongatus, Broeggeria obscura, Mirilingula? svalbardensis, Schizotreta marginalis, Conotreta convexa, Cyrtonotreta profilbekkiensis, Cyrtonotreta spinosa, Eurytreta subtriangularis, Hisingerella maniformis, Semitreta basisslettaensis, Semitreta pustulosa, Semitreta spitsbergensis, Numericoma? proclina, Eoconulus subquadratus, Dictyonites mugilis, Pelonomia sulcata, Leptella (Leptella) inequicostellata, Protosken-idioides promontorium, Anomalorthis rossi, Nothorthis subpyramidalis and Phragmorthis noda. The Ordovician succession contains both intertidal and deep-sea deposits with brachiopod faunas from nearly the whole range of environments. The Tremadocian is represented by a succession of low-diversity, rhynchonelliform-dominated assemblages occupying shallow-marine environments. With the abrupt and large-scale drowning during the Floian, these faunas were replaced by a sparse slope fauna of micromorphic linguliforms. The outer shelf environments established in the latest Floian were occupied by a highly diverse brachiopod fauna dominated by micromorphic linguliform taxa. As the environment shifted toward the mid-shelf during the Darriwilian, however, the composition of the fauna changed to an Orthidiella-dominated assemblage of mostly rhynchonelliform taxa. The very late occurrence of the Orthidiella assemblage suggests that the Dapingian Orthidiella Zone found in America is probably diachronic. Although it includes many endemic species, the Middle Ordovician fauna shows a strong resemblance to the brachiopod fauna of Nevada. This study is based on approximately 16 500 brachiopod specimens obtained from both crack-out samples and acetic-acid-treated bulk samples.
|
|
| 9. |
- Jungersted, Jakob Mutanu, et al.
(författare)
-
In vivo studies of aquaporins 3 and 10 in human stratum corneum.
- 2013
-
Ingår i: Archives of dermatological research. - : Springer Science and Business Media LLC. - 1432-069X .- 0340-3696. ; 305:8, s. 699-704
-
Tidskriftsartikel (refereegranskat)abstract
- Aquaporins (AQPs) constitute one family of transmembrane proteins facilitating transport of water across cell membranes. Due to their specificity, AQPs have a broad spectrum of physiological functions, and for keratinocytes there are indications that these channel proteins are involved in cell migration and proliferation with consequences for the antimicrobial defense of the skin. AQP3 and AQP10 are aqua-glyceroporins, known to transport glycerol as well as water. AQP3 is the predominant AQP in human skin and has previously been demonstrated in the basal layer of epidermis in normal human skin, but not in stratum corneum (SC). AQP10 has not previously been identified in human skin. Previous studies have demonstrated the presence of AQP3 and AQP10 mRNA in keratinocytes. In this study, our aim was to investigate if these aquaporin proteins were actually present in human SC cells. This can be seen as a first step toward elucidating the possible functional role of AQP3 and AQP10 in SC hydration. Specifically we investigate the presence of AQP3 and AQP10 in vivo in human SC using "minimal-invasive" technique for obtaining SC samples. SC samples were obtained from six healthy volunteers. Western blotting and immunohistochemistry were used to demonstrate the presence of AQP3 as well as AQP10. The presence of AQP3 and AQP10 was verified by Western blotting, allowing for detection of proteins by specific antibodies. Applying immunohistochemistry, cell-like structures in the shape of corneocytes were identified in all samples by AQP3 and AQP10 antibodies. In conclusion, identification of AQP3 and AQP10 protein in SC in an in vivo model is new. Together with the new "minimal-invasive" method for SC collection presented, this opens for new possibilities to study the role of AQPs in relation to function of the skin barrier.
|
|
| 10. |
- Jönsson, Jenny-Maria, et al.
(författare)
-
Molecular subtyping of serous ovarian tumors reveals multiple connections to intrinsic breast cancer subtypes.
- 2014
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:9
-
Tidskriftsartikel (refereegranskat)abstract
- Transcriptional profiling of epithelial ovarian cancer has revealed molecular subtypes correlating to biological and clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and investigate similarities with the well-established intrinsic molecular subtypes of breast cancer.
|
|
| 11. |
- McLachlan, Michael S., et al.
(författare)
-
Concentrations and Fate of Decamethylcyclopentasiloxane (D-5) in the Atmosphere
- 2010
-
Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 44:14, s. 5365-5370
-
Tidskriftsartikel (refereegranskat)abstract
- Decamethylcyclopentasiloxane (D-5) is a volatile compound used in personal care products that is released to the atmosphere in large quantities. Although D-5 is currently under consideration for regulation, there have been no field investigations of its atmospheric fate. We employed a recently developed, quality assured method to measure D-5 concentration in ambient air at a rural site in Sweden. The samples were collected with daily resolution between January and June 2009. The 05 concentration ranged from 0.3 to 9 ng m(-3), which is 1-3 orders of magnitude lower than previous reports. The measured data were compared with D-5 concentrations predicted using an atmospheric circulation model that included both OH radical and D-5 chemistry. The model was parametrized using emissions estimates and physical chemical properties determined in laboratory experiments. There was good agreement between the measured and modeled D-5 concentrations. The results show that D-5 is clearly subject to long-range atmospheric transport, but that it is also effectively removed from the atmosphere via phototransformation. Atmospheric deposition has little influence on the atmospheric fate. The good agreement between the model predictions and the field observations indicates that there is a good understanding of the major factors governing D-5 concentrations in the atmosphere.
|
|
| 12. |
|
|
| 13. |
|
|
| 14. |
|
|
| 15. |
- Persson, Roger, et al.
(författare)
-
Can the job content questionnaire be used to assess structural and organizational properties of the work environment?
- 2012
-
Ingår i: International Archives of Occupational and Environmental Health. - : Springer Science and Business Media LLC. - 1432-1246 .- 0340-0131. ; 85:1, s. 45-55
-
Tidskriftsartikel (refereegranskat)abstract
- Objective The theory behind the Job Content Questionnaire (JCQ) presumes that the "objective" social environment is measurable via self-report inventories such as the JCQ. Hence, it is expected that workers in identical work will respond highly similar. However, since no studies have evaluated this basic assumption, we decided to investigate whether workers performing highly similar work also responded similarly to the JCQ. Methods JCQ data from a rubber-manufacturing (RM: n = 95) and a mechanical assembly company (MA: n = 119) were examined. On each worksite, men and women performed identical machine-paced job tasks. A population sample (n = 8,542) served as a reference group. Results In both the RM and MA groups, the job support questions were rated most similar. Yet, there was a substantial variation as regards choosing to agree or disagree with single JCQ items. The variation was also reflected in the scale scores. In the RM and MA groups, the variance of job demand and job control scores was 64-87% of that of the population sample. For job support scores, the corresponding variation was 42-87%. Conclusion Conducting highly similar work does not lead to highly similar reports in the JCQ. In view of the large response variation, it seems that the attempt to avoid personal influence by minimizing the self-reflexive component in the questions asked, and using response alternative that indicates degree of agreement, does not seem to work as intended.
|
|
| 16. |
- Plasencia, Ines, et al.
(författare)
-
Structure and Stability of the Spinach Aquaporin SoPIP2;1 in Detergent Micelles and Lipid Membranes
- 2011
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:2
-
Tidskriftsartikel (refereegranskat)abstract
- Background: SoPIP2;1 constitutes one of the major integral proteins in spinach leaf plasma membranes and belongs to the aquaporin family. SoPIP2;1 is a highly permeable and selective water channel that has been successfully overexpressed and purified with high yields. In order to optimize reconstitution of the purified protein into biomimetic systems, we have here for the first time characterized the structural stability of SoPIP2;1. Methodology/Principal Finding: We have characterized the protein structural stability after purification and after reconstitution into detergent micelles and proteoliposomes using circular dichroism and fluorescence spectroscopy techniques. The structure of SoPIP2;1 was analyzed either with the protein solubilized with octyl-beta-D-glucopyranoside (OG) or reconstituted into lipid membranes formed by E. coli lipids, diphytanoylphosphatidylcholine (DPhPC), or reconstituted into lipid membranes formed from mixtures of 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPE), 1-palmitoyl-2-oleoyl-phosphatidylethanolamine (POPE), 1-palmitoyl-2-oleoyl-phosphatidylserine (POPS), and ergosterol. Generally, SoPIP2;1 secondary structure was found to be predominantly a-helical in accordance with crystallographic data. The protein has a high thermal structural stability in detergent solutions, with an irreversible thermal unfolding occurring at a melting temperature of 58 degrees C. Incorporation of the protein into lipid membranes increases the structural stability as evidenced by an increased melting temperature of up to 70 degrees C. Conclusion/Significance: The results of this study provide insights into SoPIP2;1 stability in various host membranes and suggest suitable choices of detergent and lipid composition for reconstitution of SoPIP2;1 into biomimetic membranes for biotechnological applications.
|
|
| 17. |
- Raghavan, Maanasa, et al.
(författare)
-
The genetic prehistory of the New World Arctic
- 2014
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 345:6200, s. 1020-
-
Tidskriftsartikel (refereegranskat)abstract
- The New World Arctic, the last region of the Americas to be populated by humans, has a relatively well-researched archaeology, but an understanding of its genetic history is lacking. We present genome-wide sequence data from ancient and present-day humans from Greenland, Arctic Canada, Alaska, Aleutian Islands, and Siberia. We show that Paleo-Eskimos (similar to 3000 BCE to 1300 CE) represent a migration pulse into the Americas independent of both Native American and Inuit expansions. Furthermore, the genetic continuity characterizing the Paleo-Eskimo period was interrupted by the arrival of a new population, representing the ancestors of present-day Inuit, with evidence of past gene flow between these lineages. Despite periodic abandonment of major Arctic regions, a single Paleo-Eskimo metapopulation likely survived in near-isolation for more than 4000 years, only to vanish around 700 years ago.
|
|
| 18. |
- Simonsson, Bengt, et al.
(författare)
-
Combination of pegylated IFN-alpha 2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia
- 2011
-
Ingår i: Blood. - Washington D.C. : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 118:12, s. 3228-3235
-
Tidskriftsartikel (refereegranskat)abstract
- Biologic and clinical observations suggest that combining imatinib with IFN-alpha may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remission either to receive a combination of pegylated IFN-alpha 2b (Peg-IFN-alpha 2b) 50 mu g weekly and imatinib 400 mg daily (n = 56) or to receive imatinib 400 mg daily monotherapy (n = 56). The primary endpoint was the major molecular response (MMR) rate at 12 months after randomization. In both arms, 4 patients (7%) discontinued imatinib treatment (1 because of blastic transformation in imatinib arm). In addition, in the combination arm, 34 patients (61%) discontinued Peg-IFN-alpha 2b, most because of toxicity. The MMR rate at 12 months was significantly higher in the imatinib plus Peg-IFN-alpha 2b arm (82%) compared with the imatinib monotherapy arm (54%; intention-to-treat, P = .002). The MMR rate increased with the duration of Peg-IFN-alpha 2b treatment (andlt; 12-week MMR rate 67%, andgt; 12-week MMR rate 91%). Thus, the addition of even relatively short periods of Peg-IFN-alpha 2b to imatinib markedly increased the MMR rate at 12 months of therapy. Lower doses of Peg-IFN-alpha 2b may enhance tolerability while retaining efficacy and could be considered in future protocols with curative intent.
|
|
| 19. |
- Strickertsson, Jesper A. B., et al.
(författare)
-
Enterococcus faecalis Infection Causes Inflammation, Intracellular Oxphos-Independent ROS Production, and DNA Damage in Human Gastric Cancer Cells
- 2013
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:4
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Achlorhydria caused by e.g. atrophic gastritis allows for bacterial overgrowth, which induces chronic inflammation and damage to the mucosal cells of infected individuals driving gastric malignancies and cancer. Enterococcus faecalis (E. faecalis) can colonize achlohydric stomachs and we therefore wanted to study the impact of E. faecalis infection on inflammatory response, reactive oxygen species (ROS) formation, mitochondrial respiration, and mitochondrial genetic stability in gastric mucosal cells. Methods: To separate the changes induced by bacteria from those of the inflammatory cells we established an in vitro E. faecalis infection model system using the gastric carcinoma cell line MKN74. Total ROS and superoxide was measured by fluorescence microscopy. Cellular oxygen consumption was characterized non-invasively using XF24 microplate based respirometry. Gene expression was examined by microarray, and response pathways were identified by Gene Set Analysis (GSA). Selected gene transcripts were verified by quantitative real-time polymerase chain reaction (qRT-PCR). Mitochondrial mutations were determined by sequencing. Results: Infection of MKN74 cells with E. faecalis induced intracellular ROS production through a pathway independent of oxidative phosphorylation (oxphos). Furthermore, E. faecalis infection induced mitochondrial DNA instability. Following infection, genes coding for inflammatory response proteins were transcriptionally up-regulated while DNA damage repair and cell cycle control genes were down-regulated. Cell growth slowed down when infected with viable E. faecalis and responded in a dose dependent manner to E. faecalis lysate. Conclusions: Infection by E. faecalis induced an oxphos-independent intracellular ROS response and damaged the mitochondrial genome in gastric cell culture. Finally the bacteria induced an NF-kappa B inflammatory response as well as impaired DNA damage response and cell cycle control gene expression.
|
|
| 20. |
- Thanassoulis, George, et al.
(författare)
-
Genetic Associations with Valvular Calcification and Aortic Stenosis
- 2013
-
Ingår i: New England Journal of Medicine. - 0028-4793. ; 368:6, s. 503-512
-
Tidskriftsartikel (refereegranskat)abstract
- Background Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. Methods We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. Results One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P = 9.0x10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P = 1.5x10(-8) and P = 1.8x10(-8), respectively), but the findings were not replicated consistently. Conclusions Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.)
|
|
