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Polygenic risk score: use in migraine research

Polygenic risk score: use in migraine research

Chalmer, M. A., Esserlind, A. L., Olesen, J. & Hansen, T. F. 1 dec. 2018 I : Journal of Headache and Pain. 19, 1, 29

Publikation: Bidrag til tidsskriftReviewForskningpeer review

Background: The latest Genome-Wide Association Study identified 38 genetic variants associated with migraine. In this type of studies the significance level is very difficult to achieve (5 × 10− 8) due to multiple testing. Thus, the identified variants only explain a small fraction of the genetic risk. It is expected that hundreds of thousands of variants also confer an increased risk but do not reach significance levels. One way to capture this information is by constructing a Polygenic Risk Score. Polygenic Risk Score has been widely used with success in genetics studies within neuropsychiatric disorders. The use of polygenic scores is highly relevant as data from a large migraine Genome-Wide Association Study are now available, which will form an excellent basis for Polygenic Risk Score in migraine studies. Results: Polygenic Risk Score has been used in studies of neuropsychiatric disorders to assess prediction of disease status in case-control studies, shared genetic correlation between co-morbid diseases, and shared genetic correlation between a disease and specific endophenotypes. Conclusion: Polygenic Risk Score provides an opportunity to investigate the shared genetic risk between known and previously unestablished co-morbidities in migraine research, and may lead to better and personalized treatment of migraine if used as a clinical assistant when identifying responders to specific drugs. Polygenic Risk Score can be used to analyze the genetic relationship between different headache types and migraine endophenotypes. Finally, Polygenic Risk Score can be used to assess pharmacogenetic effects, and perhaps help to predict efficacy of the Calcitonin Gene-Related Peptide monoclonal antibodies that soon become available as migraine treatment. Keywords: Migraine genetics; Genome-Wide Association Studies; Polygenic Risk Score; pleiotropy; endophenotype.

OriginalsprogEngelsk
Artikelnummer29
TidsskriftJournal of Headache and Pain
Vol/bind19
Tidsskriftsnummer1
ISSN1129-2369
DOI
StatusUdgivet - 1 dec. 2018
Vitamin D deficiency in a European inflammatory bowel disease inception cohort: an Epi-IBD study

Vitamin D deficiency in a European inflammatory bowel disease inception cohort: an Epi-IBD study

Zammit, S. C., Ellul, P., Girardin, G., Valpiani, D., Nielsen, K. R., Olsen, J., Goldis, A., Lazar, D., Shonová, O., Nováková, M., Sebastian, S., Whitehead, E., Carmona, A., Martinez-Cadilla, J., Dahlerup, J. F., Kievit, A. L. H., Thorsgaard, N., Katsanos, K. H., Christodoulou, D. K., Magro, F., Salupere, R., Pedersen, N., Kjeldsen, J., Carlsen, K., Ioannis, K., Bergemalm, D., Halfvarson, J., Duricova, D., Bortlik, M., Collin, P., Oksanen, P., Kiudelis, G., Kupcinskas, L., Kudsk, K., Andersen, V., O'Morain, C., Bailey, Y., Doron, S., Shmuel, O., Almer, S., Arebi, N., Misra, R., Čuković-Čavka, S., Brinar, M., Munkholm, P., Vegh, Z. & Burisch, J. nov. 2018 I : European Journal of Gastroenterology and Hepatology. 30, 11, s. 1297-1303

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

BACKGROUND: Serum vitamin D level is commonly low in patients with inflammatory bowel disease (IBD). Although there is a growing body of evidence that links low vitamin D level to certain aspects of IBD such as disease activity and quality of life, data on its prevalence and how it varies across disease phenotype, smoking status and treatment groups are still missing.

MATERIALS AND METHODS: Patients diagnosed with IBD between 2010 and 2011 were recruited. Demographic data and serum vitamin D levels were collected. Variance of vitamin D level was then assessed across different treatment groups, disease phenotype, disease activity and quality of life scores.

RESULTS: A total of 238 (55.9% male) patients were included. Overall, 79% of the patients had either insufficient or deficient levels of vitamin D at diagnosis. Patients needing corticosteroid treatment at 1 year had significantly lower vitamin D levels at diagnosis (median 36.0 nmol/l) (P=0.035). Harvey-Bradshaw Index (P=0.0001) and Simple Clinical Colitis Activity Index scores (P=0.0001) were significantly lower in patients with higher vitamin D level. Serum vitamin D level correlated significantly with SIBQ score (P=0.0001) and with multiple components of SF12. Smokers at diagnosis had the lowest vitamin D levels (vitamin D: 34 nmol/l; P=0.053).

CONCLUSION: This study demonstrates the high prevalence of low vitamin D levels in treatment-naive European IBD populations. Furthermore, it demonstrates the presence of low vitamin D levels in patients with IBD who smoke.

OriginalsprogEngelsk
TidsskriftEuropean Journal of Gastroenterology and Hepatology
Vol/bind30
Tidsskriftsnummer11
Sider (fra-til)1297-1303
ISSN0954-691X
DOI
StatusUdgivet - nov. 2018
Copenhagen Baby Heart Study: a population study of newborns with prenatal inclusion

Congenital heart diseases (CHDs) are reported in 0.8% of newborns. Numerous factors influence cardiovascular development and CHD prevalence, and possibly also development of cardiovascular disease later in life. However, known factors explain the probable etiology in only a fraction of patients. Past large-scale population-based studies have made invaluable contributions to the understanding of cardiac disease, but none recruited participants prenatally and focused on the neonatal period. The Copenhagen Baby Heart Study (CBHS) is a population-based study of the prevalence, spectrum, and prognosis of structural and functional cardiac abnormalities. The CBHS will also establish normal values for neonatal cardiac parameters and biomarkers, and study prenatal and early childhood factors potentially affecting later cardiovascular disease risk. The CBHS is an ongoing multicenter, prospective study recruiting from second trimester pregnancy (gestational weeks 18-20) (expected n = 25,000). Information on parents, pregnancy, and delivery are collected. After birth, umbilical cord blood is collected for biochemical analysis, DNA purification, and biobank storage. An echocardiographic examination, electrocardiography, and post-ductal pulse oximetry are performed shortly after birth. Infants diagnosed with significant CHD are referred to a specialist or admitted to hospital, depending on CHD severity. CBHS participants will be followed prospectively as part of specific research projects or regular clinical follow-up for CHD. CBHS design and methodology are described. The CBHS aims to identify new mechanisms underlying cardiovascular disease development and new targets for prevention, early detection, and management of CHD and other cardiac diseases presenting at birth or developing later in life.

OriginalsprogEngelsk
TidsskriftEuropean Journal of Epidemiology
ISSN0393-2990
DOI
StatusE-pub ahead of print - 10 okt. 2018
LED virtual windows are valuable in windowless consultation rooms

LED virtual windows are valuable in windowless consultation rooms

Sen, S., Nielsen, T., Nielsen, E., Pryds, O. & Cortes, D. sep. 2018 I : Danish Medical Journal. 65, 9, 5 s.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

INTRODUCTION: Due to the design of Hvidovre Hospital, the outpatient clinic of the Department of Paediatrics has windowless consultation rooms. Work environment surveys revealed that nurses and doctors working in these windowless rooms considered the lack of natural light a considerable health problem. This study evaluated the effects of installing light-emitting diode (LED) virtual windows in these rooms.

METHODS: Four similar windowless consultations rooms located next to each other were used in the study. All had older T-5 fluorescent luminaires installed. In two of these rooms, Servodan LED virtual windows depicting various natural scenes were installed. The illuminance and correlated colour temperature (CCT) of each room's lighting was measured, and a work environment questionnaire was filled out by nurses and doctors working in each room.

RESULTS: A total of 113 questionnaires were collected and evaluated. LED virtual windows produced an improved perception of lighting conditions, both at the desk (p < 0.001) and in the rooms in general (p < 0.001) and improved the overall positive experience of the rooms (p = 0.02). A tendency towards concentration difficulties was reported less often in the rooms with LED virtual windows, (p = 0.11). Retinal illuminance (p = 0.02) as well as CCT at the desk (p < 0.005) and at the retina (p < 0.01) alike were increased in rooms with LED virtual windows.

CONCLUSIONS: LED virtual windows improved the lighting experience, the impression of the space, the retinal illuminance and the CCT at the desk and at the retina in the windowless rooms.

FUNDING: none.

TRIAL REGISTRATION: not relevant.

OriginalsprogEngelsk
TidsskriftDanish Medical Journal
Vol/bind65
Tidsskriftsnummer9
Antal sider5
ISSN1603-9629
StatusUdgivet - sep. 2018
Diagnostic Yield of Next-Generation Sequencing in Very Early-Onset Inflammatory Bowel Diseases: A Multicenter Study

Diagnostic Yield of Next-Generation Sequencing in Very Early-Onset Inflammatory Bowel Diseases: A Multicenter Study

Charbit-Henrion, F., Parlato, M., Hanein, S., Duclaux-Loras, R., Nowak, J., Begue, B., Rakotobe, S., Bruneau, J., Fourrage, C., Alibeu, O., Rieux-Laucat, F., Lévy, E., Stolzenberg, M-C., Mazerolles, F., Latour, S., Lenoir, C., Fischer, A., Picard, C., Aloi, M., Amil Dias, J., Ben Hariz, M., Bourrier, A., Breuer, C., Breton, A., Bronski, J., Buderus, S., Cananzi, M., Coopman, S., Crémilleux, C., Dabadie, A., Dumant-Forest, C., Egritas Gurkan, O., Fabre, A., Fischer, A., German Diaz, M., Gonzalez-Lama, Y., Goulet, O., Guariso, G., Gurcan, N., Homan, M., Hugot, J-P., Jeziorski, E., Karanika, E., Lachaux, A., Lewindon, P., Lima, R., Magro, F., Major, J., Malamut, G., Mas, E., Mattyus, I., Mearin, L. M., Melek, J., Navas-Lopez, V. M., Paerregaard, A., Pelatan, C., Pigneur, B., Pinto Pais, I., Rebeuh, J., Romano, C., Siala, N., Strisciuglio, C., Tempia-Caliera, M., Tounian, P., Turner, D., Urbonas, V., Willot, S., Ruemmele, F. M. & Cerf-Bensussan, N. 29 aug. 2018 I : Journal of Crohn's & colitis. 12, 9, s. 1104-1112

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Background and Aims: An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases (VEO-IBD). The present study aimed at defining how next-generation sequencing (NGS) methods can be used to improve identification of known molecular diagnosis and adapt treatment.

Methods: 207 children were recruited in 45 Paediatric centres through an international collaborative network (ESPGHAN GENIUS working group) with a clinical presentation of severe VEO-IBD (n=185) or an anamnesis suggestive of a monogenic disorder (n=22). Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing (WES) of parents-child trios. Genetic findings were validated clinically and/or functionally.

Results: Molecular diagnosis was achieved in 66/207 children (32%): 61% with small bowel inflammation, 39% with colitis and perianal lesions and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations and identified large exonic copy number variations previously missed by WES.

Conclusions: Our results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD.

OriginalsprogEngelsk
TidsskriftJournal of Crohn's & colitis
Vol/bind12
Tidsskriftsnummer9
Sider (fra-til)1104-1112
ISSN1873-9946
DOI
StatusUdgivet - 29 aug. 2018
Circulating serum interleukin-6, serum chitinase-3-like protein-1, and plasma vascular endothelial growth factor are not predictive for remission and radiographic progression in patients with early rheumatoid arthritis: post-hoc explorative and validation studies based on the CIMESTRA and OPERA trials

Objective: To investigate serum interleukin-6 (IL-6), serum chitinase-3-like protein-1 (YKL-40), and plasma vascular endothelial growth factor (VEGF) as measures of disease activity and predictors of clinical remission and radiographic progression in two early rheumatoid arthritis (RA) randomized controlled trials (RCTs). Method: Treatment-naïve patients with early RA (< 6 months’ duration) and active disease, participating in two investigator-initiated RCTs, were treated according to a predefined treat-to-target algorithm aiming at inflammatory control, using methotrexate (MTX) + cyclosporine versus MTX + placebo (CIMESTRA study, n = 150, 5 year follow-up) or MTX + adalimumab versus MTX + placebo (OPERA study, n = 180, 2 year follow-up). The 28-joint Disease Activity Score (DAS28) and conventional radiography [bilateral hands and feet at baseline, 2 years and 5 years (only CIMESTRA)] were obtained at baseline and during follow-up. Serum IL-6, serum YKL-40, and plasma VEGF were measured in baseline blood samples and during follow-up. Hypotheses regarding the biomarkers’ relation with DAS28 and ability to predict clinical remission (DAS28 < 2.6) and radiographic progression (change in total Sharp van der Heijde score ≥ 2) were generated in CIMESTRA and validated in OPERA, by Spearman’s correlation and logistic regression analyses. Results: Baseline IL-6, YKL-40, and VEGF correlated significantly with DAS28 in CIMESTRA (r = 0.50, r = 0.36, r = 0.36, respectively, all p < 0.01) and these results were confirmed in OPERA patients (r = 0.52, p < 0.01; r = 0.18, p = 0.01; r = 0.23, p = 0.002, respectively). None of the biomarkers (absolute values or change) was predictive of clinical remission or radiographic progression at 2 or 5 years in either study. Conclusion: Serum IL-6, serum YKL-40, and plasma VEGF were significantly correlated with DAS28 at baseline, but did not have consistent predictive value for clinical remission or radiographic progression in two early RA RCTs.

OriginalsprogEngelsk
TidsskriftScandinavian Journal of Rheumatology
Vol/bind47
Tidsskriftsnummer4
Sider (fra-til)259-269
Antal sider11
ISSN0300-9742
DOI
StatusUdgivet - jul. 2018

Bibliografisk note

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Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families

Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families

23andMe Research Team & International Headache Genetics Consortium (IHGC) 16 maj 2018 I : Neuron. 98, 4, s. 743-753.e4

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Complex traits, including migraine, often aggregate in families, but the underlying genetic architecture behind this is not well understood. The aggregation could be explained by rare, penetrant variants that segregate according to Mendelian inheritance or by the sufficient polygenic accumulation of common variants, each with an individually small effect, or a combination of the two hypotheses. In 8,319 individuals across 1,589 migraine families, we calculated migraine polygenic risk scores (PRS) and found a significantly higher common variant burden in familial cases (n = 5,317, OR = 1.76, 95% CI = 1.71–1.81, p = 1.7 × 10−109) compared to population cases from the FINRISK cohort (n = 1,101, OR = 1.32, 95% CI = 1.25–1.38, p = 7.2 × 10−17). The PRS explained 1.6% of the phenotypic variance in the population cases and 3.5% in the familial cases (including 2.9% for migraine without aura, 5.5% for migraine with typical aura, and 8.2% for hemiplegic migraine). The results demonstrate a significant contribution of common polygenic variation to the familial aggregation of migraine. Gormley et al. use polygenic risk scores to show that common variation, captured by genome-wide association studies, in combination contributes to the aggregation of migraine in families. The results may have similar implications for other complex traits in general.

OriginalsprogEngelsk
TidsskriftNeuron
Vol/bind98
Tidsskriftsnummer4
Sider (fra-til)743-753.e4
ISSN0896-6273
DOI
StatusUdgivet - 16 maj 2018
Corrigendum: Vedolizumab in Paediatric Inflammatory Bowel Disease: A Retrospective Multi-Centre Experience From the Paediatric IBD Porto Group of ESPGHAN

Corrigendum: Vedolizumab in Paediatric Inflammatory Bowel Disease: A Retrospective Multi-Centre Experience From the Paediatric IBD Porto Group of ESPGHAN

Ledder, O., Assa, A., Levine, A., Escher, J. C., de Ridder, L., Ruemmele, F., Shah, N., Shaoul, R., Wolters, V. M., Rodrigues, A., Uhlig, H. H., Posovszky, C., Kolho, K-L., Jakobsen, C., Cohen, S., Shouval, D. S., de Meij, T., Martin-de-Carpi, J., Richmond, L., Bronsky, J., Friedman, M. & Turner, D. 27 apr. 2018 I : Journal of Crohn's & colitis. 12, 5, s. 630

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

OriginalsprogEngelsk
TidsskriftJournal of Crohn's & colitis
Vol/bind12
Tidsskriftsnummer5
Sider (fra-til)630
ISSN1873-9946
DOI
StatusUdgivet - 27 apr. 2018

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