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  1. Article ; Online: Barriers and Enablers of Healthcare Providers to Deprescribe Cardiometabolic Medication in Older Patients: A Focus Group Study.

    Abou, Jamila / Crutzen, Stijn / Tromp, Vashti / Heringa, Mette / Van Marum, Rob / Elders, Petra / Taxis, Katja / Denig, Petra / Hugtenburg, Jacqueline

    Drugs & aging

    2022  Volume 39, Issue 3, Page(s) 209–221

    Abstract: Introduction: Benefits and risks of preventive medication change over time for ageing patients and deprescribing of medication may be needed. Deprescribing of cardiovascular and antidiabetic drugs can be challenging and is not widely implemented in ... ...

    Abstract Introduction: Benefits and risks of preventive medication change over time for ageing patients and deprescribing of medication may be needed. Deprescribing of cardiovascular and antidiabetic drugs can be challenging and is not widely implemented in daily practice.
    Objective: The aim of this study was to identify barriers and enablers of deprescribing cardiometabolic medication as seen by healthcare providers (HCPs) of different disciplines, and to explore their views on their specific roles in the process of deprescribing.
    Methods: Three focus groups with five general practitioners, eight pharmacists, three nurse practitioners, two geriatricians, and two elder care physicians were conducted in three cities in The Netherlands. Interviews were recorded and transcribed verbatim. Directed content analysis was performed on the basis of the Theoretical Domains Framework. Two researchers independently coded the data.
    Results: Most HCPs agreed that deprescribing of cardiometabolic medication is relevant but that barriers include lack of evidence and expertise, negative beliefs and fears, poor communication and collaboration between HCPs, and lack of resources. Having a guideline was considered an enabler for the process of deprescribing of cardiometabolic medication. Some HCPs feared the consequences of discontinuing cardiovascular or antidiabetic medication, while others were not motivated to deprescribe when the patients experienced no problems with their medication. HCPs of all disciplines stated that adequate patient communication and involving the patients and relatives in the decision making enables deprescribing. Barriers to deprescribing included the use of medication initiated by specialists, the poor exchange of information, and the amount of time it takes to deprescribe cardiometabolic medication. The HCPs were uncertain about each other's roles and responsibilities. A multidisciplinary approach including the pharmacist and nurse practitioner was seen as the best way to support the process of deprescribing and address barriers related to resources.
    Conclusion: HCPs recognized the importance of deprescribing cardiometabolic medication as a medical decision that can only be made in close cooperation with the patient. To successfully accomplish the process of deprescribing they strongly recommended a multidisciplinary approach.
    MeSH term(s) Aged ; Cardiovascular Diseases/drug therapy ; Deprescriptions ; Focus Groups ; General Practitioners ; Humans ; Pharmacists
    Language English
    Publishing date 2022-02-21
    Publishing country New Zealand
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1075770-3
    ISSN 1179-1969 ; 1170-229X
    ISSN (online) 1179-1969
    ISSN 1170-229X
    DOI 10.1007/s40266-021-00918-7
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  2. Article: Effect of Methylprednisolone on Inflammation and Coagulation in Patients with Severe COVID-19: A Retrospective Cohort Study.

    Tromp, Katja / van der Zee, Philip / Rokx, Casper / van Kampen, Jeroen / Gommers, Diederik / Endeman, Henrik

    Biomarker insights

    2021  Volume 16, Page(s) 11772719211021647

    Abstract: Corticosteroids reduced mortality rate in patients with coronavirus disease 2019 (COVID-19). Previously, we hypothesized that corticosteroids mitigate the inflammation response resulting in reduced coagulation and thrombosis. In this retrospective study, ...

    Abstract Corticosteroids reduced mortality rate in patients with coronavirus disease 2019 (COVID-19). Previously, we hypothesized that corticosteroids mitigate the inflammation response resulting in reduced coagulation and thrombosis. In this retrospective study, we included 27 patients with COVID-19 that received high-dose corticosteroids (methylprednisolone 1000 mg i.v. daily for 3 days) for persistent respiratory failure or an excessive inflammation response. We found that inflammation, coagulation, and ventilation parameters improved significantly after methylprednisolone. The viral loads of SARS-CoV-2 remained stable or decreased. These results provides insight into the reduced mortality rate observed in patients with COVID-19 treated with corticosteroids.
    Language English
    Publishing date 2021-06-04
    Publishing country United States
    Document type Journal Article
    ISSN 1177-2719
    ISSN 1177-2719
    DOI 10.1177/11772719211021647
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  3. Article ; Online: Effect of Methylprednisolone on Inflammation and Coagulation in Patients with Severe COVID-19

    Katja Tromp / Philip van der Zee / Casper Rokx / Jeroen van Kampen / Diederik Gommers / Henrik Endeman

    Biomarker Insights, Vol

    A Retrospective Cohort Study

    2021  Volume 16

    Abstract: Corticosteroids reduced mortality rate in patients with coronavirus disease 2019 (COVID-19). Previously, we hypothesized that corticosteroids mitigate the inflammation response resulting in reduced coagulation and thrombosis. In this retrospective study, ...

    Abstract Corticosteroids reduced mortality rate in patients with coronavirus disease 2019 (COVID-19). Previously, we hypothesized that corticosteroids mitigate the inflammation response resulting in reduced coagulation and thrombosis. In this retrospective study, we included 27 patients with COVID-19 that received high-dose corticosteroids (methylprednisolone 1000 mg i.v. daily for 3 days) for persistent respiratory failure or an excessive inflammation response. We found that inflammation, coagulation, and ventilation parameters improved significantly after methylprednisolone. The viral loads of SARS-CoV-2 remained stable or decreased. These results provides insight into the reduced mortality rate observed in patients with COVID-19 treated with corticosteroids.
    Keywords Medicine (General) ; R5-920
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher SAGE Publishing
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Young children with a minor traumatic head injury: clinical observation or CT scan?

    Niele, Nicky / Plötz, Frans B / Tromp, Ellen / Boersma, Bart / Biezeveld, Maarten / Douma, Matthijs / Heitink, Katja / Tusscher, Gavin Ten / van Goudoever, Hans B / van Houten, Marlies A

    European journal of pediatrics

    2022  Volume 181, Issue 9, Page(s) 3291–3297

    Abstract: Currently, in young children with minor traumatic head injuries (MTHI) classified as intermediate risk (IR), PECARN recommends clinical observation over computer tomography (CT) scan depending on provider comfort, although both options being possible. In ...

    Abstract Currently, in young children with minor traumatic head injuries (MTHI) classified as intermediate risk (IR), PECARN recommends clinical observation over computer tomography (CT) scan depending on provider comfort, although both options being possible. In this study, we describe clinicians' choice and which factors were associated with this decision. This was a planned sub-study of a prospective multicenter observational study that enrolled 1006 children younger than 18 years with MTHI who presented to six emergency departments in The Netherlands. Of those, 280 children classified as IR group fulfilling one or more minor criteria, leaving the clinician with the choice between clinical observation and a CT scan. In our cohort, 228/280 (81%) children were admitted for clinical observation, 15/280 (5.4%) received a CT scan, 6/280 (2.1%) received a CT scan and were admitted for observation, and 31/280 (11%) children were discharged from the emergency department without any intervention. Three objective factors were associated with a CT scan, namely age above 2 years, the presence of any loss of consciousness (LOC), and presentation on weekend days.
    Conclusion: In children with MTHI in an IR group, clinicians prefer clinical observation above performing a CT scan. Older age, day of presentation, and any loss of consciousness are factors associated with a CT scan.
    What is known: • Clinical decision rules have been developed in the management of children of different risk groups with minor traumatic head injury (MTHI). • According to the Dutch national, clinical decision rules in children under 6 years of age up to 50% of children classify as intermediate risk (IR) and clinicians may choose between clinical observation and computed tomography (CT).
    What is new: • In this IR group, clinical observation is chosen in 81% children with MTHI. • In the subgroup where clinicians performed a CT scan, children were older and presented more frequently on a weekend day, and more frequently consciousness was lost.
    MeSH term(s) Child ; Child, Preschool ; Computers ; Craniocerebral Trauma/diagnostic imaging ; Emergency Service, Hospital ; Humans ; Prospective Studies ; Tomography, X-Ray Computed ; Unconsciousness/complications
    Language English
    Publishing date 2022-06-24
    Publishing country Germany
    Document type Journal Article ; Multicenter Study ; Observational Study
    ZDB-ID 194196-3
    ISSN 1432-1076 ; 0340-6199 ; 0943-9676
    ISSN (online) 1432-1076
    ISSN 0340-6199 ; 0943-9676
    DOI 10.1007/s00431-022-04514-8
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  5. Article ; Online: Multi-centre study found that strict adherence to guidelines led to computed tomography scans being overused in children with minor head injuries.

    Niele, Nicky / van Houten, Marlies A / Boersma, Bart / Biezeveld, Maarten H / Douma, Matthijs / Heitink, Katja / Ten Tusscher, Gavin W / Tromp, Ellen / van Goudoever, Johannes B / Plötz, Frans B

    Acta paediatrica (Oslo, Norway : 1992)

    2019  Volume 108, Issue 9, Page(s) 1695–1703

    Abstract: Aim: Our primary aim was to calculate the head computed tomography (CT) scan rate in children with a minor head injury (MHI) when the Dutch National guidelines were followed in clinical practice. The secondary aim was to determine the incidence of CT ... ...

    Abstract Aim: Our primary aim was to calculate the head computed tomography (CT) scan rate in children with a minor head injury (MHI) when the Dutch National guidelines were followed in clinical practice. The secondary aim was to determine the incidence of CT abnormalities and the guideline predictors associated with traumatic abnormalities.
    Methods: We performed a multi-centre, prospective observational cross-sectional study in the emergency departments of six hospitals in The Netherlands between 1 April 2015 and 31 December 2016.
    Results: Data on 1002 patients were studied and 69% of cases complied with the guidelines. The overall CT rate was 44% and the incidence of traumatic abnormal CT findings was 13%. CT scans were performed in 19% of children under two years of age, 48% of children between two and five years and 63% of children aged six years or more. Multivariate regression analysis for all age categories showed that CT abnormalities were predicted by a Glasgow Coma Scale of less than 15, suspicion of a basal skull fracture, vomiting and scalp haematomas or external lesions of the skull.
    Conclusion: Strict adherence to the Dutch national guidelines resulted in CT overuse. New guidelines are needed to safely reduce CT scan indications.
    MeSH term(s) Child ; Child, Preschool ; Craniocerebral Trauma/diagnostic imaging ; Female ; Guideline Adherence/statistics & numerical data ; Humans ; Infant ; Male ; Medical Overuse ; Prospective Studies ; Tomography, X-Ray Computed/statistics & numerical data
    Language English
    Publishing date 2019-03-04
    Publishing country Norway
    Document type Journal Article ; Multicenter Study ; Observational Study
    ZDB-ID 203487-6
    ISSN 1651-2227 ; 0365-1436 ; 0803-5253
    ISSN (online) 1651-2227
    ISSN 0365-1436 ; 0803-5253
    DOI 10.1111/apa.14742
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  6. Article ; Online: Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial.

    Facon, Thierry / Kumar, Shaji K / Plesner, Torben / Orlowski, Robert Z / Moreau, Philippe / Bahlis, Nizar / Basu, Supratik / Nahi, Hareth / Hulin, Cyrille / Quach, Hang / Goldschmidt, Hartmut / O'Dwyer, Michael / Perrot, Aurore / Venner, Christopher P / Weisel, Katja / Mace, Joseph R / Raje, Noopur / Tiab, Mourad / Macro, Margaret /
    Frenzel, Laurent / Leleu, Xavier / Ahmadi, Tahamtan / Wang, Jianping / Van Rampelbergh, Rian / Uhlar, Clarissa M / Tromp, Brenda / Delioukina, Maria / Vermeulen, Jessica / Usmani, Saad Z

    The Lancet. Oncology

    2021  Volume 22, Issue 11, Page(s) 1582–1596

    Abstract: Background: In the primary analysis of the phase 3 MAIA trial (median follow-up 28·0 months), a significant improvement in progression-free survival was observed with daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone ... ...

    Abstract Background: In the primary analysis of the phase 3 MAIA trial (median follow-up 28·0 months), a significant improvement in progression-free survival was observed with daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in transplantation-ineligible patients with newly diagnosed multiple myeloma. Here, we report the updated efficacy and safety results from a prespecified interim analysis for overall survival.
    Methods: MAIA is an ongoing, multicentre, randomised, open-label, phase 3 trial that enrolled patients at 176 hospitals in 14 countries across North America, Europe, the Middle East, and the Asia-Pacific region. Eligible patients were aged 18 years or older, had newly diagnosed multiple myeloma, had an Eastern Cooperative Oncology Group performance status score of 0-2, and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation because of their age (≥65 years) or comorbidities. Patients were randomly assigned (1:1) using randomly permuted blocks (block size 4) by an interactive web response system to receive 28-day cycles of intravenous daratumumab (16 mg/kg, once per week during cycles 1-2, once every 2 weeks in cycles 3-6, and once every 4 weeks thereafter) plus oral lenalidomide (25 mg on days 1-21 of each cycle) and oral dexamethasone (40 mg on days 1, 8, 15, and 22 of each cycle; daratumumab group) or lenalidomide and dexamethasone alone (control group). Randomisation was stratified by International Staging System disease stage, geographical region, and age. Neither patients nor investigators were masked to treatment assignment. The primary endpoint was progression-free survival, which was centrally assessed, and a secondary endpoint was overall survival (both assessed in the intention-to-treat population). The safety population included patients who received at least one dose of the study treatment. The results presented here are from a prespecified interim analysis for overall survival, for which the prespecified stopping boundary was p=0·0414. This trial is registered with ClinicalTrials.gov, NCT02252172.
    Findings: Between March 18, 2015, and Jan 15, 2017, 952 patients were assessed for eligibility, of whom 737 patients were enrolled and randomly assigned to the daratumumab group (n=368) or the control group (n=369). At a median follow-up of 56·2 months (IQR 52·7-59·9), median progression-free survival was not reached (95% CI 54·8-not reached) in the daratumumab group versus 34·4 months (29·6-39·2) in the control group (hazard ratio [HR] 0·53 [95% CI 0·43-0·66]; p<0·0001). Median overall survival was not reached in either group (daratumumab group, 95% CI not reached-not reached; control group, 95% CI 55·7-not reached; HR 0·68 [95% CI 0·53-0·86]; p=0·0013). The most common (>15%) grade 3 or higher treatment-emergent adverse events were neutropenia (197 [54%] patients in the daratumumab group vs 135 [37%] patients in the control group), pneumonia (70 [19%] vs 39 [11%]), anaemia (61 [17%] vs 79 [22%]), and lymphopenia (60 [16%] vs 41 [11%]). Serious adverse events occurred in 281 (77%) patients in the daratumumab group and 257 (70%) patients in the control group. Treatment-related deaths occurred in 13 (4%) patients in the daratumumab group and ten (3%) patients in the control group.
    Interpretation: Daratumumab plus lenalidomide and dexamethasone increased overall survival and progression-free survival in patients ineligible for stem-cell transplantation with newly diagnosed multiple myeloma. There were no new safety concerns. Our results support the frontline use of daratumumab plus lenalidomide and dexamethasone for patients with multiple myeloma who are ineligible for transplantation.
    Funding: Janssen Research & Development.
    MeSH term(s) Aged ; Antibodies, Monoclonal/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Dexamethasone/therapeutic use ; Drug-Related Side Effects and Adverse Reactions/diagnosis ; Drug-Related Side Effects and Adverse Reactions/epidemiology ; Female ; Humans ; Lenalidomide/therapeutic use ; Male ; Multiple Myeloma/drug therapy ; Multiple Myeloma/mortality ; Progression-Free Survival ; Survival Rate
    Chemical Substances Antibodies, Monoclonal ; daratumumab (4Z63YK6E0E) ; Dexamethasone (7S5I7G3JQL) ; Lenalidomide (F0P408N6V4)
    Language English
    Publishing date 2021-10-13
    Publishing country England
    Document type Clinical Trial, Phase III ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ZDB-ID 2049730-1
    ISSN 1474-5488 ; 1470-2045
    ISSN (online) 1474-5488
    ISSN 1470-2045
    DOI 10.1016/S1470-2045(21)00466-6
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    Zs.MO 460: Show issues

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  7. Article ; Online: Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.

    Haycock, Philip C / Burgess, Stephen / Nounu, Aayah / Zheng, Jie / Okoli, George N / Bowden, Jack / Wade, Kaitlin Hazel / Timpson, Nicholas J / Evans, David M / Willeit, Peter / Aviv, Abraham / Gaunt, Tom R / Hemani, Gibran / Mangino, Massimo / Ellis, Hayley Patricia / Kurian, Kathreena M / Pooley, Karen A / Eeles, Rosalind A / Lee, Jeffrey E /
    Fang, Shenying / Chen, Wei V / Law, Matthew H / Bowdler, Lisa M / Iles, Mark M / Yang, Qiong / Worrall, Bradford B / Markus, Hugh Stephen / Hung, Rayjean J / Amos, Chris I / Spurdle, Amanda B / Thompson, Deborah J / O'Mara, Tracy A / Wolpin, Brian / Amundadottir, Laufey / Stolzenberg-Solomon, Rachael / Trichopoulou, Antonia / Onland-Moret, N Charlotte / Lund, Eiliv / Duell, Eric J / Canzian, Federico / Severi, Gianluca / Overvad, Kim / Gunter, Marc J / Tumino, Rosario / Svenson, Ulrika / van Rij, Andre / Baas, Annette F / Bown, Matthew J / Samani, Nilesh J / van t'Hof, Femke N G / Tromp, Gerard / Jones, Gregory T / Kuivaniemi, Helena / Elmore, James R / Johansson, Mattias / Mckay, James / Scelo, Ghislaine / Carreras-Torres, Robert / Gaborieau, Valerie / Brennan, Paul / Bracci, Paige M / Neale, Rachel E / Olson, Sara H / Gallinger, Steven / Li, Donghui / Petersen, Gloria M / Risch, Harvey A / Klein, Alison P / Han, Jiali / Abnet, Christian C / Freedman, Neal D / Taylor, Philip R / Maris, John M / Aben, Katja K / Kiemeney, Lambertus A / Vermeulen, Sita H / Wiencke, John K / Walsh, Kyle M / Wrensch, Margaret / Rice, Terri / Turnbull, Clare / Litchfield, Kevin / Paternoster, Lavinia / Standl, Marie / Abecasis, Gonçalo R / SanGiovanni, John Paul / Li, Yong / Mijatovic, Vladan / Sapkota, Yadav / Low, Siew-Kee / Zondervan, Krina T / Montgomery, Grant W / Nyholt, Dale R / van Heel, David A / Hunt, Karen / Arking, Dan E / Ashar, Foram N / Sotoodehnia, Nona / Woo, Daniel / Rosand, Jonathan / Comeau, Mary E / Brown, W Mark / Silverman, Edwin K / Hokanson, John E / Cho, Michael H / Hui, Jennie / Ferreira, Manuel A / Thompson, Philip J / Morrison, Alanna C / Felix, Janine F / Smith, Nicholas L / Christiano, Angela M / Petukhova, Lynn / Betz, Regina C / Fan, Xing / Zhang, Xuejun / Zhu, Caihong / Langefeld, Carl D / Thompson, Susan D / Wang, Feijie / Lin, Xu / Schwartz, David A / Fingerlin, Tasha / Rotter, Jerome I / Cotch, Mary Frances / Jensen, Richard A / Munz, Matthias / Dommisch, Henrik / Schaefer, Arne S / Han, Fang / Ollila, Hanna M / Hillary, Ryan P / Albagha, Omar / Ralston, Stuart H / Zeng, Chenjie / Zheng, Wei / Shu, Xiao-Ou / Reis, Andre / Uebe, Steffen / Hüffmeier, Ulrike / Kawamura, Yoshiya / Otowa, Takeshi / Sasaki, Tsukasa / Hibberd, Martin Lloyd / Davila, Sonia / Xie, Gang / Siminovitch, Katherine / Bei, Jin-Xin / Zeng, Yi-Xin / Försti, Asta / Chen, Bowang / Landi, Stefano / Franke, Andre / Fischer, Annegret / Ellinghaus, David / Flores, Carlos / Noth, Imre / Ma, Shwu-Fan / Foo, Jia Nee / Liu, Jianjun / Kim, Jong-Won / Cox, David G / Delattre, Olivier / Mirabeau, Olivier / Skibola, Christine F / Tang, Clara S / Garcia-Barcelo, Merce / Chang, Kai-Ping / Su, Wen-Hui / Chang, Yu-Sun / Martin, Nicholas G / Gordon, Scott / Wade, Tracey D / Lee, Chaeyoung / Kubo, Michiaki / Cha, Pei-Chieng / Nakamura, Yusuke / Levy, Daniel / Kimura, Masayuki / Hwang, Shih-Jen / Hunt, Steven / Spector, Tim / Soranzo, Nicole / Manichaikul, Ani W / Barr, R Graham / Kahali, Bratati / Speliotes, Elizabeth / Yerges-Armstrong, Laura M / Cheng, Ching-Yu / Jonas, Jost B / Wong, Tien Yin / Fogh, Isabella / Lin, Kuang / Powell, John F / Rice, Kenneth / Relton, Caroline L / Martin, Richard M / Davey Smith, George

    JAMA oncology

    2017  Volume 3, Issue 5, Page(s) 636–651

    Abstract: Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.: ... ...

    Abstract Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.
    Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.
    Data sources: Genomewide association studies (GWAS) published up to January 15, 2015.
    Study selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.
    Data extraction and synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.
    Main outcomes and measures: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.
    Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).
    Conclusions and relevance: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Cardiovascular Diseases/genetics ; Female ; Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study ; Germ-Line Mutation ; Humans ; Male ; Mendelian Randomization Analysis/methods ; Middle Aged ; Neoplasms/genetics ; Polymorphism, Single Nucleotide ; Risk Assessment/methods ; Telomere/genetics ; Telomere Homeostasis/genetics
    Language English
    Publishing date 2017-02-23
    Publishing country United States
    Document type Journal Article
    ISSN 2374-2445
    ISSN (online) 2374-2445
    DOI 10.1001/jamaoncol.2016.5945
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  8. Article ; Online: Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm.

    Gretarsdottir, Solveig / Baas, Annette F / Thorleifsson, Gudmar / Holm, Hilma / den Heijer, Martin / de Vries, Jean-Paul P M / Kranendonk, Steef E / Zeebregts, Clark J A M / van Sterkenburg, Steven M / Geelkerken, Robert H / van Rij, Andre M / Williams, Michael J A / Boll, Albert P M / Kostic, Jelena P / Jonasdottir, Adalbjorg / Jonasdottir, Aslaug / Walters, G Bragi / Masson, Gisli / Sulem, Patrick /
    Saemundsdottir, Jona / Mouy, Magali / Magnusson, Kristinn P / Tromp, Gerard / Elmore, James R / Sakalihasan, Natzi / Limet, Raymond / Defraigne, Jean-Olivier / Ferrell, Robert E / Ronkainen, Antti / Ruigrok, Ynte M / Wijmenga, Cisca / Grobbee, Diederick E / Shah, Svati H / Granger, Christopher B / Quyyumi, Arshed A / Vaccarino, Viola / Patel, Riyaz S / Zafari, A Maziar / Levey, Allan I / Austin, Harland / Girelli, Domenico / Pignatti, Pier Franco / Olivieri, Oliviero / Martinelli, Nicola / Malerba, Giovanni / Trabetti, Elisabetta / Becker, Lewis C / Becker, Diane M / Reilly, Muredach P / Rader, Daniel J / Mueller, Thomas / Dieplinger, Benjamin / Haltmayer, Meinhard / Urbonavicius, Sigitas / Lindblad, Bengt / Gottsäter, Anders / Gaetani, Eleonora / Pola, Roberto / Wells, Philip / Rodger, Marc / Forgie, Melissa / Langlois, Nicole / Corral, Javier / Vicente, Vicente / Fontcuberta, Jordi / España, Francisco / Grarup, Niels / Jørgensen, Torben / Witte, Daniel R / Hansen, Torben / Pedersen, Oluf / Aben, Katja K / de Graaf, Jacqueline / Holewijn, Suzanne / Folkersen, Lasse / Franco-Cereceda, Anders / Eriksson, Per / Collier, David A / Stefansson, Hreinn / Steinthorsdottir, Valgerdur / Rafnar, Thorunn / Valdimarsson, Einar M / Magnadottir, Hulda B / Sveinbjornsdottir, Sigurlaug / Olafsson, Isleifur / Magnusson, Magnus Karl / Palmason, Robert / Haraldsdottir, Vilhelmina / Andersen, Karl / Onundarson, Pall T / Thorgeirsson, Gudmundur / Kiemeney, Lambertus A / Powell, Janet T / Carey, David J / Kuivaniemi, Helena / Lindholt, Jes S / Jones, Gregory T / Kong, Augustine / Blankensteijn, Jan D / Matthiasson, Stefan E / Thorsteinsdottir, Unnur / Stefansson, Kari

    Nature genetics

    2010  Volume 42, Issue 8, Page(s) 692–697

    Abstract: We performed a genome-wide association study on 1,292 individuals with abdominal aortic aneurysms (AAAs) and 30,503 controls from Iceland and The Netherlands, with a follow-up of top markers in up to 3,267 individuals with AAAs and 7,451 controls. The A ... ...

    Abstract We performed a genome-wide association study on 1,292 individuals with abdominal aortic aneurysms (AAAs) and 30,503 controls from Iceland and The Netherlands, with a follow-up of top markers in up to 3,267 individuals with AAAs and 7,451 controls. The A allele of rs7025486 on 9q33 was found to associate with AAA, with an odds ratio (OR) of 1.21 and P = 4.6 x 10(-10). In tests for association with other vascular diseases, we found that rs7025486[A] is associated with early onset myocardial infarction (OR = 1.18, P = 3.1 x 10(-5)), peripheral arterial disease (OR = 1.14, P = 3.9 x 10(-5)) and pulmonary embolism (OR = 1.20, P = 0.00030), but not with intracranial aneurysm or ischemic stroke. No association was observed between rs7025486[A] and common risk factors for arterial and venous diseases-that is, smoking, lipid levels, obesity, type 2 diabetes and hypertension. Rs7025486 is located within DAB2IP, which encodes an inhibitor of cell growth and survival.
    MeSH term(s) Alleles ; Aortic Aneurysm, Abdominal/complications ; Aortic Aneurysm, Abdominal/genetics ; Aortic Aneurysm, Abdominal/mortality ; Base Sequence ; Disease Susceptibility/complications ; Genome-Wide Association Study ; Humans ; Hypertension/complications ; Hypertension/genetics ; Iceland ; Myocardial Infarction/complications ; Myocardial Infarction/genetics ; Netherlands ; Odds Ratio ; Risk Factors ; ras GTPase-Activating Proteins
    Chemical Substances DAB2IP protein, human ; ras GTPase-Activating Proteins
    Language English
    Publishing date 2010-07-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108734-1
    ISSN 1546-1718 ; 1061-4036
    ISSN (online) 1546-1718
    ISSN 1061-4036
    DOI 10.1038/ng.622
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

    Turcot, Valérie / Lu, Yingchang / Highland, Heather M / Schurmann, Claudia / Justice, Anne E / Fine, Rebecca S / Bradfield, Jonathan P / Esko, Tõnu / Giri, Ayush / Graff, Mariaelisa / Guo, Xiuqing / Hendricks, Audrey E / Karaderi, Tugce / Lempradl, Adelheid / Locke, Adam E / Mahajan, Anubha / Marouli, Eirini / Sivapalaratnam, Suthesh / Young, Kristin L /
    Alfred, Tamuno / Feitosa, Mary F / Masca, Nicholas G D / Manning, Alisa K / Medina-Gomez, Carolina / Mudgal, Poorva / Ng, Maggie C Y / Reiner, Alex P / Vedantam, Sailaja / Willems, Sara M / Winkler, Thomas W / Abecasis, Gonçalo / Aben, Katja K / Alam, Dewan S / Alharthi, Sameer E / Allison, Matthew / Amouyel, Philippe / Asselbergs, Folkert W / Auer, Paul L / Balkau, Beverley / Bang, Lia E / Barroso, Inês / Bastarache, Lisa / Benn, Marianne / Bergmann, Sven / Bielak, Lawrence F / Blüher, Matthias / Boehnke, Michael / Boeing, Heiner / Boerwinkle, Eric / Böger, Carsten A / Bork-Jensen, Jette / Bots, Michiel L / Bottinger, Erwin P / Bowden, Donald W / Brandslund, Ivan / Breen, Gerome / Brilliant, Murray H / Broer, Linda / Brumat, Marco / Burt, Amber A / Butterworth, Adam S / Campbell, Peter T / Cappellani, Stefania / Carey, David J / Catamo, Eulalia / Caulfield, Mark J / Chambers, John C / Chasman, Daniel I / Chen, Yii-Der I / Chowdhury, Rajiv / Christensen, Cramer / Chu, Audrey Y / Cocca, Massimiliano / Collins, Francis S / Cook, James P / Corley, Janie / Galbany, Jordi Corominas / Cox, Amanda J / Crosslin, David S / Cuellar-Partida, Gabriel / D'Eustacchio, Angela / Danesh, John / Davies, Gail / Bakker, Paul I W / Groot, Mark C H / Mutsert, Renée / Deary, Ian J / Dedoussis, George / Demerath, Ellen W / Heijer, Martin / Hollander, Anneke I / Ruijter, Hester M / Dennis, Joe G / Denny, Josh C / Di Angelantonio, Emanuele / Drenos, Fotios / Du, Mengmeng / Dubé, Marie-Pierre / Dunning, Alison M / Easton, Douglas F / Edwards, Todd L / Ellinghaus, David / Ellinor, Patrick T / Elliott, Paul / Evangelou, Evangelos / Farmaki, Aliki-Eleni / Farooqi, I Sadaf / Faul, Jessica D / Fauser, Sascha / Feng, Shuang / Ferrannini, Ele / Ferrieres, Jean / Florez, Jose C / Ford, Ian / Fornage, Myriam / Franco, Oscar H / Franke, Andre / Franks, Paul W / Friedrich, Nele / Frikke-Schmidt, Ruth / Galesloot, Tessel E / Gan, Wei / Gandin, Ilaria / Gasparini, Paolo / Gibson, Jane / Giedraitis, Vilmantas / Gjesing, Anette P / Gordon-Larsen, Penny / Gorski, Mathias / Grabe, Hans-Jörgen / Grant, Struan F A / Grarup, Niels / Griffiths, Helen L / Grove, Megan L / Gudnason, Vilmundur / Gustafsson, Stefan / Haessler, Jeff / Hakonarson, Hakon / Hammerschlag, Anke R / Hansen, Torben / Harris, Kathleen Mullan / Harris, Tamara B / Hattersley, Andrew T / Have, Christian T / Hayward, Caroline / He, Liang / Heard-Costa, Nancy L / Heath, Andrew C / Heid, Iris M / Helgeland, Øyvind / Hernesniemi, Jussi / Hewitt, Alex W / Holmen, Oddgeir L / Hovingh, G Kees / Howson, Joanna M M / Hu, Yao / Huang, Paul L / Huffman, Jennifer E / Ikram, M Arfan / Ingelsson, Erik / Jackson, Anne U / Jansson, Jan-Håkan / Jarvik, Gail P / Jensen, Gorm B / Jia, Yucheng / Johansson, Stefan / Jørgensen, Marit E / Jørgensen, Torben / Jukema, J Wouter / Kahali, Bratati / Kahn, René S / Kähönen, Mika / Kamstrup, Pia R / Kanoni, Stavroula / Kaprio, Jaakko / Karaleftheri, Maria / Kardia, Sharon L R / Karpe, Fredrik / Kathiresan, Sekar / Kee, Frank / Kiemeney, Lambertus A / Kim, Eric / Kitajima, Hidetoshi / Komulainen, Pirjo / Kooner, Jaspal S / Kooperberg, Charles / Korhonen, Tellervo / Kovacs, Peter / Kuivaniemi, Helena / Kutalik, Zoltán / Kuulasmaa, Kari / Kuusisto, Johanna / Laakso, Markku / Lakka, Timo A / Lamparter, David / Lange, Ethan M / Lange, Leslie A / Langenberg, Claudia / Larson, Eric B / Lee, Nanette R / Lehtimäki, Terho / Lewis, Cora E / Li, Huaixing / Li, Jin / Li-Gao, Ruifang / Lin, Honghuang / Lin, Keng-Hung / Lin, Li-An / Lin, Xu / Lind, Lars / Lindström, Jaana / Linneberg, Allan / Liu, Ching-Ti / Liu, Dajiang J / Liu, Yongmei / Lo, Ken S / Lophatananon, Artitaya / Lotery, Andrew J / Loukola, Anu / Luan, Jian'an / Lubitz, Steven A / Lyytikäinen, Leo-Pekka / Männistö, Satu / Marenne, Gaëlle / Mazul, Angela L / McCarthy, Mark I / McKean-Cowdin, Roberta / Medland, Sarah E / Meidtner, Karina / Milani, Lili / Mistry, Vanisha / Mitchell, Paul / Mohlke, Karen L / Moilanen, Leena / Moitry, Marie / Montgomery, Grant W / Mook-Kanamori, Dennis O / Moore, Carmel / Mori, Trevor A / Morris, Andrew D / Morris, Andrew P / Müller-Nurasyid, Martina / Munroe, Patricia B / Nalls, Mike A / Narisu, Narisu / Nelson, Christopher P / Neville, Matt / Nielsen, Sune F / Nikus, Kjell / Njølstad, Pål R / Nordestgaard, Børge G / Nyholt, Dale R / O'Connel, Jeffrey R / O'Donoghue, Michelle L / Loohuis, Loes M Olde / Ophoff, Roel A / Owen, Katharine R / Packard, Chris J / Padmanabhan, Sandosh / Palmer, Colin N A / Palmer, Nicholette D / Pasterkamp, Gerard / Patel, Aniruddh P / Pattie, Alison / Pedersen, Oluf / Peissig, Peggy L / Peloso, Gina M / Pennell, Craig E / Perola, Markus / Perry, James A / Perry, John R B / Pers, Tune H / Person, Thomas N / Peters, Annette / Petersen, Eva R B / Peyser, Patricia A / Pirie, Ailith / Polasek, Ozren / Polderman, Tinca J / Puolijoki, Hannu / Raitakari, Olli T / Rasheed, Asif / Rauramaa, Rainer / Reilly, Dermot F / Renström, Frida / Rheinberger, Myriam / Ridker, Paul M / Rioux, John D / Rivas, Manuel A / Roberts, David J / Robertson, Neil R / Robino, Antonietta / Rolandsson, Olov / Rudan, Igor / Ruth, Katherine S / Saleheen, Danish / Salomaa, Veikko / Samani, Nilesh J / Sapkota, Yadav / Sattar, Naveed / Schoen, Robert E / Schreiner, Pamela J / Schulze, Matthias B / Scott, Robert A / Segura-Lepe, Marcelo P / Shah, Svati H / Sheu, Wayne H-H / Sim, Xueling / Slater, Andrew J / Small, Kerrin S / Smith, Albert V / Southam, Lorraine / Spector, Timothy D / Speliotes, Elizabeth K / Starr, John M / Stefansson, Kari / Steinthorsdottir, Valgerdur / Stirrups, Kathleen E / Strauch, Konstantin / Stringham, Heather M / Stumvoll, Michael / Sun, Liang / Surendran, Praveen / Swift, Amy J / Tada, Hayato / Tansey, Katherine E / Tardif, Jean-Claude / Taylor, Kent D / Teumer, Alexander / Thompson, Deborah J / Thorleifsson, Gudmar / Thorsteinsdottir, Unnur / Thuesen, Betina H / Tönjes, Anke / Tromp, Gerard / Trompet, Stella / Tsafantakis, Emmanouil / Tuomilehto, Jaakko / Tybjaerg-Hansen, Anne / Tyrer, Jonathan P / Uher, Rudolf / Uitterlinden, André G / Uusitupa, Matti / Laan, Sander W / Duijn, Cornelia M / Leeuwen, Nienke / van Setten, Jessica / Vanhala, Mauno / Varbo, Anette / Varga, Tibor V / Varma, Rohit / Edwards, Digna R Velez / Vermeulen, Sita H / Veronesi, Giovanni / Vestergaard, Henrik / Vitart, Veronique / Vogt, Thomas F / Völker, Uwe / Vuckovic, Dragana / Wagenknecht, Lynne E / Walker, Mark / Wallentin, Lars / Wang, Feijie / Wang, Carol A / Wang, Shuai / Wang, Yiqin / Ware, Erin B / Wareham, Nicholas J / Warren, Helen R / Waterworth, Dawn M / Wessel, Jennifer / White, Harvey D / Willer, Cristen J / Wilson, James G / Witte, Daniel R / Wood, Andrew R / Wu, Ying / Yaghootkar, Hanieh / Yao, Jie / Yao, Pang / Yerges-Armstrong, Laura M / Young, Robin / Zeggini, Eleftheria / Zhan, Xiaowei / Zhang, Weihua / Zhao, Jing Hua / Zhao, Wei / Zhou, Wei / Zondervan, Krina T / Rotter, Jerome I / Pospisilik, John A / Rivadeneira, Fernando / Borecki, Ingrid B / Deloukas, Panos / Frayling, Timothy M / Lettre, Guillaume / North, Kari E / Lindgren, Cecilia M / Hirschhorn, Joel N / Loos, Ruth J F

    Nature genetics

    2019  Volume 51, Issue 7, Page(s) 1191–1192

    Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...

    Abstract An amendment to this paper has been published and can be accessed via a link at the top of the paper.
    Language English
    Publishing date 2019-06-04
    Publishing country United States
    Document type Published Erratum
    ZDB-ID 1108734-1
    ISSN 1546-1718 ; 1061-4036
    ISSN (online) 1546-1718
    ISSN 1061-4036
    DOI 10.1038/s41588-019-0447-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Rare and low-frequency coding variants alter human adult height.

    Marouli, Eirini / Graff, Mariaelisa / Medina-Gomez, Carolina / Lo, Ken Sin / Wood, Andrew R / Kjaer, Troels R / Fine, Rebecca S / Lu, Yingchang / Schurmann, Claudia / Highland, Heather M / Rüeger, Sina / Thorleifsson, Gudmar / Justice, Anne E / Lamparter, David / Stirrups, Kathleen E / Turcot, Valérie / Young, Kristin L / Winkler, Thomas W / Esko, Tõnu /
    Karaderi, Tugce / Locke, Adam E / Masca, Nicholas G D / Ng, Maggie C Y / Mudgal, Poorva / Rivas, Manuel A / Vedantam, Sailaja / Mahajan, Anubha / Guo, Xiuqing / Abecasis, Goncalo / Aben, Katja K / Adair, Linda S / Alam, Dewan S / Albrecht, Eva / Allin, Kristine H / Allison, Matthew / Amouyel, Philippe / Appel, Emil V / Arveiler, Dominique / Asselbergs, Folkert W / Auer, Paul L / Balkau, Beverley / Banas, Bernhard / Bang, Lia E / Benn, Marianne / Bergmann, Sven / Bielak, Lawrence F / Blüher, Matthias / Boeing, Heiner / Boerwinkle, Eric / Böger, Carsten A / Bonnycastle, Lori L / Bork-Jensen, Jette / Bots, Michiel L / Bottinger, Erwin P / Bowden, Donald W / Brandslund, Ivan / Breen, Gerome / Brilliant, Murray H / Broer, Linda / Burt, Amber A / Butterworth, Adam S / Carey, David J / Caulfield, Mark J / Chambers, John C / Chasman, Daniel I / Chen, Yii-Der Ida / Chowdhury, Rajiv / Christensen, Cramer / Chu, Audrey Y / Cocca, Massimiliano / Collins, Francis S / Cook, James P / Corley, Janie / Galbany, Jordi Corominas / Cox, Amanda J / Cuellar-Partida, Gabriel / Danesh, John / Davies, Gail / de Bakker, Paul I W / de Borst, Gert J / de Denus, Simon / de Groot, Mark C H / de Mutsert, Renée / Deary, Ian J / Dedoussis, George / Demerath, Ellen W / den Hollander, Anneke I / Dennis, Joe G / Di Angelantonio, Emanuele / Drenos, Fotios / Du, Mengmeng / Dunning, Alison M / Easton, Douglas F / Ebeling, Tapani / Edwards, Todd L / Ellinor, Patrick T / Elliott, Paul / Evangelou, Evangelos / Farmaki, Aliki-Eleni / Faul, Jessica D / Feitosa, Mary F / Feng, Shuang / Ferrannini, Ele / Ferrario, Marco M / Ferrieres, Jean / Florez, Jose C / Ford, Ian / Fornage, Myriam / Franks, Paul W / Frikke-Schmidt, Ruth / Galesloot, Tessel E / Gan, Wei / Gandin, Ilaria / Gasparini, Paolo / Giedraitis, Vilmantas / Giri, Ayush / Girotto, Giorgia / Gordon, Scott D / Gordon-Larsen, Penny / Gorski, Mathias / Grarup, Niels / Grove, Megan L / Gudnason, Vilmundur / Gustafsson, Stefan / Hansen, Torben / Harris, Kathleen Mullan / Harris, Tamara B / Hattersley, Andrew T / Hayward, Caroline / He, Liang / Heid, Iris M / Heikkilä, Kauko / Helgeland, Øyvind / Hernesniemi, Jussi / Hewitt, Alex W / Hocking, Lynne J / Hollensted, Mette / Holmen, Oddgeir L / Hovingh, G Kees / Howson, Joanna M M / Hoyng, Carel B / Huang, Paul L / Hveem, Kristian / Ikram, M Arfan / Ingelsson, Erik / Jackson, Anne U / Jansson, Jan-Håkan / Jarvik, Gail P / Jensen, Gorm B / Jhun, Min A / Jia, Yucheng / Jiang, Xuejuan / Johansson, Stefan / Jørgensen, Marit E / Jørgensen, Torben / Jousilahti, Pekka / Jukema, J Wouter / Kahali, Bratati / Kahn, René S / Kähönen, Mika / Kamstrup, Pia R / Kanoni, Stavroula / Kaprio, Jaakko / Karaleftheri, Maria / Kardia, Sharon L R / Karpe, Fredrik / Kee, Frank / Keeman, Renske / Kiemeney, Lambertus A / Kitajima, Hidetoshi / Kluivers, Kirsten B / Kocher, Thomas / Komulainen, Pirjo / Kontto, Jukka / Kooner, Jaspal S / Kooperberg, Charles / Kovacs, Peter / Kriebel, Jennifer / Kuivaniemi, Helena / Küry, Sébastien / Kuusisto, Johanna / La Bianca, Martina / Laakso, Markku / Lakka, Timo A / Lange, Ethan M / Lange, Leslie A / Langefeld, Carl D / Langenberg, Claudia / Larson, Eric B / Lee, I-Te / Lehtimäki, Terho / Lewis, Cora E / Li, Huaixing / Li, Jin / Li-Gao, Ruifang / Lin, Honghuang / Lin, Li-An / Lin, Xu / Lind, Lars / Lindström, Jaana / Linneberg, Allan / Liu, Yeheng / Liu, Yongmei / Lophatananon, Artitaya / Luan, Jian'an / Lubitz, Steven A / Lyytikäinen, Leo-Pekka / Mackey, David A / Madden, Pamela A F / Manning, Alisa K / Männistö, Satu / Marenne, Gaëlle / Marten, Jonathan / Martin, Nicholas G / Mazul, Angela L / Meidtner, Karina / Metspalu, Andres / Mitchell, Paul / Mohlke, Karen L / Mook-Kanamori, Dennis O / Morgan, Anna / Morris, Andrew D / Morris, Andrew P / Müller-Nurasyid, Martina / Munroe, Patricia B / Nalls, Mike A / Nauck, Matthias / Nelson, Christopher P / Neville, Matt / Nielsen, Sune F / Nikus, Kjell / Njølstad, Pål R / Nordestgaard, Børge G / Ntalla, Ioanna / O'Connel, Jeffrey R / Oksa, Heikki / Loohuis, Loes M Olde / Ophoff, Roel A / Owen, Katharine R / Packard, Chris J / Padmanabhan, Sandosh / Palmer, Colin N A / Pasterkamp, Gerard / Patel, Aniruddh P / Pattie, Alison / Pedersen, Oluf / Peissig, Peggy L / Peloso, Gina M / Pennell, Craig E / Perola, Markus / Perry, James A / Perry, John R B / Person, Thomas N / Pirie, Ailith / Polasek, Ozren / Posthuma, Danielle / Raitakari, Olli T / Rasheed, Asif / Rauramaa, Rainer / Reilly, Dermot F / Reiner, Alex P / Renström, Frida / Ridker, Paul M / Rioux, John D / Robertson, Neil / Robino, Antonietta / Rolandsson, Olov / Rudan, Igor / Ruth, Katherine S / Saleheen, Danish / Salomaa, Veikko / Samani, Nilesh J / Sandow, Kevin / Sapkota, Yadav / Sattar, Naveed / Schmidt, Marjanka K / Schreiner, Pamela J / Schulze, Matthias B / Scott, Robert A / Segura-Lepe, Marcelo P / Shah, Svati / Sim, Xueling / Sivapalaratnam, Suthesh / Small, Kerrin S / Smith, Albert Vernon / Smith, Jennifer A / Southam, Lorraine / Spector, Timothy D / Speliotes, Elizabeth K / Starr, John M / Steinthorsdottir, Valgerdur / Stringham, Heather M / Stumvoll, Michael / Surendran, Praveen / 't Hart, Leen M / Tansey, Katherine E / Tardif, Jean-Claude / Taylor, Kent D / Teumer, Alexander / Thompson, Deborah J / Thorsteinsdottir, Unnur / Thuesen, Betina H / Tönjes, Anke / Tromp, Gerard / Trompet, Stella / Tsafantakis, Emmanouil / Tuomilehto, Jaakko / Tybjaerg-Hansen, Anne / Tyrer, Jonathan P / Uher, Rudolf / Uitterlinden, André G / Ulivi, Sheila / van der Laan, Sander W / Van Der Leij, Andries R / van Duijn, Cornelia M / van Schoor, Natasja M / van Setten, Jessica / Varbo, Anette / Varga, Tibor V / Varma, Rohit / Edwards, Digna R Velez / Vermeulen, Sita H / Vestergaard, Henrik / Vitart, Veronique / Vogt, Thomas F / Vozzi, Diego / Walker, Mark / Wang, Feijie / Wang, Carol A / Wang, Shuai / Wang, Yiqin / Wareham, Nicholas J / Warren, Helen R / Wessel, Jennifer / Willems, Sara M / Wilson, James G / Witte, Daniel R / Woods, Michael O / Wu, Ying / Yaghootkar, Hanieh / Yao, Jie / Yao, Pang / Yerges-Armstrong, Laura M / Young, Robin / Zeggini, Eleftheria / Zhan, Xiaowei / Zhang, Weihua / Zhao, Jing Hua / Zhao, Wei / Zheng, He / Zhou, Wei / Rotter, Jerome I / Boehnke, Michael / Kathiresan, Sekar / McCarthy, Mark I / Willer, Cristen J / Stefansson, Kari / Borecki, Ingrid B / Liu, Dajiang J / North, Kari E / Heard-Costa, Nancy L / Pers, Tune H / Lindgren, Cecilia M / Oxvig, Claus / Kutalik, Zoltán / Rivadeneira, Fernando / Loos, Ruth J F / Frayling, Timothy M / Hirschhorn, Joel N / Deloukas, Panos / Lettre, Guillaume

    Nature

    2017  Volume 542, Issue 7640, Page(s) 186–190

    Abstract: Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies ( ... ...

    Abstract Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
    MeSH term(s) ADAMTS Proteins/genetics ; Adult ; Alleles ; Body Height/genetics ; Cell Adhesion Molecules/genetics ; Female ; Gene Frequency/genetics ; Genetic Variation/genetics ; Genome, Human/genetics ; Glycoproteins/genetics ; Glycoproteins/metabolism ; Glycosaminoglycans/biosynthesis ; Hedgehog Proteins/genetics ; Humans ; Intercellular Signaling Peptides and Proteins/genetics ; Intercellular Signaling Peptides and Proteins/metabolism ; Interferon Regulatory Factors/genetics ; Interleukin-11 Receptor alpha Subunit/genetics ; Male ; Multifactorial Inheritance/genetics ; NADPH Oxidase 4 ; NADPH Oxidases/genetics ; Phenotype ; Pregnancy-Associated Plasma Protein-A/metabolism ; Procollagen N-Endopeptidase/genetics ; Proteoglycans/biosynthesis ; Proteolysis ; Receptors, Androgen/genetics ; Somatomedins/metabolism
    Chemical Substances AR protein, human ; CRISPLD2 protein, human ; Cell Adhesion Molecules ; Glycoproteins ; Glycosaminoglycans ; Hedgehog Proteins ; IHH protein, human ; IL11RA protein, human ; Intercellular Signaling Peptides and Proteins ; Interferon Regulatory Factors ; Interleukin-11 Receptor alpha Subunit ; Proteoglycans ; Receptors, Androgen ; STC2 protein, human ; Somatomedins ; NADPH Oxidase 4 (EC 1.6.3.-) ; NADPH Oxidases (EC 1.6.3.-) ; NOX4 protein, human (EC 1.6.3.-) ; ADAMTS Proteins (EC 3.4.24.-) ; ADAMTS3 protein, human (EC 3.4.24.-) ; Pregnancy-Associated Plasma Protein-A (EC 3.4.24.-) ; Procollagen N-Endopeptidase (EC 3.4.24.14)
    Language English
    Publishing date 2017-02-01
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/nature21039
    Database MEDical Literature Analysis and Retrieval System OnLINE

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