____________________________Vitamin D and Cardio-metabolic Health in the Elderly To my son Maximiliaan 1 This thesis is based on research enabled by Erasmus Mundus Western Balkans (ERAWEB) grant and conducted within ErasmusAGE group and Cardio-vascular epidemiology group, Department of Epidemiology, University Medical Center in Rotterdam. ErasmusAGE, Rotterdam intergenerational ageing research center is funded by Nestlé Nutrition (Nestec Ltd.), Metagenics Inc. and AXA. These funding sources had no role in design and conduct of the study, collection, management, analysis, and interpretation of the data; and preparation, review or approval of the manuscripts. The Rotterdam Study is funded by the Erasmus Medical Center and Erasmus University, the Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The contributions of the inhabitants, general practitioners and pharmacists of the Ommoord district of the Rotterdam Study are gratefully acknowledged. Financial support by the Dutch Heart Foundation for publication of this thesis is gratefully acknowledged. Cover: Edwin Herks and http://www.freedigitalphotos.net/ Layout: Martina Vitezova Printed by: Offpage ©2015, Anna Vitezova All rights reserved. The copyright is transferred to the respective publisher upon publication of the manuscript. No part of this thesis may be reproduced, stored in a retrieval system, or transmitted in any form or by any means without prior permission of the author or the publisher of the manuscript. ____________________________Vitamin D and Cardio-metabolic Health in the Elderly Vitamin D and Cardio-metabolic Health in the Elderly The Rotterdam Study Vitamine D en cardiometabole gezondheid in ouderen: De Rotterdam Studie Thesis to obtain the degree of Doctor from the Erasmus University Rotterdam by command of the rector magnificus Prof.dr. H.A.P. Pols and in accordance with the decision of the Doctorate Board. The public defence shall be held on Wednesday, 30th September 2015 at 13:30 hrs by Anna Vitezova born in Novi Sad, Serbia 1 Vitamin D and Cardio-metabolic Health in the Elderly Doctoral Committee: Promotors: Prof.dr. O.H. Franco Prof.dr. A.G. Uitterlinden Other members: Prof.dr. E.J.G. Sijbrands Prof.dr. H.M. Evenhuis Prof.dr. L.C.P.G.M. de Groot Copromotors: Dr. J.C. Kiefte- de Jong Dr. M.C. Zillikens 4 Vitamin D and Cardio-metabolic Health in the Elderly Content Page Chapter 1: General Introduction ................................ ............................ ........... 9 Chapter 2: Vitamin D and Mortality ............................................................... 17 2.1 Vitamin D and risk of cause specific death: systematic review and meta- analysis of observational cohort and randomized intervention studies ............. 19 Chapter 3: Vitamin D and Metabolic Health .................................................. 41 3.1 Vitamin D status and metabolic syndrome in the elderly: The Rotterdam Study ................................................................................................................. 43 3.2 Vitamin D status and body composition in the elderly ............................... 59 Chapter 4: Vitamin D and Cardio-vascular Health ......................................... 75 4.1 Vitamin D status and atrial fibrillation in the elderly: The Rotterdam Study ................................................................................................................. 77 Chapter 5: Pathways of Vitamin D and Health ............................................... 89 5.1 The interplay between magnesium, vitamin D status and incidence of type 2 diabetes mellitus ............................................................................................. 91 5.2 Bidirectional associations between circulating vitamin D and cholesterol levels: The Rotterdam Study ........................................................................... 103 Chapter 6: General Discussion ...................................................................... 117 Chapter 7: Summary...................................................................................... 129 Chapter 8: Appendices .................................................................................. 137 8.1 References ................................................................................................. 139 8.2 Acknowledgements ................................................................................... 167 8.3 PhD Portfolio ............................................................................................ 169 5 Vitamin D and Cardio-metabolic Health in the Elderly 6 Vitamin D and Cardio-metabolic Health in the Elderly Manuscripts included into the thesis Chapter 2 Rajiv Chowdhury, Setor Kunutsor*, Anna Vitezova*, Clare Oliver-Williams, Susmita Chowdhury, Jessica C. Kiefte-de Jong, Hassan Khan, Cristina P. Baena, Dorairaj Prabhakaran, Moshe B. Hoshen, Becca S. Feldman, An Pan, Laura Johnson, Francesca Crowe, Frank B Hu, and Oscar H. Franco. Vitamin D and risk of cause-specific death: a systematic review and meta-analysis of prospective observational and randomised intervention studies. **Denotes equal contribution. BMJ. 2014 Apr 1;348:g1903 Chapter 3 Anna Vitezova, M. Carola Zillikens, Thijs T. van Herpt, Eric J.G. Sijbrands, Albert Hofman, Andre G. Uitterlinden, Oscar H. Franco, Jessica C. Kiefte – de Jong. Vitamin D status and metabolic syndrome in the elderly: the Rotterdam Study. Eur J Endocrinol. 2015 Mar;172(3):327-35 Anna Vitezova, Taulant Muka, M. Carola Zillikens, Trudy Voortman, Andre G. Uitterlinden, Albert Hofman, Fernando Rivadeneira, Jessica C. Kiefte- de Jong, Oscar H. Franco. Vitamin D and body composition in the elderly. Clinical Nutrition (under review) Chapter 4 Anna Vitezova, Natasha S. Cartolano, Jan Heeringa, M. Carola Zillikens, Albert Hofman, Oscar H. Franco, Jessica C. Kiefte-de Jong. Vitamin D Status and Atrial Fibrillation in the Elderly: The Rotterdam Study. PLoSOne:2015 May 1;10(5):e0125161 Chapter 5 Anna Vitezova, Jessica C. Kiefte-de Jong, Brenda C.T. Kieboom, Symen Ligthart, Bruno H.C. Stricker, Andre G. Uitterlinden, Albert Hofman, M. Carola Zillikens, Oscar H. Franco. The interplay between magnesium and vitamin D status on incidence of type 2 diabetes mellitus: The Rotterdam Study. Anna Vitezova, Trudy Voortman, M. Carola Zillikens, Pauline W. Jansen, Albert Hofman, Andre G. Uitterlinden, Oscar H. Franco, Jessica C. Kiefte-de Jong. Bidirectional associations between circulating vitamin D and cholesterol levels: The Rotterdam Study. Maturitas (accepted for publication) 7 Vitamin D and Cardio-metabolic Health in the Elderly 8 Vitamin D and Cardio-metabolic Health in the Elderly Chapter 1 General Introduction 9 Vitamin D and Cardio-metabolic Health in the Elderly 10 Vitamin D and Cardio-metabolic Health in the Elderly 1.1 Vitamin D metabolism Figure 1.1.1. Vitamin D metabolism(1). Vitamin D has been discovered at the beginning of the 20th century as a cure for rickets, a disease softening the bones in children (2, 3). Since then it has been established as an important factor in bone health, more specifically in bone metabolism and calcium homeostasis(3). Vitamin D is a lipid soluble vitamin which has a function of a hormone in the human body(4). There are two forms of vitamin D present in nature: vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol)(3). Vitamin D2 is found naturally in some mushrooms while D3 comes from animal foods as fish and eggs and can be produced in the skin under the effect of solar irradiation(3, 5, 6). Regardless of the form, both vitamin D2 and D3 when entered in the bloodstream bind to a protein called vitamin D binding protein (VBP) which is the main transporter of vitamin D in the circulation(3). Both of these forms of vitamin D are biologically inert and need to undergo chemical transformations in order to get activated. The first transformation is 25-hydroxylation which takes place in the liver. As a result 25-hydroxyvitamin D is produced. This is the main circulating form of vitamin D in the human body(7). It is used to assess the vitamin D status of the individual(7). Even though in recent years scientists acknowledge that it has certain functions in the human body, it is 11 Vitamin D and Cardio-metabolic Health in the Elderly still not considered as an active vitamin D metabolite. In order to get activated 25-hydroxyvitamin D needs to undergo further transformation in the kidney and as a product of this reaction 1,25-dihydroxyvitamin D is synthesized(3). This is the active form of vitamin D which has a function of a hormone in the human body. This active form binds to a member of the nuclear receptor family called vitamin D receptor (VDR) present in many different tissues and by this manner influences among other things calcium metabolism in the human body, such as calcium absorption in the intestines or calcium reabsorption in the kidneys (see Figure 1.1.1)(8). Finally, the excess active vitamin D can stimulate its own destruction by upregulating the expression of enzyme 25-hydroxyvitamin D-24-hydroxylase which metabolizes 25- hydroxyvitamin D but also the active form into inactive forms which are soluble in water(6, 9). 1.2 Vitamin D sources, recommendations and optimal status Naturally, humans obtain their vitamin D from two sources: by