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Lancet Diabetes Endocrinol. 2014 Sep;2(9):719-29. doi: 10.1016/S2213-8587(14)70113-5. Epub 2014 Jun 25.

Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study.

Vimaleswaran KS1, Cavadino A2, Berry DJ2; LifeLines Cohort Study investigators, Jorde R3, Dieffenbach AK4, Lu C5, Alves AC6, Heerspink HJ7, Tikkanen E8, Eriksson J9, Wong A10, Mangino M11, Jablonski KA12, Nolte IM13, Houston DK14, Ahluwalia TS15, van der Most PJ13, Pasko D16, Zgaga L17, Thiering E18, Vitart V19, Fraser RM20, Huffman JE19, de Boer RA21, Schöttker B4, Saum KU4, McCarthy MI22, Dupuis J23, Herzig KH24, Sebert S25, Pouta A26, Laitinen J27, Kleber ME28, Navis G29, Lorentzon M9, Jameson K30, Arden N31, Cooper JA32, Acharya J32, Hardy R10, Raitakari O33, Ripatti S34, Billings LK35, Lahti J36, Osmond C30, Penninx BW37, Rejnmark L38, Lohman KK39, Paternoster L40, Stolk RP13, Hernandez DG41, Byberg L42, Hagström E43, Melhus H43, Ingelsson E44, Mellström D9, Ljunggren O43, Tzoulaki I45, McLachlan S20, Theodoratou E20, Tiesler CM46, Jula A47, Navarro P19, Wright AF19, Polasek O48; International Consortium for Blood Pressure (ICBP); Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium; Global Blood Pressure Genetics (Global BPGen) consortium; Caroline Hayward, Wilson JF20, Rudan I20, Salomaa V49, Heinrich J50, Campbell H20, Price JF20, Karlsson M51, Lind L43, Michaëlsson K42, Bandinelli S52, Frayling TM16, Hartman CA53, Sørensen TI54, Kritchevsky SB14, Langdahl BL38, Eriksson JG55, Florez JC56, Spector TD11, Lehtimäki T57, Kuh D10, Humphries SE32, Cooper C31, Ohlsson C9, März W58, de Borst MH29, Kumari M59, Kivimaki M59, Wang TJ60, Power C2, Brenner H4, Grimnes G3, van der Harst P21, Snieder H13, Hingorani AD61, Pilz S62, Whittaker JC63, Järvelin MR64, Hyppönen E65.

Author information

1
Population, Policy and Practice, UCL Institute of Child Health, London, UK; Hugh Sinclair Unit of Human Nutrition, Department of Food & Nutritional Sciences, School of Chemistry, Food & Pharmacy, University of Reading, Reading, UK.
2
Population, Policy and Practice, UCL Institute of Child Health, London, UK.
3
Tromsø Endocrine Research Group, Department of Clinical Medicine, University of Tromsø, Tromsø, Norway.
4
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
5
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
6
Department of Epidemiology and Biostatistics, Imperial College London, London, UK; Institute of Health Sciences, University of Oulu, Oulu, Finland.
7
Department of Clinical Pharmacology, University Medical Center, University of Groningen, Groningen, Netherlands.
8
Institute for Molecular Medicine Finland, Tukholmankatu, Finland; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Hjelt Institute, University of Helsinki, Helsinki, Finland.
9
Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
10
MRC Unit for Lifelong Health and Ageing, University College London, London, UK.
11
Department of Twin Research & Genetic Epidemiology, King's College London, St Thomas' Campus, London, UK.
12
Biostatistics Center, Department of Epidemiology and Biostatistics, School of Public Health, George Washington University, Rockville, MD, USA.
13
Department of Epidemiology, University Medical Center, University of Groningen, Groningen, Netherlands.
14
Gerontology and Geriatric Medicine, Department of Internal Medicine, and J Paul Sticht Center on Aging, Wake Forest School of Medicine, Winston-Salem, NC, USA.
15
Metabolic Genetics, Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Danish Pediatric Asthma Center, Gentofte Hospital, Copenhagen, Denmark.
16
Genetics of Complex Traits, University of Exeter Medical School, Exeter, UK.
17
Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK; Department of Public Health and Primary Care, Trinity College Dublin, Dublin, Ireland.
18
Institute of Epidemiology I, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Division of Metabolic Diseases and Nutritional Medicine, Ludwig Maximilian University of Munich, Dr von Hauner Children's Hospital, Munich, Germany.
19
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
20
Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
21
Department of Cardiology, University Medical Center, University of Groningen, Groningen, Netherlands.
22
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Oxford NIHR Biomedical Research Centre, Oxford, UK.
23
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
24
Institute of Biomedicine, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland; Medical Research Center Oulu, Oulu University Hospital, Oulu, Finland.
25
Biocenter Oulu, University of Oulu, Oulu, Finland; Institute of Health Sciences, University of Oulu, Oulu, Finland.
26
Obstetrics and Gynecology, Department of Clinical Sciences, Oulu University Hospital, Oulu, Finland; National Institute for Health and Welfare, Oulu, Finland.
27
Finnish Institute of Occupational Health, Helsinki, Finland.
28
Medical Clinic V (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany.
29
Department of Internal Medicine, Division of Nephrology, University Medical Center, University of Groningen, Groningen, Netherlands.
30
MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.
31
NIHR Oxford Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK; MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.
32
Cardiovascular Genetics, BHF Laboratories, Institute of Cardiovascular Science, University College London, London, UK.
33
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
34
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
35
Center for Human Genetic Research and Diabetes Research Center, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; NorthShore University HealthSystem, Evanston, IL, USA.
36
Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland.
37
Department of Psychiatry, EMGO Institute, VU University Medical Centre, Amsterdam, Netherlands.
38
Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
39
Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
40
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK.
41
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
42
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
43
Uppsala Clinical Research Centre, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
44
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Uppsala Clinical Research Centre, Department of Medical Sciences, Uppsala University, Uppsala, Sweden; Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
45
Faculty of Medicine, School of Public Health, Imperial College London, London, UK.
46
Institute of Epidemiology I, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Medical Informatics, Biometry and Epidemiology, Ludwig Maximilian University of Munich, Dr von Hauner Children's Hospital, Munich, Germany.
47
Department of Chronic Disease Prevention, National Institute for Health and Welfare, Turku, Finland.
48
Croatian Centre for Global Health, University of Split Medical School, Split, Croatia.
49
National Institute for Health and Welfare, Helsinki, Finland.
50
Institute of Epidemiology I, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
51
Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences and Orthopaedic Surgery, Lund University, Skåne University Hospital, Malmö, Sweden.
52
Geriatric Unit, Azienda Sanitaria Firenze, Florence, Italy.
53
Department of Psychiatry, University Medical Center, University of Groningen, Groningen, Netherlands.
54
Metabolic Genetics, Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.
55
Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland; Vasa Central Hospital, Vasa, Finland; Folkhälsan Research Centre, Helsinki, Finland; Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland.
56
Center for Human Genetic Research and Diabetes Research Center, Massachusetts General Hospital, Boston, MA, USA.
57
Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine, University of Tampere, Tampere, Finland.
58
Medical Clinic V (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany; Synlab Academy, Mannheim, Germany; Department of Internal Medicine, Division of Endocrinology and Metabolism, and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
59
Department of Epidemiology and Public Health, University College London, London, UK.
60
Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN, USA.
61
Genetic Epidemiology Group, University College London, London, UK.
62
Department of Internal Medicine, Division of Endocrinology and Metabolism, and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
63
Quantitative Sciences, GlaxoSmithKline, Stevenage, UK.
64
Department of Epidemiology and Biostatistics, Imperial College London, London, UK; MRC-PHE Centre for Environment & Health, Imperial College London, London, UK; Biocenter Oulu, University of Oulu, Oulu, Finland; Institute of Health Sciences, University of Oulu, Oulu, Finland; Unit of Primary Care, Oulu University Hospital, Oulu, Finland; National Institute for Health and Welfare, Oulu, Finland.
65
Population, Policy and Practice, UCL Institute of Child Health, London, UK; School of Population Health, Sansom Institute for Health Research, University of South Australia, Adelaide, SA, Australia; South Australian Health and Medical Research Institute, Adelaide, SA, Australia. Electronic address: elina.hypponen@unisa.edu.au.

Abstract

BACKGROUND:

Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk.

METHODS:

In this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which we used as a proxy for 25(OH)D concentration. We meta-analysed data for up to 108 173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. We complemented these analyses with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium.

FINDINGS:

In phenotypic analyses (up to n=49 363), increased 25(OH)D concentration was associated with decreased systolic blood pressure (β per 10% increase, -0·12 mm Hg, 95% CI -0·20 to -0·04; p=0·003) and reduced odds of hypertension (odds ratio [OR] 0·98, 95% CI 0·97-0·99; p=0·0003), but not with decreased diastolic blood pressure (β per 10% increase, -0·02 mm Hg, -0·08 to 0·03; p=0·37). In meta-analyses in which we combined data from D-CarDia and the ICBP (n=146 581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of -0·10 mm Hg in systolic blood pressure (-0·21 to -0·0001; p=0·0498) and a change of -0·08 mm Hg in diastolic blood pressure (-0·15 to -0·02; p=0·01). When D-CarDia and consortia data for hypertension were meta-analysed together (n=142 255), the synthesis score was associated with a reduced odds of hypertension (OR per allele, 0·98, 0·96-0·99; p=0·001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH)D concentration was associated with a change of -0·29 mm Hg in diastolic blood pressure (-0·52 to -0·07; p=0·01), a change of -0·37 mm Hg in systolic blood pressure (-0·73 to 0·003; p=0·052), and an 8·1% decreased odds of hypertension (OR 0·92, 0·87-0·97; p=0·002).

INTERPRETATION:

Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study.

FUNDING:

British Heart Foundation, UK Medical Research Council, and Academy of Finland.

PMID:
24974252
PMCID:
PMC4582411
DOI:
10.1016/S2213-8587(14)70113-5
[Indexed for MEDLINE]
Free PMC Article

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