title: Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study.
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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study.
  
  
  BACKGROUND
  British Heart Foundation, UK Medical Research Council, and Academy of Finland.
authors: 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.
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authors: Aida Karina
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authors: 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.
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authors: Population, Policy and Practice, UCL Institute of Child Health, London, UK.
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authors: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
authors: Hermann
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authors: Brenner
authors: Tromsø Endocrine Research Group, Department of Clinical Medicine, University of Tromsø, Tromsø, Norway.
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authors: Pim
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authors: van der Harst
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authors: Aroon D
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authors: Hingorani
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authors: Pilz
authors: Quantitative Sciences, GlaxoSmithKline, Stevenage, UK.
authors: John C
authors: JC
authors: Whittaker
authors: 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.
authors: Marjo-Riitta
authors: MR
authors: Järvelin
authors: 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.
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mesh_terms: D000328:Adult; D015992:Body Mass Index; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics*; D000072467:Cytochrome P450 Family 2; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000235:genetics / Q000517:prevention & control*; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016032:Randomized Controlled Trials as Topic; D014807:Vitamin D / Q000008:administration & dosage / Q000031:analogs & derivatives*; D014808:Vitamin D Deficiency / Q000097:blood / Q000235:genetics / Q000517:prevention & control*
chemical_list: D014807:Vitamin D; C104450:25-hydroxyvitamin D; D000072467:Cytochrome P450 Family 2; C506833:CYP2R1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase