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

Karani S Vimaleswaran; Alana Cavadino; Diane J Berry; LifeLines Cohort Study investigators; Rolf Jorde; Aida Karina Dieffenbach; Chen Lu; Alexessander Couto Alves; Hiddo J Lambers Heerspink; Emmi Tikkanen; +98 more... Joel Eriksson; Andrew Wong; Massimo Mangino; Kathleen A Jablonski; Ilja M Nolte; Denise K Houston; Tarunveer Singh Ahluwalia; Peter J van der Most; Dorota Pasko; Lina Zgaga; Elisabeth Thiering; Veronique Vitart; Ross M Fraser; Jennifer E Huffman; Rudolf A de Boer; Ben Schöttker; Kai-Uwe Saum; Mark I McCarthy; Josée Dupuis; Karl-Heinz Herzig; Sylvain Sebert; Anneli Pouta; Jaana Laitinen; Marcus E Kleber; Gerjan Navis; Mattias Lorentzon; Karen Jameson; Nigel Arden; Jackie A Cooper; Jayshree Acharya; Rebecca Hardy; Olli Raitakari; Samuli Ripatti; Liana K Billings; Jari Lahti; Clive Osmond; Brenda W Penninx; Lars Rejnmark; Kurt K Lohman; Lavinia Paternoster; Ronald P Stolk; Dena G Hernandez; Liisa Byberg; Emil Hagström; Håkan Melhus; Erik Ingelsson; Dan Mellström; Osten Ljunggren; Ioanna Tzoulaki; Stela McLachlan; Evropi Theodoratou; Carla MT Tiesler; Antti Jula; Pau Navarro; Alan F Wright; Ozren Polasek; International Consortium for Blood Pressure (ICBP); Cohorts for Heart and Aging Research in Genomic Epidemiology (CH; Global Blood Pressure Genetics (Global BPGen) consortium; Caroline Hayward; James F Wilson; Igor Rudan; Veikko Salomaa; Joachim Heinrich; Harry Campbell; Jacqueline F Price; Magnus Karlsson; Lars Lind; Karl Michaëlsson; Stefania Bandinelli; Timothy M Frayling; Catharina A Hartman; Thorkild IA Sørensen; Stephen B Kritchevsky; Bente Lomholt Langdahl; Johan G Eriksson; Jose C Florez; Tim D Spector; Terho Lehtimäki; Diana Kuh; Steve E Humphries; Cyrus Cooper; Claes Ohlsson; Winfried März; Martin H de Borst; Meena Kumari; Mika Kivimaki; Thomas J Wang; Chris Power; Hermann Brenner; Guri Grimnes; Pim van der Harst; Harold Snieder; Aroon D Hingorani; Stefan Pilz; John C Whittaker; Marjo-Riitta Järvelin; Elina Hyppönen; (2014) Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study. The lancet Diabetes & endocrinology, 2 (9). pp. 719-729. ISSN 2213-8587 DOI: 10.1016/S2213-8587(14)70113-5

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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.