Vimaleswaran, Karani S3; Cavadino, Alana3; Berry, Diane J3; Jorde, Rolf3; Dieffenbach, Aida Karina3; Lu, Chen3; Alves, Alexessander Couto3; Heerspink, Hiddo J Lambers3; Tikkanen, Emmi3; Eriksson, Joel3; Wong, Andrew3; Mangino, Massimo3; Jablonski, Kathleen A3; Nolte, Ilja M3; Houston, Denise K3; Ahluwalia, Tarun Veer Singh4; van der Most, Peter J3; Pasko, Dorota3; Zgaga, Lina3; Thiering, Elisabeth3; Vitart, Veronique3; Fraser, Ross M3; Huffman, Jennifer E3; de Boer, Rudolf A3; Schöttker, Ben3; Saum, Kai-Uwe3; McCarthy, Mark I3; Dupuis, Josée3; Herzig, Karl-Heinz3; Sebert, Sylvain3; Pouta, Anneli3; Laitinen, Jaana3; Kleber, Marcus E3; Navis, Gerjan3; Lorentzon, Mattias3; Jameson, Karen3; Arden, Nigel3; Cooper, Jackie A3; Acharya, Jayshree3; Hardy, Rebecca3; Raitakari, Olli3; Ripatti, Samuli3; Billings, Liana K3; Lahti, Jari3; Osmond, Clive3; Penninx, Brenda W3; Rejnmark, Lars3; Lohman, Kurt K3; Paternoster, Lavinia3; Stolk, Ronald P3; Hernandez, Dena G3; Byberg, Liisa3; Hagström, Emil3; Melhus, Håkan3; Ingelsson, Erik3; Mellström, Dan3; Ljunggren, Osten3; Tzoulaki, Ioanna3; McLachlan, Stela3; Theodoratou, Evropi3; Tiesler, Carla M T3; Jula, Antti3; Navarro, Pau3; Wright, Alan F3; Polasek, Ozren3; Wilson, James F3; Rudan, Igor3; Salomaa, Veikko3; Heinrich, Joachim3; Campbell, Harry3; Price, Jacqueline F3; Karlsson, Magnus3; Lind, Lars3; Michaëlsson, Karl3; Bandinelli, Stefania3; Frayling, Timothy M3; Hartman, Catharina A3; Sørensen, Thorkild I A4; Kritchevsky, Stephen B3; Langdahl, Bente Lomholt3; Eriksson, Johan G3; Florez, Jose C3; Spector, Tim D3; Lehtimäki, Terho3; Kuh, Diana3; Humphries, Steve E3; Cooper, Cyrus3; Ohlsson, Claes3; März, Winfried3; de Borst, Martin H3; Kumari, Meena3; Kivimaki, Mika3; Wang, Thomas J3; Power, Chris3; Brenner, Hermann3; Grimnes, Guri3; van der Harst, Pim3; Snieder, Harold3; Hingorani, Aroon D3; Pilz, Stefan3; Whittaker, John C3; Järvelin, Marjo-Riitta3; Hyppönen, Elina3
1 Section for Metabolic Genetics, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, Københavns Universitet2 Department of Public Health, Department of Public Health, Faculty of Health and Medical Sciences, Københavns Universitet3 unknown4 Section for Metabolic Genetics, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, Københavns Universitet
a mendelian randomisation study
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.
Lancet Diabetes and Endocrinology, 2014, Vol 2, Issue 9, p. 719-729