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

• Published in: The lancet. Diabetes & endocrinology 2014-09, Vol.2 (9), p.719-729
• Main Authors: Vimaleswaran, Karani S, PhD, Cavadino, Alana, MSc, Berry, Diane J, PhD, Jorde, Rolf, Prof, Dieffenbach, Aida Karina, PhD, Lu, Chen, PhD, Heerspink, Hiddo J Lambers, PhD, Tikkanen, Emmi, PhD, Eriksson, Joel, MD, Wong, Andrew, PhD, Mangino, Massimo, PhD, Jablonski, Kathleen A, PhD, Nolte, Ilja M, PhD, Houston, Denise K, PhD, Ahluwalia, Tarunveer Singh, PhD, van der Most, Peter J, MSc, Pasko, Dorota, MSc, Zgaga, Lina, PhD, Thiering, Elisabeth, MSc, Vitart, Veronique, PhD, Fraser, Ross M, PhD, Huffman, Jennifer E, MSc, de Boer, Rudolf A, Prof, Schöttker, Ben, PhD, Saum, Kai-Uwe, MPH, McCarthy, Mark I, Prof, Dupuis, Josée, Prof, Herzig, Karl-Heinz, Prof, Sebert, Sylvain, PhD, Pouta, Anneli, MD, Laitinen, Jaana, PhD, Kleber, Marcus E, PhD, Navis, Gerjan, Prof, Lorentzon, Mattias, Prof, Jameson, Karen, MSc, Arden, Nigel, Prof, Cooper, Jackie A, MSc, Acharya, Jayshree, PhD, Hardy, Rebecca, Prof, Raitakari, Olli, Prof, Billings, Liana K, MD, Lahti, Jari, PhD, Osmond, Clive, Prof, Penninx, Brenda W, Prof, Rejnmark, Lars, MD, Lohman, Kurt K, MStat, Paternoster, Lavinia, PhD, Stolk, Ronald P, Prof, Hernandez, Dena G, MS, Byberg, Liisa, PhD, Hagström, Emil, MD, Melhus, Håkan, Prof, Ingelsson, Erik, Prof, Mellström, Dan, Prof, Ljunggren, Östen, Prof, Tzoulaki, Ioanna, PhD, McLachlan, Stela, MD, Theodoratou, Evropi, PhD, Tiesler, Carla M T, MSc, Jula, Antti, MD, Navarro, Pau, PhD, Wright, Alan F, Prof, Polasek, Ozren, MD, Wilson, James F, DPhil, Rudan, Igor, Prof, Salomaa, Veikko, Prof, Heinrich, Joachim, PhD, Campbell, Harry, Prof, Price, Jacqueline F, MD, Karlsson, Magnus, Prof, Lind, Lars, MD, Michaëlsson, Karl, Prof, Bandinelli, Stefania, Frayling, Timothy M, Prof, Hartman, Catharina A, PhD, Sørensen, Thorkild I A, Prof, Kritchevsky, Stephen B, Prof, Langdahl, Bente Lomholt, Prof, Eriksson, Johan G, Prof, Florez, Jose C, Prof, Spector, Tim D, Prof, Lehtimäki, Terho, Prof, Kuh, Diana, Prof, Humphries, Steve E, Prof, Cooper, Cyrus, Prof, Ohlsson, Claes, Prof, März, Winfried, Prof, Kumari, Meena, Prof, Kivimaki, Mika, Prof, Wang, Thomas J, Prof, Power, Chris, Prof, Brenner, Hermann, Prof, Grimnes, Guri, MD, van der Harst, Pim, MD, Snieder, Harold, Prof, Hingorani, Aroon D, Prof, Pilz, Stefan, Prof, Whittaker, John C, Prof, Järvelin, Marjo-Riitta, Prof, Hyppönen, Elina, Prof
• Format: Article
• Language: English
• Subjects: Adult; Body Mass Index; Cholestanetriol 26-Monooxygenase - genetics; Clinical Medicine; Cytochrome P450 Family 2; Endocrinology & Metabolism; Endocrinology and Diabetes; Endokrinologi och diabetes; Female; Genetic Predisposition to Disease; Humans; Hypertension - blood; Hypertension - genetics; Hypertension - prevention & control; Klinisk medicin; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Mendelian Randomization Analysis; Middle Aged; Other; Oxidoreductases Acting on CH-CH Group Donors - genetics; Phenotype; Polymorphism, Single Nucleotide; Randomized Controlled Trials as Topic; Vitamin D - administration & dosage; Vitamin D - analogs & derivatives; Vitamin D Deficiency - blood; Vitamin D Deficiency - genetics; Vitamin D Deficiency - prevention & control
• ISSN: 2213-8587; 2213-8595; 2213-8595
• DOI: 10.1016/S2213-8587(14)70113-5

Summary 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 warran