Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study.
Vimaleswaran KS., Cavadino A., Berry DJ., LifeLines Cohort Study investigators None., Jorde R., Dieffenbach AK., Lu C., Alves AC., Heerspink HJL., Tikkanen E., Eriksson J., Wong A., Mangino M., Jablonski KA., Nolte IM., Houston DK., Ahluwalia TS., van der Most PJ., Pasko D., Zgaga L., Thiering E., Vitart V., Fraser RM., Huffman JE., de Boer RA., Schöttker B., Saum K-U., McCarthy MI., Dupuis J., Herzig K-H., Sebert S., Pouta A., Laitinen J., Kleber ME., Navis G., Lorentzon M., Jameson K., Arden N., Cooper JA., Acharya J., Hardy R., Raitakari O., Ripatti S., Billings LK., Lahti J., Osmond C., Penninx BW., Rejnmark L., Lohman KK., Paternoster L., Stolk RP., Hernandez DG., Byberg L., Hagström E., Melhus H., Ingelsson E., Mellström D., Ljunggren O., Tzoulaki I., McLachlan S., Theodoratou E., Tiesler CMT., Jula A., Navarro P., Wright AF., Polasek O., International Consortium for Blood Pressure (ICBP) None., Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium None., Global Blood Pressure Genetics (Global BPGen) consortium None., Caroline Hayward None., Wilson JF., Rudan I., Salomaa V., Heinrich J., Campbell H., Price JF., Karlsson M., Lind L., Michaëlsson K., Bandinelli S., Frayling TM., Hartman CA., Sørensen TIA., Kritchevsky SB., Langdahl BL., Eriksson JG., Florez JC., Spector TD., Lehtimäki T., Kuh D., Humphries SE., Cooper C., Ohlsson C., März W., de Borst MH., Kumari M., Kivimaki M., Wang TJ., Power C., Brenner H., Grimnes G., van der Harst P., Snieder H., Hingorani AD., Pilz S., Whittaker JC., Järvelin M-R., Hyppönen E.
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.