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Circulating Total Bilirubin and Future Risk of Hypertension in the General Population: The Prevention of Renal and Vascular End-Stage Disease (PREVEND) Prospective Study and a Mendelian Randomization Approach

Published version
Peer-reviewed

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Authors

Kunutsor, Setor K 
Kieneker, Lyanne M 
Bakker, Stephan JL 
Dullaart, Robin PF 

Abstract

BACKGROUND: Circulating total bilirubin is known to be inversely and independently associated with future risk of cardiovascular disease. However, the relationship of circulating total bilirubin with incident hypertension is uncertain. We aimed to assess the association of total bilirubin with future hypertension risk and supplemented this with a Mendelian randomization approach to investigate any causal relevance to the association. METHODS AND RESULTS: Plasma total bilirubin levels were measured at baseline in the PREVEND (Prevention of Renal and Vascular End-Stage Disease) prospective study of 3989 men and women without hypertension. Hazard ratios (95% confidence intervals) of total bilirubin with incident hypertension were assessed. New-onset hypertension was recorded in 1206 participants during a median follow-up of 10.7 years. Baseline total bilirubin was approximately log-linearly associated with hypertension risk. Age- and sex-adjusted hazard ratio for hypertension per 1-SD increase in loge total bilirubin was 0.86 (0.81-0.92; P<0.001), which was attenuated to 0.94 (0.88-0.99; P=0.040) after further adjustment for established risk factors and other potential confounders. The association was marginally significant on further adjustment for high-sensitivity C-reactive protein (0.94; 0.88-1.00; P=0.067). A genetic variant at the UGT1A1*28 locus consistently shown to be strongly associated with circulating bilirubin levels-rs6742078-was not significantly associated with blood pressure or hypertension (P>0.05 for all), arguing against a strong causal association of circulating bilirubin with blood pressure. CONCLUSIONS: The weak and inverse association of circulating total bilirubin with future hypertension risk may be driven by biases such as unmeasured confounding and/or reverse causation. Further evaluation is warranted.

Description

Keywords

Mendelian randomization, bilirubin, cohort study, hypertension, risk factor

Journal Title

Journal of the American Heart Association : Cardiovascular and Cerebrovascular Disease

Conference Name

Journal ISSN

2047-9980
2047-9980

Volume Title

6

Publisher

Wiley
Sponsorship
Medical Research Council (MR/L003120/1)
British Heart Foundation (None)
Medical Research Council (MC_UU_00002/7)
Wellcome Trust (204623/Z/16/Z)
The Dutch Kidney Foundation supported the infrastructure of the PREVEND program from 1997 to 2003 (Grant E.033). The University Medical Center Groningen supported the infrastructure from 2003 to 2006. Dade Behring, Ausam, Roche, and Abbott financed laboratory equipment and reagents by which various laboratory determinations could be performed. The Dutch Heart Foundation supported studies on lipid metabolism (Grant 2001‐005). The funding sources had no role in study design; in data collection, analysis, or interpretation of the data; in writing of the report; or in the decision to submit for publication.