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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 log e  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  UGT 1A1*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.

journal of the american heart association

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