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

Abstract

BackgroundCirculating 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 ResultsPlasma 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.ConclusionsThe 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.

Plasma neutrophil gelatinase-associated lipocalin and risk of cardiovascular disease: Findings from the PREVEND prospective cohort study

“…The study design and recruitment processes have been described previously. [27][28][29] The PREVEND cohort consists of a representative sample of men and women living in the city of Groningen in the Netherlands. The current cohort involved 6894 individuals aged 32-80 years who were invited for the second screening phase of the PREVEND study and who had baseline assessments performed between 2001 and 2003.…”

Circulating total bilirubin and risk of non-alcoholic fatty liver disease in the PREVEND study: observational findings and a Mendelian randomization study

“…The PREVEND study was designed to investigate the natural course of urinary albumin excretion and its relationship to renal and CVD progression. The study design and recruitment procedures have been described in detail in several previous reports [2,32]. Briefly, 8592 inhabitants aged 28-75 years living in the city of Groningen, the Netherlands were recruited into the PREVEND study with baseline measurements performed between 1997 and 1998.…”

“…Briefly, 8592 inhabitants aged 28-75 years living in the city of Groningen, the Netherlands were recruited into the PREVEND study with baseline measurements performed between 1997 and 1998. For the present analysis, we excluded participants (1) with a prevalent history of CVD, renal disease, malignancy, or NAFLD (for the analysis of FLI outcome, participants with prevalent NAFLD as measured by FLI were excluded and vice versa for HSI) and (2) with excessive alcohol use (defined as four or more drinks per day), which left a cohort of 3824 participants (based on FLI) with non-missing information on total bilirubin levels, relevant covariates, and outcomes. Of these participants, 1610 individuals had complete phenotypic and genotypic data.…”

“…Circulating total bilirubin has been consistently shown to be inversely and independently associated with adverse cardiometabolic outcomes such as cardiovascular disease (CVD), hypertension and type 2 diabetes [1][2][3]. Though a causal association has been demonstrated for total bilirubin and type 2 diabetes [4], there is no strong evidence for a causal association between total bilirubin levels and CVD [5,6].…”

Research update for articles published in EJCI in 2016

“…39 In line, low serum bilirubin levels were observed to be associated with incident hypertension. 40 The heme oxygenase (HO) system is pivotal for bilirubin generation, and the expression of HO-2 isoenzyme is upregulated by glucocorticoids. Our randomized trial among 47 hypopituitary patients showed that doubling of the hydrocortisone replacement dose elicited a significant 10% increase in serum total bilirubin.…”