Dataset Information

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: 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.

SUBMITTER: Kunutsor SK

PROVIDER: S-EPMC5721749 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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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.

Kunutsor Setor K SK Kieneker Lyanne M LM Burgess Stephen S Bakker Stephan J L SJL Dullaart Robin P F RPF

Journal of the American Heart Association 20171113 11

<h4>Background</h4>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.<h4>Methods and results</h4>Plasma total bilirubin level ...[more]

PMID: 29133521

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Project description:BackgroundBilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex.MethodsIn a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10-8) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study.ResultsThe associations between circulating UCB levels and CRC risk differed by sex (Pheterogeneity = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (Pheterogeneity ≥ 0.2).ConclusionsAdditional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development.

Project description:BackgroundPostpartum depression (PPD) is one of the most common complications of delivery and is usually disregarded. Several risk factors of PPD have been identified, but its pathogenesis has not been completely understood. Serum bilirubin has been found to be a predictor of depression, whose relationship with PPD has not been investigated.MethodsObservational research was performed followed by a two-sample Mendelian randomization (MR) analysis. From 2017 to 2020, the clinical data of pregnant women were retrospectively extracted. Logistic regression and random forest algorithm were employed to assess the risk factors of PPD, including the serum levels of total bilirubin and direct bilirubin. To further explore their potential causality, univariable and multivariable Mendelian randomization (MVMR) were conducted. Sensitivity analyses for MR were performed to test the robustness of causal inference.ResultsA total of 1,810 patients were included in the PPD cohort, of which 631 (34.87%) were diagnosed with PPD. Compared with the control group, PPD patients had a significantly lower level of total bilirubin (9.2 μmol/L, IQR 7.7, 11.0 in PPD; 9.7 μmol/L, IQR 8.0, 12.0 in control, P < 0.001) and direct bilirubin (2.0 μmol/L, IQR 1.6, 2.6 in PPD; 2.2 μmol/L, IQR 1.7, 2.9 in control, P < 0.003). The prediction model identified eight independent predictive factors of PPD, in which elevated total bilirubin served as a protective factor (OR = 0.94, 95% CI 0.90-0.99, P = 0.024). In the MR analyses, genetically predicted total bilirubin was associated with decreased risk of PPD (IVW: OR = 0.86, 95% CI 0.76-0.97, P = 0.006), which remained consistent after adjusting educational attainment, income, and gestational diabetes mellitus. Conversely, there is a lack of solid evidence to support the causal relationship between PPD and bilirubin.ConclusionOur results suggested that decreased total bilirubin was associated with the incidence of PPD. Future studies are warranted to investigate its potential mechanisms and illuminate the pathogenesis of PPD.

Dataset Information

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.

Publications

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.

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