Bilirubin acts as a multipotent guardian of cardiovascular integrity: more than just a radical idea

Bulmer, Andrew Cameron; Bakrania, Bhavisha; Toit, Eugene F. Du; Boon, Ai-Ching; Clark, Paul J.; Powell, Lawrie W.; Wagner, Karl‐Heinz; Headrick, John P.

doi:10.1152/ajpheart.00417.2017

Cited by 58 publications

(63 citation statements)

References 112 publications

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“…Interest in the study of the factors associated with serum bilirubin concentrations has increased recently since there is more evidence of its antioxidant and anti-inflammatory effects [22,31,32,33] and its protective effect (U-shaped) against the incidence of diabetes, kidney disease, cardiovascular disease, other cardiovascular phenotypes, and even mortality [20,21,23,34,35,36,37,38,39,40,41,42,43,44]. Initially, the focus was between the association of high bilirubin concentrations and jaundice in children and other related syndromes (Gilbert, etc.)…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, we focused our study on the analysis of sex-specific GWAS and the exploration of gene-diet interactions. We selected the serum concentrations of total bilirubin as the central phenotype taking into account that there is a growing interest in it due to its potential protection against cardiovascular disease [20,21,22,23], and mainly, because it is highly heritable [24]. Hence, statistically significant results at the GWAS level can be obtained with a relatively small number of study subjects.…”

Section: Introductionmentioning

confidence: 99%

“…Despite its historical association with toxicity, recently bilirubin has been recognized as a powerful antioxidant and anti-inflammatory protective molecule [31,32,33], which is gaining more attention due to its pleiotropic protective effects against several diseases associated with increased oxidative stress [20,31,33]. Thus, for this paradoxical compound, a protective, mainly U-shaped relationship has been reported for the incidence of diabetic retinopathy [34], diabetic kidney disease [35], cardiovascular diseases [20,23,36], cardiovascular and total death [21,37], diabetes [38,39], carotid atherosclerosis [40,41], and kidney disease [42,43] among others [22,44]. Furthermore, recent findings have shown that bilirubin is a novel signaling molecule capable of binding to peroxisome proliferator-activated receptor-alpha PPARα.…”

Section: Introductionmentioning

confidence: 99%

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Genome-Wide Association Study (GWAS) on Bilirubin Concentrations in Subjects with Metabolic Syndrome: Sex-Specific GWAS Analysis and Gene-Diet Interactions in a Mediterranean Population

et al. 2019

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Although, for decades, increased serum bilirubin concentrations were considered a threatening sign of underlying liver disease and had been associated with neonatal jaundice, data from recent years show that bilirubin is a powerful antioxidant and suggest that slightly increased serum bilirubin concentrations are protective against oxidative stress-related diseases, such as cardiovascular diseases. Therefore, a better understanding of the gene-diet interactions in determining serum bilirubin concentrations is needed. None of the previous genome-wide association studies (GWAS) on bilirubin concentrations has been stratified by sex. Therefore, considering the increasing interest in incorporating the gender perspective into nutritional genomics, our main aim was to carry out a GWAS on total serum bilirubin concentrations in a Mediterranean population with metabolic syndrome, stratified by sex. Our secondary aim was to explore, as a pilot study, the presence of gene-diet interactions at the GWAS level. We included 430 participants (188 men and 242 women, aged 55–75 years, and with metabolic syndrome) in the PREDIMED Plus-Valencia study. Global and sex-specific GWAS were undertaken to analyze associations and gene-diet interaction on total serum bilirubin. Adherence (low and high) to the Mediterranean diet (MedDiet) was analyzed as the dietary modulator. In the GWAS, we detected more than 55 SNPs associated with serum bilirubin at p < 5 × 10−8 (GWAS level). The top-ranked were four SNPs (rs4148325 (p = 9.25 × 10−24), rs4148324 (p = 9.48 × 10−24), rs6742078 (p = 1.29 × 10−23), rs887829 (p = 1.39 × 10−23), and the rs4148324 (p = 9.48 × 10−24)) in the UGT1A1 (UDP glucuronosyltransferase family 1 member A1) gene, which replicated previous findings revealing the UGT1A1 as the major locus. In the sex-specific GWAS, the top-ranked SNPs at the GWAS level were similar in men and women (the lead SNP was the rs4148324-UGT1A1 in both men (p = 4.77 × 10−11) and women (p = 2.15 × 10−14), which shows homogeneous genetic results for the major locus. There was more sex-specific heterogeneity for other minor genes associated at the suggestive level of GWAS significance (p < 1 × 10−5). We did not detect any gene-MedDiet interaction at p < 1 × 10−5 for the major genetic locus, but we detected some gene-MedDiet interactions with other genes at p < 1 × 10−5, and even at the GWAS level for the IL17B gene (p = 3.14 × 10−8). These interaction results, however, should be interpreted with caution due to our small sample size. In conclusion, our study provides new data, with a gender perspective, on genes associated with total serum bilirubin concentrations in men and women, and suggests possible additional modulations by adherence to MedDiet.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genome-Wide Association Study (GWAS) on Bilirubin Concentrations in Subjects with Metabolic Syndrome: Sex-Specific GWAS Analysis and Gene-Diet Interactions in a Mediterranean Population

et al. 2019

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“…Bilirubin, far from being just a waste product highly toxic for neurons, has been recognized as a powerful antioxidant and anti-inflammatory molecule. The potential application of bilirubin for the treatment of human diseases is driven by its ability to prevent endothelial dysfunction, thus affecting not only the treatment and prevention of CVDs (Ayer et al, 2016;Bulmer et al, 2018;Maruhashi et al, 2019), but also many other pathologies in which the alterations of endothelial cells has been proved to play a role (Figure 3 and Tables 1, 2).…”

Section: Conclusion and Future Researchmentioning

confidence: 99%

Heme Oxygenase Dependent Bilirubin Generation in Vascular Cells: A Role in Preventing Endothelial Dysfunction in Local Tissue Microenvironment?

2020

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Among antioxidants in the human body, bilirubin has been recognized over the past 20 years to afford protection against different chronic conditions, including inflammation and cardiovascular disease. Moderate increases in plasma concentration and cellular bilirubin generation from metabolism of heme via heme oxygenase (HMOX) in virtually all tissues can modulate endothelial and vascular function and exert antioxidant and antiinflammatory roles. This review aims to provide an up-to-date and critical overview of the molecular mechanisms by which bilirubin derived from plasma or from HMOX1 activation in vascular cells affects endothelial function. Understanding the molecular actions of bilirubin may critically improve the management not only of key cardiovascular diseases, but also provide insights into a broad spectrum of pathologies driven by endothelial dysfunction. In this context, therapeutic interventions aimed at mildly increasing serum bilirubin as well as bilirubin generated endogenously by endothelial HMOX1 should be considered.

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“…An association of lower bilirubin levels with mortality fits well with the suggested cardiovascular-protective actions of bilirubin. As reviewed by Bulmer and colleagues [16], bilirubin within the normal range is associated with a reduction in oxidative lipid and protein modifications, as well as a reduced platelet activation. In addition, it has been noted that individuals with Gilbert´s syndrome, a state of unconjugated hyperbilirubinemia, are protected from cardiovascular disease and associated mortality [17].…”

Section: Comparison With the Literaturementioning

confidence: 95%

Commonly used clinical chemistry tests as mortality predictors: Results from two large cohort studies

et al. 2020

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Background The normal ranges for clinical chemistry tests are usually defined by cut-offs given by the distribution in healthy individuals. This approach does however not indicate if individuals outside the normal range are more prone to disease. Methods We studied the associations and risk prediction of 11 plasma and serum biomarkers with all-cause mortality in two population-based cohorts: a Swedish cohort (X69) initiated in 1969, and the UK Biobank (UKB) initiated in 2006–2010, with up to 48- and 9-years follow-up, respectively. Results In X69 and in UKB, 18,529 and 425,264 individuals were investigated, respectively. During the follow-up time, 14,475 deaths occurred in X69 and 17,116 in UKB. All evaluated tests were associated with mortality in X69 (P<0.0001, except bilirubin P<0.005). For calcium, blood urea nitrogen, bilirubin, hematocrit, uric acid, and iron, U-shaped associations were seen (P<0.0001). For leukocyte count, gamma-glutamyl transferase, alkaline phosphatases and lactate dehydrogenase, linear positive associations were seen, while for albumin the association was negative. Similar associations were seen in UKB. Addition of all biomarkers to a model with classical risk factors improved mortality prediction (delta C-statistics: +0.009 in X69 and +0.023 in UKB, P<0.00001 in both cohorts). Conclusions Commonly used clinical chemistry tests were associated with all-cause mortality both in the medium- and long-term perspective, and improved mortality prediction beyond classical risk factors. Since both linear and U-shaped relationships were found, we propose to define the normal range of a clinical chemistry test based on its association with mortality, rather than from the distribution.

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Bilirubin acts as a multipotent guardian of cardiovascular integrity: more than just a radical idea

Cited by 58 publications

References 112 publications

Genome-Wide Association Study (GWAS) on Bilirubin Concentrations in Subjects with Metabolic Syndrome: Sex-Specific GWAS Analysis and Gene-Diet Interactions in a Mediterranean Population

Genome-Wide Association Study (GWAS) on Bilirubin Concentrations in Subjects with Metabolic Syndrome: Sex-Specific GWAS Analysis and Gene-Diet Interactions in a Mediterranean Population

Heme Oxygenase Dependent Bilirubin Generation in Vascular Cells: A Role in Preventing Endothelial Dysfunction in Local Tissue Microenvironment?

Commonly used clinical chemistry tests as mortality predictors: Results from two large cohort studies

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