Gilbert’s syndrome, circulating bilirubin and lung cancer: a genetic advantage?

Freisling, Heinz; Khoei, Nazlisadat Seyed; Viallon, Vivian; Wagner, Karl‐Heinz

doi:10.1136/thoraxjnl-2020-215642

Cited by 5 publications

(4 citation statements)

References 13 publications

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“…Furthermore, in our study, we observed a robust inverse association with risk of squamous cell lung cancer subtype (OR 0.80, 95% CI 0.65-0.99 after excluding SNPs with potential pleiotropy), which is known to be strongly related to smoking. Taken together, genetically raised bilirubin levels may confer an advantage in terms of protecting people exposed to smoke oxidants against lung cancer [14,49].…”

Section: Lung Cancermentioning

confidence: 99%

Genetically Raised Circulating Bilirubin Levels and Risk of Ten Cancers: A Mendelian Randomization Study

Khoei

Carreras‐Torres

Murphy

et al. 2021

Cells

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Bilirubin, an endogenous antioxidant, may play a protective role in cancer development. We applied two-sample Mendelian randomization to investigate whether genetically raised bilirubin levels are causally associated with the risk of ten cancers (pancreas, kidney, endometrium, ovary, breast, prostate, lung, Hodgkin’s lymphoma, melanoma, and neuroblastoma). The number of cases and their matched controls of European descent ranged from 122,977 and 105,974 for breast cancer to 1200 and 6417 for Hodgkin’s lymphoma, respectively. A total of 115 single-nucleotide polymorphisms (SNPs) associated (p < 5 × 10−8) with circulating total bilirubin, extracted from a genome-wide association study in the UK Biobank, were used as instrumental variables. One SNP (rs6431625) in the promoter region of the uridine-diphosphoglucuronate glucuronosyltransferase1A1 (UGT1A1) gene explained 16.9% and the remaining 114 SNPs (non-UGT1A1 SNPs) explained 3.1% of phenotypic variance in circulating bilirubin levels. A one-standarddeviation increment in circulating bilirubin (≈ 4.4 µmol/L), predicted by non-UGT1A1 SNPs, was inversely associated with risk of squamous cell lung cancer and Hodgkin’s lymphoma (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.73–0.99, P 0.04 and OR 0.64, 95% CI 0.42–0.99, p 0.04, respectively), which was confirmed after removing potential pleiotropic SNPs. In contrast, a positive association was observed with the risk of breast cancer after removing potential pleiotropic SNPs (OR 1.12, 95% CI 1.04–1.20, p 0.002). There was little evidence for robust associations with the other seven cancers investigated. Genetically raised bilirubin levels were inversely associated with risk of squamous cell lung cancer as well as Hodgkin’s lymphoma and positively associated with risk of breast cancer. Further studies are required to investigate the utility of bilirubin as a low-cost clinical marker to improve risk prediction for certain cancers.

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Section: Lung Cancermentioning

confidence: 99%

Genetically Raised Circulating Bilirubin Levels and Risk of Ten Cancers: A Mendelian Randomization Study

Khoei

Carreras‐Torres

Murphy

et al. 2021

Cells

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“…Dodatkowo, obserwuje się również związek między poziomem krążącej bilirubiny a zachorowalnością na raka płuc. Wyższe stężenie bilirubiny wiąże się ze zmniejszonym ryzykiem zachorowania na raka płuca [26].…”

Section: Nowotworyunclassified

Gilbert’s syndrome as a protection against the development of other diseases

Miazga,

Maziarczyk,

Surdacka

et al. 2023

J Educ Health Sport

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Introduction and purpose Gilbert's syndrome is a condition caused by a mutation in the gene responsible for the enzyme UDP-glucuronosyltransferase 1A1, which conjugates bilirubin in hepatocytes. Its less efficient functioning results in disorder of bilirubin metabolism which leads to increased level of this compound. It has been observed that there is interesting correlation between elevated levels of bilirubin and the risk of developing certain diseases in patients with this condition. The aim of this review is to understand the correlation between elevated bilirubin levels and the risk of developing selected diseases in individuals with Gilbert's syndrome and how to use this knowledge in innovative therapeutic options. State of knowledge Bilirubin was considered a non-functional waste product of heme breakdown, used to be seen as a concerning indicator of liver disease or even a potentially harmful substance for the nervous system. However, lately it turns out that bilirubin has strong antioxidant properties, which help to scavenge free radicals and inhibit lipid oxidation. Recent studies have shown that even slightly elevated levels of bilirubin in the blood, such as those commonly found in individuals with Gilbert's syndrome may protect these patients against diseases associated with increased oxidative stress, an overactive immune response and metabolic dysfunction. Conclusions As a result, individuals with Gilbert's syndrome are observed to have a lower risk of developing diseases related to oxidative stress, such as cardiovascular diseases and cancer. In these patients mortality rate compared to the population with normobilirubinemia is decreased. Based on available studies, it has also been concluded that inducing mild hyperbilirubinemia - iatrogenic Gilbert's syndrome - using appropriate substances may have health benefits.

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“…Unconjugated bilirubin is known to be one of the most potent endogenous antioxidant substances, because it has strong ROS-scavenging, anti-oxidant, and cytoprotective properties [ 121 , 122 , 123 ]. Therefore, it is expected to contribute to protection against diseases associated with increased oxidative stress, such as cardiovascular diseases, diabetes, and colorectal cancer [ 124 , 125 , 126 , 127 ].…”

Section: Role Of Bilirubin In the Intestinal Tractmentioning

confidence: 99%

Role of Heme Oxygenase in Gastrointestinal Epithelial Cells

Akagi

2022

Antioxidants

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The gastrointestinal tract is a unique organ containing both vascular and luminal routes lined by epithelial cells forming the mucosa, which play an important role in the entry of nutrients and act as a selective barrier, excluding potentially harmful agents. Mucosal surfaces establish a selective barrier between hostile external environments and the internal milieu. Heme is a major nutritional source of iron and is a pro-oxidant that causes oxidative stress. Heme oxygenases (HOs) catalyze the rate-limiting step in heme degradation, resulting in the formation of iron, carbon monoxide, and biliverdin, which are subsequently converted to bilirubin by biliverdin reductase. In gastrointestinal pathogenesis, HO-1, an inducible isoform of HO, is markedly induced in epithelial cells and plays an important role in protecting mucosal cells. Recent studies have focused on the biological effects of the products of this enzymatic reaction, which have antioxidant, anti-inflammatory, and cytoprotective functions. In this review, the essential roles of HO in the gastrointestinal tract are summarized, focusing on nutrient absorption, protection against cellular stresses, and the maintenance and regulation of tight junction proteins, emphasizing the potential therapeutic implications. The biochemical basis of the potential therapeutic implications of glutamine for HO-1 induction in gastrointestinal injury is also discussed.

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Gilbert’s syndrome, circulating bilirubin and lung cancer: a genetic advantage?

Cited by 5 publications

References 13 publications

Genetically Raised Circulating Bilirubin Levels and Risk of Ten Cancers: A Mendelian Randomization Study

Genetically Raised Circulating Bilirubin Levels and Risk of Ten Cancers: A Mendelian Randomization Study

Gilbert’s syndrome as a protection against the development of other diseases

Role of Heme Oxygenase in Gastrointestinal Epithelial Cells

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