Genetically Regulated Bilirubin and Risk of Non-alcoholic Fatty Liver Disease: A Mendelian Randomization Study

Abstract

Mildly elevated serum bilirubin levels were reported to be associated with decreased risk of non-alcoholic fatty liver disease (NAFLD). Whether this is a causal relationship remains unclear. We tested the hypothesis that genetically elevated plasma bilirubin levels are causally related to reduce risk of NAFLD. A total of 403 eligible participants were enrolled. NAFLD was determined by liver ultrasonography. The uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene variants (UGT1A1*6 and UGT1A1*28) were genotyped through sequencing. We applied a Mendelian randomization approach to assess the effects of genetically elevated bilirubin levels on NAFLD. NAFLD was diagnosed in 19% of participants in our study (NAFLD = 76; Non-NAFLD = 327). The variants of UGT1A1*28 and UGT1A1*6 were strongly associated with increased total bilirubin (TB), direct bilirubin (DB), and indirect bilirubin (IB) levels (each P < 0.001). These two common variants explain 12.7% (TB), 11.4% (IB), and 10.2% (DB) of the variance in bilirubin levels, respectively. In logistic regression model, after multifactorial adjustment for sex, age, aminotransferase (ALT), white blood count (WBC), and body mass index (BMI), variant UGT1A1*28 (OR = 1.39; 95%CI: 0.614–3.170; P = 0.43) and UGT1A1*6 (OR = 1.64, 95%CI, 0.78–3.44; P = 0.19) genotypes were not significantly associated with the risk of NAFLD. Moreover, the plasma bilirubin level (TB, IB, and DB) were not significantly associated with the risk of NAFLD (P > 0.30). A Mendelian randomization analysis of the UGT1A1 variants suggests that bilirubin is unlikely causally related with the risk of NAFLD.

Fucus vesiculosus and Ascophyllum nodosum Ameliorate Liver Function by Reducing Diet-Induced Steatosis in Rats

“…The findings we obtained about plasma bilirubin levels deserve further discussion. Indeed, it is well-known that a controversial relationship exists between plasma bilirubin and NAFLD, since, although a mild increase of serum bilirubin levels had been associated with a reduction of liver steatosis risk [23], a more recent study [24] provided convincing evidences against this hypothesis. Our data indicate that the algal extract decreases bilirubin plasma levels, as well as ALT and AST, thereby confirming its beneficial effects on liver function, which are also demonstrated by histology.…”

Western Diet-Induced Metabolic Alterations Affect Circulating Markers of Liver Function before the Development of Steatosis

“…The relationship between plasma bilirubin and NAFLD is controversial. Indeed, although mildly elevated serum bilirubin levels were reported to reduce the risk of developing this disease [41,42], a recent study [43] provided evidences against this hypothesis. Therefore, the observed increase in total and direct bilirubin, together with the one of AST, is probably related to an early impairment of liver function.…”

Bilirubin is not associated with urinary bladder cancer risk and prognosis: A Mendelian Randomization Study in the UK Biobank

“…Rs6742078 was chosen as the instrumental variable (IV) for bilirubin levels. Rs6742078 shows high correlation (r2>0.8) with the causative locus for GS and has been successfully used for other MR studies on various phenotypes [15, 16, 17],…”

“…It is difficult to establish whether hyperbilirubinemia is the actual causal agent for these benefits or merely a correlated marker, but the use of Mendelian Randomization (MR) makes it possible to decipher its’ role in human health. MR studies on bilirubinaemia and cardiovascular disease [14], stroke [15], and non-fatty liver disease [16] showed bilirubin is unlikely to play a role in these traits. On the other hand, a report on diabetes risk indicates increased bilirubin levels exhibit a protective effect [17], It has to be noted most MR studies (with the exception of Luo et al .…”

“…On the other hand, a report on diabetes risk indicates increased bilirubin levels exhibit a protective effect [17], It has to be noted most MR studies (with the exception of Luo et al . [16]) have only considered total serum bilirubin (TB) levels. Instead, high TB levels may reflect impaired liver function, and hence only unconjugated bilirubin (UB) is hypothesized to offer health benefits, if any [9].…”