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.
Highlights
Bilirubin, the by-product of hemoglobin catabolism, is generally considered to be a lipid-soluble waste product that needs to be excreted (Fujiwara et al, 2018; Hamoud et al, 2018)
Individuals in the study distributed into 4 genotype groups: 162 (40.2%) homozygous for wild-type genotypes, 87 (21.6%) with variant uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1)∗6 genotypes, 126(31.3%) with variant UGT1A1∗28 genotypes, and 28 (6.9%) with compound variant genotypes
Except for body mass index (BMI), there were no obvious difference among the four genotype groups in respect to ALT, aspartate aminotransferase (AST), total protein (TP), ALB, Total bile acid (TBA), alkaline phosphatase (ALP), γGT, white blood count (WBC), HB, PLT, fasting plasma glucose (FPG), total cholesterol (TC), TG, high-density lipoprotein (HDL), low-density lipoprotein (LDL), uric acid (UA), and diastolic blood pressure (Table 1)
Summary
The by-product of hemoglobin catabolism, is generally considered to be a lipid-soluble waste product that needs to be excreted (Fujiwara et al, 2018; Hamoud et al, 2018). It has been reported that elevated plasma levels of bilirubin are associated with reduced risk of non-alcoholic fatty liver disease (NAFLD) in case-control studies (Hjelkrem et al, 2012; Salomone et al, 2013) and in retrospective epidemiological studies(Chang et al, 2012; Tian et al, 2016). Whether these associations reflect a true biological protective effect of bilirubin rather than confounding or reverse causation remains unknown. An artificially increasing plasma unconjugated bilirubin strategy as “Iatrogenic Gilbert syndrome” were proposed for reducing cardiovascular disease and cancer risks (Mccarty, 2007; Schwertner and Vítek, 2008)
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