AUTHOR=Luo Lei , An Ping , Jia Xinyong , Yue Xiaobian , Zheng Sujun , Liu Shuang , Chen Yu , An Wei , Winkler Cheryl A. , Duan Zhongping 

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

JOURNAL=Frontiers in Genetics

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2018.00662

DOI=10.3389/fgene.2018.00662

ISSN=1664-8021

ABSTRACT=<p>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 (<italic>UGT1A1</italic>) gene variants (<italic>UGT1A1</italic><sup>*</sup>6 and <italic>UGT1A1</italic><sup>*</sup>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 <italic>UGT1A1</italic><sup>*</sup>28 and <italic>UGT1A1</italic><sup>*</sup>6 were strongly associated with increased total bilirubin (TB), direct bilirubin (DB), and indirect bilirubin (IB) levels (each <italic>P</italic> &lt; 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 <italic>UGT1A1</italic><sup>*</sup>28 (OR = 1.39; 95%CI: 0.614–3.170; <italic>P</italic> = 0.43) and <italic>UGT1A1</italic><sup>*</sup>6 (OR = 1.64, 95%CI, 0.78–3.44; <italic>P</italic> = 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 (<italic>P</italic> &gt; 0.30). A Mendelian randomization analysis of the <italic>UGT1A1</italic> variants suggests that bilirubin is unlikely causally related with the risk of NAFLD.</p>