Journal
FRONTIERS IN GENETICS
Volume 9, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fgene.2018.00662
Keywords
bilirubin; NAFLD; variant; UGT1A1; mendelian randomization
Categories
Funding
- Beijing Municipal Science and Technology Project [Z171100002217070]
- National Key R&D Program of China [2017YFA0103000]
- National Science and Technology Key Project on Major Infectious Diseases HIV/AIDS, Viral Hepatitis Prevention and Treatment [2012ZX10002004-006, 2017ZX10203201-005, 2017ZX10201201, 2017ZX10202203-006-001, 2017ZX10302201-004-002]
- Beijing Municipal Administration of Hospitals Ascent Plan [DFL20151601]
- Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support [ZYLX201806]
- Digestive Medical Coordinated Development Center of Beijing Municipal Administration of Hospitals [XXZ0503]
- National Cancer Institute, National Institutes of health [HHSN26120080001E]
- Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research
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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 (UGT1Al*6 and UGT1Al*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.
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