Journal of hepatology (2020) pg 1-41
A non-invasive method to grade the severity of steatohepatitis and liver
fibrosis is magnetic resonance imaging (MRI) based corrected T1 (cT1). We aimed to
identify genetic variants influencing liver cT1 and use genetics to understand mechanisms
underlying liver fibroinflammatory disease and its link with other metabolic traits and
First, we performed a genome-wide association study (GWAS) in 14,440
Europeans in UK Biobank with liver cT1 measures. Second, we explored the effects of the
cT1 variants on liver blood tests, and a range of metabolic traits and diseases. Third, we
used Mendelian randomisation to test the causal effects of 24 predominantly metabolic traits
on liver cT1 measures.
Results: We identified six independent genetic variants associated with liver cT1 that
reached GWAS significance threshold (p<5×10-8). Four of the variants (rs75935921 in
SLC30A10, rs13107325 in SLC39A8, rs58542926 in TM6SF2, rs738409 in PNPLA3) were
also associated with elevated transaminases and had variable effects on liver fat and other
metabolic traits. Insulin resistance, type 2 diabetes, non-alcoholic fatty liver and BMI were
causally associated with elevated cT1 whilst favourable adiposity (instrumented by variants
associated with higher adiposity but lower risk of cardiometabolic disease and lower liver fat)
was found to be protective.
The association between two metal ion transporters and cT1 indicates an
important new mechanism in steatohepatitis. Future studies are needed to determine
whether interventions targeting the identified transporters might prevent liver disease in at
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