Abstract
Chronic liver disease presents a major global public health challenge. Stratification of asymptomatic, at-risk patients in primary care using non-invasive methods has the potential to address this by identifying those likely to progress. We, therefore, evaluated variant alleles at loci associated with non-alcoholic fatty liver disease as genetic determinants of substantial liver injury in patients with disease risk factors. Levels of serum procollagen III (PIIINP), an established fibrosis and steatohepatitis marker, were determined in 467 people who had type 2 diabetes and/or BMI>27.3 (identified from registration with general practitioners) in this observational cross-sectional study. Patients were genotyped for characterised risk alleles in PNPLA3 (rs738409), GCKR (rs1260326) and TM6SF2 (rs58542926) and associations with PIIINP assessed. The risk alleles in PNPLA3, GCKR or TM6SF2 were not found to be individually associated with the presence of a disease risk factor and were not significantly more common in patients with raised serum PIIINP. The prevalence of possession of both PNPLA3 and GCKR variant alleles combined was significantly higher in at-risk patients with clinically significant liver disease indicated by serum PIIINP above 11ng/mL (P=.014). Genotyping, therefore, has limited value for predicting severe liver disease in at-risk individuals identified in a community setting.
Highlights
Chronic liver disease presents a major global public health challenge: liver-related deaths are rising in the UK [1] with liver cirrhosis being the third most common cause of premature death in people aged below 55 years [2]
The risk alleles in PNPLA3, GCKR or TM6SF2 were not found to be individually associated with the presence of a disease risk factor and were not significantly more common in patients with raised serum PIIINP
If only our 240 obese, non-alcoholic fatty liver disease (NAFLD)-risk patients were considered, we found a significant association between possession of the PNPLA3 variant and serum PIIINP levels (P=0.040; 8.43 ng/ml in carriers versus 7.61 ng/ml in non-carriers)
Summary
Chronic liver disease presents a major global public health challenge: liver-related deaths are rising in the UK [1] with liver cirrhosis being the third most common cause of premature death in people aged below 55 years [2]. Given that many culprits in the aetiopathogenesis of chronic liver disease (alcohol, obesity and insulin resistance) are potentially preventable, there exists an unmet need to risk-stratify individuals prior to the onset of established cirrhosis, in order to introduce effective intervention. Non-invasive methods for quantifying liver fibrosis, such as the enhanced liver fibrosis (ELF) serum biomarker panel, represent a major advance in availability of strategies with which to assess patients at risk of liver disease in the community [5, 6]. Measurement of amino-terminal peptide of procollagen III (PIIINP), a component of this panel, has been established for determining hepatic fibrosis in methotrexate therapy [7] and was identified as an accurate biomarker in discriminating between early-stage disease and more severe steatohepatitis [8]
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