Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. The most common cause of mortality in NAFLD is cardiovascular disease (CVD), and a key of focus in drug development is to discover therapies that target both liver injury and CVD risk. NAFLD and CVD are complex disease spectra with complex heritability patterns. Nevertheless, genome wide association studies and meta-analyses of these have identified genetic loci that are associated with increased risk of relevant pathological features of disease or clinical endpoints. This review focuses on the genetic risk loci identified in the NAFLD spectrum and asks whether any of these are also risk factors for CVD. Surprisingly, given the shared co-morbidities and risk factors, little robust evidence exists that NAFLD and CVD share genetic risk. Despite this, therapeutic intervention that targets both liver disease and CVD remains an important clinical need and a major focus for pharmaceutical development.
Highlights
Specialty section: This article was submitted to Pharmacogenetics and Pharmacogenomics, a section of the journal Frontiers in Pharmacology
This review focuses on the genetic risk loci identified in the Non-alcoholic fatty liver disease (NAFLD) spectrum and asks whether any of these are risk factors for cardiovascular disease (CVD)
MBOAT7 is highly expressed in hepatocytes, hepatic stellate cells, and hepatic sinusoidal cells, and the rs641738 T allele increases risk of hepatic triglyceride content and NAFLD spectrum, with each T allele increasing the risk of steatosis (OR: 1.42, 95% CI 1.07–1.91, p = 0.015), non-alcoholic steatohepatitis (NASH) (OR: 1.18, 95% CI 1.00–1.40, p = 0.05), hepatic fibrosis stage F2-4 (OR: 1.30, 95% CI 1.06–1.70, p = 0.012), and hepatocellular carcinoma (HCC) in the absence of advanced fibrosis (OR: 2.10, 95% CI 1.33–3.31) (Buch et al, 2015; Mancina et al, 2016; Donati et al, 2017)
Summary
Barts Liver Centre, Blizard Institute, Queen Mary University of London, London, United Kingdom. A large body of evidence indicates that cardiovascular disease (CVD) is a common cause of death among patients with NAFLD (Rafiq et al, 2009; Söderberg et al, 2010; Stepanova and Younossi, 2012; Angulo et al, 2015; Targher et al, 2016; Mahfood Haddad et al, 2017; Younossi et al, 2017) this is not a universal finding (Lazo et al, 2011; Wu et al, 2016; Zeb et al, 2016; Alexander et al, 2019a; Morrison et al, 2019) Some of this dissonance may relate to variable adjustment for existing risk factors including diabetes, obesity, smoking, ethnicity, and social deprivation. After adjusting for confounding variables, the co-existence of PNPLA3 rs738409 and TM6SF2 rs58542926 in a Korean cohort increased the risk of NASH (OR per risk allele: 2.03, 95% CI 1.50–2.73 p < 0.001) and significant fibrosis (OR for each risk allele: 1.61, 95% CI 1.19–2.17, p < 0.002) (Koo et al, 2018) with similar findings from a Chinese cohort
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