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Identification of clinical and inherited genetic variants associated with severe complications of chronic liver diseases

par Otero Sanchez, Lukas
Président du jury Verhoeven, Caroline
Promoteur Trepo, Eric
Co-Promoteur Moreno, Christophe
Publication Non publié, 2023-04-27

Thèse de doctorat

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Résumé :

Chronic liver disease (CLD) accounts for 2 million deaths yearly worldwide. Fatty liver disease (FLD) is the most prevalent cause of CLD and includes alcohol-related liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). FLD affects nearly 30% of the world's population. The two major risk factors for FLD are alcohol misuse and metabolic syndrome, including obesity and diabetes. Among that large population, only a fraction will progress to more severe stages. It includes decompensated cirrhosis and hepatocellular carcinoma (HCC). Decompensated cirrhosis and HCC are highly refractory to therapeutic intervention. Identifying and characterizing at-risk populations for CLD-related complications are needed for proper and impactful prevention strategies and treatment. However, identifying at-risk patients is challenging due to the scarcity of relevant biomarkers. We aim through this thesis to identify risk factors associated with liver-related complications, specifically in patients with diabetes, severe forms of ALD, and decompensated cirrhosis. Firstly, we evaluated whether a novel machine learning-based classification of patients with diabetes could identify individuals with an increased risk of liver-related complications. In this study, we included 1,068 adult patients with diabetes. Using competing-risk analysis, we observed that patients allocated to the severe-insulin resistant (SIR) group and patients with excessive alcohol consumption at baseline have the highest risk for liver-related events. Furthermore, being a member of the SIR group, excessive alcohol consumption and hypertension were independently associated with clinically significant fibrosis, evaluated by liver biopsy or FibroScan. Secondly, we evaluated in another retrospective study whether, in ALD patients, severe alcoholic hepatitis (sAH) modified the risk and severity of infection compared to an alcohol-related cirrhosis (DAC) without sAH. A total of 207 patients were included (139 with sAH and 68 with DAC). In multivariable analysis, factors associated with the development of infection were the presence of sAH and baseline MELD score. In both groups, pneumonia was the most prevalent bacterial infection, and Gram-negative bacilli were the primary pathogens. Our study showed that patients with sAH are more susceptible to developing infections than those with DAC. In these life-threatening forms of ALD, infected patients shared a similar mortality rate. The severity of liver dysfunction (MELD score) was the leading risk factor for infection. Corticosteroid treatment and not sAH seemed to be the leading risk factor, driving invasive fungal infection.Thirdly, we conducted the first multi-ancestry genome-wide association study (GWAS) for serum creatinine (sCr) levels in decompensated cirrhotic patients. We identified genetic variants in the SUSD1 gene as a risk factor for this population's serum creatinine levels (sCr). We showed that the SUSD1 rs7875137 variant was strongly associated with sCr levels, even after adjustment for extra-renal factors. We also showed that the SUSD1 rs7875132[T] allele mitigated the risk of severe renal outcomes, indicating the potential clinical relevance of this risk allele. Interestingly, an enrichment in SUSD1 expression was observed in plasmacytoid dendritic cells (pDC) from cirrhotic patients compared to healthy control patients. In addition, we showed that the level of SUSD1 expression, and pDC infiltration in the liver, were significantly higher in decompensated cirrhotic patients compared to compensated and non-cirrhotic patients.In conclusion, we identified novel clinical and inherited risk factors associated with liver-related complications. Our results provide novel insights and may also help design future functional experiments to understand better the underlying biological mechanism leading to the development of severe forms of CLD.