Molecular Epidemiology towards Deciphering Underlying Mechanisms of Fatty Liver Disease

Research output: Types of ThesisDoctoral ThesisInternal

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Abstract

A substantial burden of illness and mortality worldwide is caused by fatty liver disease (FLD) and its complications, including type 2 diabetes (T2D), obesity, hypertension, NBHJY98and dyslipidemia. Among the FLD patients, the majority of fatty liver patients develop non-alcoholic fatty liver disease (NAFLD), which is the most common cause of chronic liver disease worldwide. Although there are no or few symptoms, a subpopulation can progress to end-stage liver disease or even liver cancer. Recently, a consensus by an international panel of experts recommended a change in name for NAFLD to metabolic dysfunction associated fatty liver disease (MAFLD). It does not only eliminate alcohol from both the name and definition. However, the underlying mechanism of FLD and how to early diagnose FLD are still not clear. Understanding the pathophysiology of FLD can help to facilitate the prevention and treatment strategies. In this thesis, I aim to provide novel insights into the molecular mechanisms of FLD through several omics approaches and integration of multi-omics, centering on genomics, transcriptomics, metabolomics, and gut microbiota.
In Chapter 2, I found that in Rotterdam Study, lower sex hormone-binding globulin (SHBG) was associated with NAFLD both in men and women. Lower testosterone was associated with NAFLD among women. Similarly, the meta-analysis of 16 studies also indicated that there is no sex-specific association between SHBG and NAFLD. Moreover, men with NAFLD had lower testosterone levels than those without NAFLD, while women with NAFLD had higher testosterone levels than those without. In addition, men with NAFLD had lower estradiol levels than those without NAFLD.
Chapter 3 focused on investigating the impact of klotho (KL) rs495392 C>A polymorphism on the histological severity of NAFLD. In Chapter 3.1, I found that carriage of the klotho rs495392 A allele, a variant commonly reported to be associated with liver diseases, had a protective effect on steatosis severity in Chinese patients. The effect on NAFLD was confirmed in the Rotterdam Study cohort. The findings also showed the association between serum vitamin D levels and NAFLD specifically in rs495392 A allele carriers, but not in non-carriers. Moreover, I found that the rs495392 A allele attenuated the detrimental impact of the PNPLA3 rs738409 G allele on the risk of severe NAFLD in the Chinese cohort.
In Chapter 4, I mainly focused on exploring the epigenetic regulation of FLD and metabolic disorders. In Chapter 4.1, I found two recent epigenome-wide association studies conducted among large population-based cohorts that have reported the association between cg06690548 (SLC7A11) and FLD. Moreover, several studies have demonstrated the association between microRNAs (miRNAs) and FLD, in which miR-122, miR-34a, and miR-192 were recognized as the most relevant miRNAs as biomarkers for FLD. In Chapter 4.2, I found few circulating miRNAs correlated with various non-invasive markers of fatty liver, due to either non-alcoholic or alcohol FLD. The response to the editorial that commented on our paper can be found in Chapter 4.3. In Chapter 4.4, I found the relationship between plasma levels of miRNAs with obesity, body fat distribution, and fat mass using data from the Rotterdam Study. Interestingly, miR-193a-5p, the top obesity-associated miRNA was among the miRNAs I found to be significantly associated with FLD in Chapter 4.1.
Finally, in Chapter 5 I explored the potential role of the gut microbiome in liver health and disease. Chapter 5.1, I found that lower microbial alpha diversity was associated with a higher prevalence of MAFLD. Three genera were significantly associated with MAFLD after the false discovery rate was corrected (q-value
Original languageEnglish
Awarding Institution
  • Erasmus University Rotterdam
Supervisors/Advisors
  • Ikram, Arfan, Supervisor
  • Ghanbari, Mohsen, Co-supervisor
Award date13 Sept 2022
Place of PublicationRotterdam
Print ISBNs978-94-6423-960-7
Publication statusPublished - 13 Sept 2022

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