Genetics and Epigenetics in Systemic Lupus Erythematosus

Student thesis: Doctoral ThesisDoctor of Philosophy


Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease associated with a wide range of clinical features involving different organs and the prognosis is also highly variable. It is a complex genetic trait in which more than 80 susceptibility loci show robust genetic association with disease risk.
Firstly, I preformed eQTL mapping, incorporating co-localization analysis of GWAS in the functional immune cells, in order to identify likely causal genes. The results indicate that eQTLs present in a diverse set of immune cells, encompassing both the innate and adaptive immune responses for more than half of the loci. I then integrated genetics, epigenetics and gene expression to delineate the regulatory map of SLE risk loci across human cells and tissues. Using GARFIELD and GoShifter, I demonstrated that SLE genetic associations displayed a marked enrichment pattern for areas of open chromatin in blood, including B cells, T cells, monocytes, and NK cells. Moreover, I found that a large proportion (66%) of the SLE eQTLs showed to overlap with areas of open chromatin, denoting extensive local coordination of genetic influences on gene expression and epigenetics.
SLE patients with renal involvement have more severe clinical outcomes and an increased mortality risk. By calculating the genetic risk score (GRS) using a list of SNPs that are reported to be significantly associated with SLE, I found a significant correlation between GRS and patients with renal involvement – the higher the GRS, the higher probability of getting renal disease. The GRS also correlated inversely with age of SLE onset.
As part of the functional study of post-GWAS, I investigated the protein expression of selected SLE-susceptibility gene products, namely Ikaros family members and OX40L, in a range of immune cells, using multi-parameter flow cytometry. The results reveal some cellular specificity in gene expression in disease. In particular, IKZF3 expression on activated regulatory T cell subsets was decreased, while OX40L expression on B cell subsets was increased in SLE.
In summary, I combined eQTLs and epigenomes to identify the functional tissues and causal genes. In addition, I measured the expression of OX40L and Ikraos family to help understand the cell effects at protein level. Finally, I found that the genetic risk factors that influence the severity of SLE are through a quantitative way but not qualitative way, suggesting that the GRS approach may become a useful factor in predicting outcome in this clinically heterogeneous disease.
Date of Award2018
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorTimothy Vyse (Supervisor) & David Morris (Supervisor)

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