| Summary: | <p>My D.Phil project investigated if women with endometriosis have an increased risk of immunological diseases, if endometriosis is causal to (any) immunological diseases and if there could be shared genetic risk factors between endometriosis and (any) immunological diseases.</p>
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<p>Firstly, existing evidence was summarized by a systematic review of population-based studies that reported an association between endometriosis and (auto)immune diseases. However, many of the studies reviewed were of suboptimal quality. Five studies provided high quality evidence suggesting a significantly increased risk of systemic lupus erythematosus, Sjogren’s syndrome, rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease in women with endometriosis as well as a significantly increased risk of endometriosis in women with coeliac disease. Meta-analysis with combinable study results found a significantly increased risk of systemic lupus erythematosus and Sjogren’s syndrome in women with endometriosis.</p>
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<p>Next, a cross-sectional and a prospective cohort study were conducted analysing UK Biobank data collected from 273,404 UK women. In both cross-sectional study and cohort study analyses, a significantly increased risk was observed for overall immunological diseases, classic autoimmune diseases and for autoinflammatory diseases. A significantly increased risk for mixed-pattern diseases was also observed in cross-sectional study, but this increased risk became non-significant in the prospective cohort study, likely due to a reduced sample size. In the cross-sectional study, women with endometriosis were found to have a significantly increased risk for (systemic) lupus erythematosus, rheumatoid arthritis, coeliac disease, myasthenia gravis, inflammatory bowel disease, osteoarthritis, gout (including pseudogout, crystal arthropathy), ankylosing spondylitis and a borderline significant risk for type 1 diabetes, ulcerative colitis and psoriasis. Yet the cohort study approach only found a significantly increased risk of incident rheumatoid arthritis (HR [95%CI] = 2.25[1.33-3.79], P = 0.002*) and incident osteoarthritis (HR [95%CI] = 1.26 [1.01-1.58], P = 0.042*) in women with endometriosis aged < 50 years old women and for (systemic) lupus erythematosus (HR [95%CI] = 2.37[1.21-4.65], P = 0.012*) in women of endometriosis aged ≥ 60 years old.</p>
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<p>Genome-wide association study (GWAS) data in UKBB were meta-analysed with publicly available GWAS to investigate at genetic level the association between endometriosis and immunological diseases. Endometriosis was found to be significantly genetically correlated with multiple sclerosis (RG[SE] = 0.093[0.034], P = 0.006*), osteoarthritis (RG[SE] = 0.278[0.035], P = 3.248x10<sup>-15</sup>) and rheumatoid arthritis (RG[SE] = 0.180[0.041], P = 1.25x10<sup>-5</sup>), but not for other immunological diseases. Mendelian randomisation (MR) analysis did not show endometriosis to be causal to any of the 3 genetically correlated immunological diseases. Multi-trait genetic analysis for endometriosis, multiple sclerosis, osteoarthritis and rheumatoid arthritis identified 10 novel variants for endometriosis, and 4 shared genetic variants between endometriosis and osteoarthritis. Their potential functional roles through eQTL analysis provided insights into key molecular players in disease processes.</p>
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<p>Further work could be done to validate my study results by conducting studies with a larger sample size (especially in female-only study population), strict diagnosis criteria and investigation of disease sub-types as well as more robust instrumental variables in MR analysis.</p>
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