Idiopathic inflammatory myopathies and cancer : familial risk, genetics and consequences

Sammanfattning: Idiopathic inflammatory myopathies (IIMs) are a group of rare rheumatic inflammatory diseases (RIDs), characterised by a diverse range of clinical, serological and histopathological characteristics, with muscle weakness as a shared hallmark. While advancements in disease management have improved the survival rates of patients with IIM, the mortality rate among patients with IIM is still higher than the general population, mainly due to association with comorbidities such as cancer. The pathogenesis of IIM, the pathological link between IIM and cancer and the impact of cancer on the survival of patients with IIM remain a subject of uncertainty. The rarity and heterogeneity inherent in IIM pose significant challenges in filing these knowledge gaps. This thesis encompasses five studies, which aimed at addressing research questions concerning the genetic contribution to IIM and its link with other autoimmune diseases and cancer, as well as the disease burden in the context of cancer in a large representative population of patients with IIM. Study I was a population-based case-control family study including 7,615 first-degree relatives of 1,620 patients with IIM diagnosis between 1997 and 2016 and 37,309 first-degree relatives of 7,797 matched comparators without IIM. Patients with IIM were four times more likely to have at least one first-degree relative affected by IIM compared to matched comparators without IIM. The heritability of IIM, a proportion of the phenotypic variance that can be explained by additive genetic variance, was 22% in the Swedish population. Study II, with the same study population as in Study I, analysed the familial associations between IIM and a variety of autoimmune diseases under a causal framework. We found shared familial factors between IIM and other RIDs, inflammatory bowel diseases, autoimmune thyroid diseases and celiac disease. Study III, with a similar study population and analytical approach as in Study II, comprehensively investigated the familial co-aggregation of IIM and cancer. We did not observe a familial association between IIM and cancer overall but modification effect by sex was noted: there was a modest familial association (adjusted odds ratio=1.39) with cancer in male first-degree relatives of patients with IIM. We also found that offspring of patients with IIM were more likely to have a cancer diagnosis at age younger than 50 years compared to those of matched comparators without IIM. In the exploratory analysis by specific cancer types, findings suggest that IIM shared familial factors with myeloid malignancies and liver cancer. Study IV explored genetic correlation between IIM and B-cell lymphomas via a cross-trait secondary analysis using summary statistics from genome-wide associations studies of IIM and four common B-cell lymphoma subtypes including diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukaemia and marginal zone lymphoma. We detected a limited number of genomic loci, predominantly within the human leukocyte antigen region, demonstrating significant genetic correlations between IIM and common Bcell lymphoma subtypes. Study V, a cohort study, followed 1,826 patients to (first and second) cancer and death (overall and cause-specific death) events since IIM diagnosis for more than 20 years. Compared to patients with no cancer diagnosis after IIM, patients with a first cancer diagnosis after IIM faced a greater five-year mortality (22% versus 49%). This excessive risk was due to an increased risk of death from cancer. In patients with a first cancer diagnosis after IIM, the one-year risk of having a second primary cancer was 11% and having a second cancer diagnosis slightly increased the risk of death. We also reported several prognostic factors associated with increased risks of cancer and death (overall, from cancer and from other causes). This thesis offers useful insight into the role of genetics in IIM pathogenesis and its connections with other autoimmune diseases and cancer, as well as the impact of cancer on the survival of patients with IIM. The observed familial aggregation of IIM and familial associations between IIM and other autoimmune diseases suggest genetic involvement in the development of IIM. Family history of IIM, other RIDs, inflammatory bowel diseases, autoimmune thyroid diseases and celiac disease may serve as indicators pointing towards an IIM diagnosis. Missing heritability is suggested by the discrepancy between our family-based heritability and the SNP-based heritability, implying yet-to-be discovered genetic variants associated with IIM. The acquired knowledge of shared familial factors between IIM and other autoimmune diseases may inform future genetic studies aiming to uncover novel IIMassociated genetic variants. There is a limited shared familial/genetic susceptibility between IIM and cancer. The human leukocyte antigen region plays an important role in the limited shared genetic susceptibility between IIM and common B-cell lymphoma subtypes. IIM concomitant with cancer leads to a substantial increase in mortality, mainly due to cancer. Future research should focus on reducing cancer-related disease burden in patients with IIM.