Epidemiological studies on comorbidity, heritability and co-aggregation in organ-specific autoimmune diseases

Abstract

Autoimmunity is caused by loss of tolerance, whereby the immune system fails to distinguish self from non-self. The autoimmune panorama entails more than 100 diseases that collectively affect close to 5% of the total population, with a higher prevalence in women than in men. Depending on which tissues are targeted, autoimmunity is classified as organ-specific or systemic. For unknown reasons, organ-specific autoimmunity often targets the endocrine system, leading to organ failure and lifelong need of hormone replacement.

Most autoimmune diseases show familial clustering, but co-aggregation of different disorders in family members, and co-occurrence of multiple diseases in a single individual, is also common. This points to shared etiologies in autoimmunity. Twin studies can help explain to what extent genetic and environmental influences contribute to differences in traits, and can thus provide a framework for genetic studies. In autoimmunity, twin studies have helped explain genetic contributions (heritability) for some diseases, but for many they are still lacking. In other scientific fields, twin studies have also been used to shed light on disease overlap, but no attempts of explaining clustering of autoimmunity using twins have been published.

In this thesis we explore different aspects of organ-specific autoimmunity. In Study I, we use the Swedish Twin Registry to demonstrate that the heritability for Addison’s disease is very high, making it suitable for further genetic studies. In Study II we use national health registries to explore cardiovascular morbidity for Addison’s disease, and show that women are at increased risk of cardiac events. We also demonstrate a dose-dependent correlation between adrenal hormone replacement-therapy and risk of cardiovascular disease. Study III addresses genetic versus non-genetic components to clustering in seven autoimmune diseases, and we find evidence of genetic factors explaining co-aggregation. In Study III we also validate previous estimates of heritability in autoimmunity by using a larger cohort of twins than ever before used. In Study IV, we take a closer look at Hashimoto’s thyroiditis and Graves’ disease, again using twins. Results imply that they are distantly related diseases, in contrast with current dogma. We also find that heritability is higher in men than in women, most notably for Hashimoto’s thyroiditis. This could mean that the mechanisms leading to disease differ between the sexes.