Review
Twin studies in autoimmune disease: Genetics, gender and environment

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Abstract

Twin studies are powerful tools to discriminate whether a complex disease is due to genetic or environmental factors. High concordance rates among monozygotic (MZ) twins support genetic factors being predominantly involved, whilst low rates are suggestive of environmental factors. Twin studies have often been utilised in the study of systemic and organ specific autoimmune diseases. As an example, type I diabetes mellitus has been investigated to establish that that disease is largely affected by genetic factors, compared to rheumatoid arthritis or scleroderma, which have a weaker genetic association. However, large twin studies are scarce or virtually non-existent in other autoimmune diseases which have been limited to few sets of twins and individual case reports. In addition to the study of the genetic and environmental contributions to disease, it is likely that twin studies will also provide data in regards to the clinical course of disease, as well as risk for development in related individuals. More importantly, genome-wide association studies have thus far reported genomic variants that only account for a minority of autoimmunity cases, and cannot explain disease discordance in MZ twins. Future research is therefore encouraged not only in the analysis of twins with autoimmune disease, but also in regards to epigenetic factors or rare variants that may be discovered with next-generation sequencing. This review will examine the literature surrounding twin studies in autoimmune disease including discussions of genetics and gender.

Highlights

► Twin studies delineate genetic and environmental influences in disease pathogenesis. ► Twin studies in autoimmune diseases range from comprehensive to non-existent. ► The rarity of some autoimmune diseases may limit or prohibit twin studies. ► Epigenetic and sex-linked factors should be taken into account with twin studies. ► Twin studies have demonstrated a female predominance in most autoimmune diseases.

Introduction

Twin studies are an invaluable source to researchers attempting to distinguish whether genetic or environmental factors (or varying degrees of both) contribute to the development of disease, and possibly its outcome [1], [2]. This quantification is based on a comparison of disease concordance between monozygotic (MZ, identical), and dizygotic (DZ, fraternal) twins. These concordance rates can be expressed as either pairwise or probandwise concordance. Pairwise concordance provides the proportion of affected pairs concordant for the disease. For example, if 40 pairs are concordant for a disease in a cohort of 100 pairs, the pairwise concordance would be 40%. Probandwise concordance provides an estimation of the risk that one twin will develop the disease if their co-twin has been diagnosed. If 40 previously non-affected twins become affected in a cohort of 100 pairs, then the probandwise concordance would be 57%. The presumed idea is that as MZ twins share 100% of their genomic sequence, a phenotype concordance significantly higher compared to DZ twins would be suggestive of predominant genetic influences, while low concordance rates would indicate stronger environmental factors. Concordance rates in most conditions generally support both genetic and environmental influences, with varying degrees of each. These environmental factors include chemicals and xenobiotics, in some cases are related to lifestyle (alcohol, smoking, diet, exercise), as well as microorganisms [3]. A combination of environmental and genetic influences has formed the basis of a complex multi-hit model of disease, where a genetically predisposed individual encounters several environmental exposures over a lifetime, which culminate in disease development after a final series of crucial hits. This model has been proposed for several multifactorial diseases, including autoimmune disease, and the limited applicability of the most robust genomic associations from genome-wide association studies (GWAS) have supported this notion.

Twin studies have been performed in many autoimmune diseases (Table 1, Table 2), with varying degrees of robustness and cohort sizes, particularly since solid population-based studies cannot be performed in most rare conditions. Some autoimmune diseases such as autoimmune liver diseases (AiLD) [4], [5], [6], [7] have received little attention in regards to twin studies, which is surprising given that many AiLD have been shown to have clear genetic and environmental influences. This review will present the current data surrounding twin studies in autoimmune diseases. Twin studies in autoimmune diseases highlight the complexity and obstacles that may be faced from one disease to the next, such as the variability of MZ and DZ concordance rates between reports of the same disease. The path marked by twin studies in DM, both in relation to aetiology and progression, demonstrates the need for further twin studies in other autoimmune diseases, which are somewhat lacking. It is likely that twin studies will contribute to the understanding and elucidation of genetic and environmental factors involved in the pathogenesis of autoimmunity [8].

Section snippets

Twin studies in autoimmune diseases

Autoimmune diseases form a complex group of conditions, with varying aetiologies, clinical characteristics, ages, sex distribution, geoepidemiology, genetic characteristics, and ethnicities. The aetiology of many of these conditions remains largely unknown. Twin studies have shown that several autoimmune disease, such as celiac disease (CD), have a strong genetic component with concordance rates among MZ twins being 75–83% [9], [10]. Likewise, several conditions, such as rheumatoid arthritis

Conclusions

The aetiopathogenesis of autoimmune disease is poorly understood but it appears that a close interplay between environmental and genetic factors is responsible for the loss of immunological tolerance [240], [241], [242], [243], [244], [245], [246], [247], [248], [249], [250], [251], [252], [253], [254], [255], [256], [257]. The use of twin studies have been extremely variable among autoimmune diseases. In those which have utilised twin studies, a tremendous amount of data has been obtained in

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