Lessons learned from twins in autoimmune and chronic inflammatory diseases
Introduction
Autoimmune diseases cumulatively affect 5% of Western countries' population, with a significant impact on the patient quality of life and healthcare costs [1], [2]. Despite the growing knowledge of the disease pathogenesis and the continuous development of new therapies, the causes of autoimmune diseases remain enigmatic [3]. It is now widely accepted that genetic factors are necessary but insufficient for the development of an autoimmune phenotype and environmental triggers concur to disease onset. Among non-genetic factors, candidates proposed for specific autoimmune diseases is continuously growing as new evidence is reported for infectious agents and chemicals/xenobiotics (Table 1), with various mechanisms are implied (Table 2) [4]. The resulting multi-hit model has been proposed for various multifactorial diseases, including autoimmune diseases and the limited applicability of the most robust genomic associations from genome-wide association studies (GWAS) have supported it [5]. Furthermore, similarities between autoimmune diseases outnumber differences, as well represented by the shared autoantibody profiles (i.e. antinuclear antibody), by the striking female predominance in nearly all conditions, or the common treatment approaches, as for TNFα inhibitors. Twin studies are powerful tools to discriminate whether a complex disease is dominated by genetic or environmental factors as twins represent naturally occurring models to weigh the role of individual hereditary factors. In particular, monozygotic (MZ) twins share an identical genetic background, therefore diseases with high concordance rates between MZ twins suggest a genetic predisposition, while low concordance rates will support an environmental factor [5]. This is of particular importance when concordance rates in MZ twins are compared to those in dizygotic (DZ) twins, which share 50% of their genes, as in regular siblings, but also young-age environmental factors. A major advantage of twin studies is the possibility to calculate the genetic heritability of each condition, i.e. the proportion of total variance in disease liability that is explained by genetic variance. Since heritability is a proportion, its value will range from 0 (when genes do not contribute to phenotypic differences) to 1 (when the environment does not contribute to phenotypic differences). This estimate depends on numerous variables, including the prevalence of the trait in the general population and does not reflect the risk of getting a disease but the variance between twins. We may identify sources of individual variation into additive and dominant genetic effects (A, D), common environmental effects (C) and random environmental effects (E) with “heritability” defined as the proportion of the phenotypic variance attributable to genetic variance (A + D). From a semantic standpoint, the term “environmentability” represents the proportion of phenotypic variance attributable to environmental variance (or 1-heritability). Of particular importance in the discussion of environmental factors is the fact that environmentability includes environmental influences that are sum of the common/shared environmental factors and individual environmental variance while also including the variance due to measurement errors or observation bias [6].
We will herein focus on the most recent findings in twin studies for selected autoimmune and chronic inflammatory diseases, discuss the utilized methodology, and stress the importance of rigorous methods in case ascertainment with adequate observation periods to warrant the identification of incident cases.
Section snippets
Methods used in twin studies
Twin studies can be subdivided in classical and case-control studies. In the former type, the classical twin study exploits the identical genetic background of MZ twin pairs compared to DZ twins sharing 50% of their genetic background [7]. The degree of phenotypic similarity is evaluated by means of twin concordance rates or correlation coefficients. Concordance can be expressed as either pairwise or probandwise rates. The pairwise concordance rate illustrates the proportion of affected pairs
Twin studies in autoimmune diseases
Twin studies have been extensively performed in several autoimmune conditions and cumulatively suggest that some autoimmune diseases, i.e. celiac disease (CD), are highly genetically determined, while rheumatoid arthritis (RA) or systemic sclerosis (SSc) have a lesser role for genetics [5]. In the present article, we will review the existing literature regarding twin studies and in particular in diabetes mellitus (DM), RA, SSc, systemic lupus erythematosous (SLE), psoriasis and psoriatic
Concluding remarks
The wide range of autoimmune and chronic inflammatory diseases continue to increase in number and size, as unsuspected conditions manifest laboratory or clinical features suggesting an involvement of the immune system. This is well represented by coronary heart disease and atherosclerosis in which the genetic predisposition is largely based on IL6 receptor polymorphisms [136], [137] and severity correlates with the extent and duration of chronic inflammation [138]. In general terms, we continue
Acknowledgements
This work was supported by the 2014 Young Investigator Award to Angela Ceribelli from the Eli-Lilly foundation for Medical Research ONLUS for the project “Aging, epigenetic drift, and chronic inflammation in monozygotic twins”.
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These authors contributed equally to the study.