Genetic Predisposition and Autoimmune Disease

Nearly 24 million Americans have been diagnosed with an autoimmune disease.¹ Recently, a number of significant advances in our understanding of the genetics of autoimmunity have been made through genome-wide association studies and the use of omics technologies. These research findings are helping scientists move toward a more personalized treatment approach for patients with autoimmune disease.

Key features of autoimmune disease

Autoimmune diseases are marked by their complexity, and the heterogeneity of many of these diseases has made them difficult to define and treat.² A number of confirmed gene coding regions predispose an individual to autoimmunity; for instance, the human leukocyte antigen (HLA) region is associated with all autoimmune disease.³ Other loci associated with multiple autoimmune diseases are IL23R, TNFAIP3, and IL2RA.³ Yet despite these commonalities, the genetic heritability of autoimmune diseases is exceedingly variable, ranging from very high in Crohn’s disease and ankylosing spondylitis to almost negligible in systemic sclerosis.³ One estimate is that less than 15% of genes related to autoimmune risk have been identified.⁴

Many autoimmune diseases, including lupus, disproportionately affect women.⁵ Scientists recently looked at blood cells from healthy women and men with Klinefelter syndrome (who carry one or more supernumerary X chromosomes and are also at an increased risk of lupus) and found that the gene that codes for toll-like receptor 7 (TLR7) escapes X-inactivation, a process that occurs during embryonic development and switches off one of the two X chromosomes to prevent the overexpression of genes.⁵ TLR7 binds single-stranded RNA and activates type I interferon signaling, a pathway that is also activated in systemic lupus erythematosus (SLE) patients. The authors concluded that biallelic expression of TLR7 contributes to greater risk of lupus in individuals with two X chromosomes.⁵

Autoimmune diseases tend to run in families, but inheritance is not Mendelian.⁶ Generally, familial autoimmunity does not cluster by condition, but rather, diverse autoimmune conditions can run in families.^7,8 The relatives of individuals with a specific autoimmune disease have a heightened incidence of systemic autoimmune diseases, such as SLE and rheumatoid arthritis, or organ-specific autoimmune diseases, such as chronic thyroiditis, Graves’ disease, insulin-dependent diabetes mellitus, and related autoimmune endocrinopathies. Only a few families have been shown to exhibit both systemic and organ-specific autoimmune diseases.⁹

Genetic factors

Genome-wide association studies have identified hundreds of susceptibility genes among autoimmune diseases, largely affecting adults. One study of the pediatric population found that many of the autoimmune-related gene signals were in biological pathways functionally linked to cell activation, cell proliferation, and signaling systems important in immune processes.¹⁰