The role of genetic factors in autoimmune disease: Implications for environmental research

Studies in both humans and in animal models of specific disorders suggest t hat polymorphisms of multiple genes are involved in conferring either a pre disposition to or protection from autoimmune diseases. Genes encoding polym orphic proteins that regulate immune responses or the rates and extent of m etabolism of certain chemical structures have been the focus of much of the research regarding genetic susceptibility. We examine the type and strengt h of evidence concerning genetic factors and disease etiology, drawing exam ples from a number of autoimmune diseases. Twin studies of rheumatoid arthr itis (RA), systemic lupus erythematosus (SLE), type I diabetes, and multipl e sclerosis (MS) indicate that disease concordance in monozygotic twins is 4 or more times higher than in dizygotic twins. Strong familial association s (odds ratio ranging from 5-10) are seen in studies of MS, type I diabetes , Graves disease, discoid lupus, and SLE. Familial association studies have also reported an increased risk of several systemic autoimmune diseases am ong relatives of patients with a systemic autoimmune disease. This associat ion may reflect a common etiologic pathway with shared genetic or environme ntal influences among these diseases. Recent genomewide searches in RA, SLE , and MS provide evidence for multiple susceptibility genes involving major histocompatibility complex (MHC) and non-MHC loci; there is also evidence that many autoimmune diseases share a common set of susceptibility genes. T he multifactorial nature of the genetic risk factors and the low penetrance of disease underscore the potential influence of environmental factors and gene-environment interactions on the etiology of autoimmune diseases.