Genetics, environment, and gene-environment interactions in the development of systemic rheumatic diseases

Abstract

Rheumatic diseases offer distinct challenges to researchers because of heterogeneity in disease phenotypes, low disease incidence, and geographic variation in genetic and environmental factors. Emerging research areas, including epigenetics, metabolomics, and the microbiome, may provide additional links between genetic and environmental risk factors in the pathogenesis of rheumatic disease. This article reviews the methods used to establish genetic and environmental risk factors and studies gene-environment interactions in rheumatic diseases, and provides specific examples of successes and challenges in identifying gene-environment interactions in rheumatoid arthritis, systemic lupus erythematosus, and ankylosing spondylitis. Emerging research strategies and future challenges are discussed.

Keywords: Ankylosing spondylitis; Environment; Genetics; Interaction; Rheumatoid arthritis; Smoking; Systemic lupus erythematosus.

Figure 1

Schematic showing the pre-clinical phases of RA. Other rheumatic diseases likely follow similar phases of progression from genetic susceptibility, immune dysregulation, and sub-clinical disease to classifiable disease. Environmental factors and gene-environment interactions likely occur throughout this process of disease pathogenesis. From Karlson EW, Deane K. Environmental and gene-environment interactions and risk of rheumatoid arthritis. Rheum Dis Clin North Am 2012;38(2):405–26; with permission.

Figure 2

Schematic of HLA-DRB1-cigarette smoking interaction in the development of seropositive RA. Individuals with one or more HLA-DRB1 shared epitope alleles smoke cigarettes, which induces inflammation in the airways and alveolar mucosa. Peptidylarginine deiminase (PAD) is activated, which citrullinates self-antigens. Antigen-presenting cells stimulate T cells through aberrant HLA-DRβ1 interactions and stimulate B cells to produce anti-citrullinated peptide antibodies (ACPA). Immune tolerance is lost specifically in joints, which manifests clinically as synovitis with signs and symptoms compatible with RA. From Klareskog L, Ronnelid J, Lundberg K, Padyukov L, Alfredsson L. Immunity to citrullinated proteins in rheumatoid arthritis. Annu Rev Immunol 2008;26:651–75; with permissions.