Rheumatoid arthritis: identifying and characterising polymorphisms using rat models

Abstract

Rheumatoid arthritis is a chronic inflammatory joint disorder characterised by erosive inflammation of the articular cartilage and by destruction of the synovial joints. It is regulated by both genetic and environmental factors, and, currently, there is no preventative treatment or cure for this disease. Genome-wide association studies have identified ∼100 new loci associated with rheumatoid arthritis, in addition to the already known locus within the major histocompatibility complex II region. However, together, these loci account for only a modest fraction of the genetic variance associated with this disease and very little is known about the pathogenic roles of most of the risk loci identified. Here, we discuss how rat models of rheumatoid arthritis are being used to detect quantitative trait loci that regulate different arthritic traits by genetic linkage analysis and to positionally clone the underlying causative genes using congenic strains. By isolating specific loci on a fixed genetic background, congenic strains overcome the challenges of genetic heterogeneity and environmental interactions associated with human studies. Most importantly, congenic strains allow functional experimental studies be performed to investigate the pathological consequences of natural genetic polymorphisms, as illustrated by the discovery of several major disease genes that contribute to arthritis in rats. We discuss how these advances have provided new biological insights into arthritis in humans.

A RATional choice for translational research?

“…Traditional quantitative trait locus studies, with the need for lengthy fine-mapping and testing of candidate genes, continue to give valuable insights (for example Zhao et al, 2015; Fernandez-Duenas et al, 2015; Wang et al, 2016, and reviewed in Yau and Holmdahl, 2016), but, as with research using other model organisms, these approaches are being replaced by gene targeting using CRISPR/Cas9 and other techniques, as exemplified by the GERRC programme () and the osteocalcin study in this issue (Lambert et al, 2016). These programmes use gene targeting to knock out genes implicated in the aetiology of common human diseases via genome-wide association studies (GWAS) or other patient-based studies, and allow analysis of gene function that will give insights into disease pathogenesis.…”

“…A second Review in this issue, contributed by Anthony Yau and Rikard Holmdahl, describes arthritis-associated genetic polymorphisms that have been identified by genetic linkage and positional cloning using rat congenic strains (Yau and Holmdahl, 2016). The authors provide examples to illustrate how exploration of arthritis-linked polymorphisms using rats has provided new insights that are relevant to clinical autoimmune arthritis.…”

The role of genetic variants in FCGR2A on the risk of rheumatoid arthritis in the Han Chinese population

“…It is believed that the development of RA is triggered by complex interactions between genetic and environmental factors 5 . The common environmental factors include smoking, female, and oral contraceptive use 6 . Moreover, previous studies have suggested that genetic factors may account for approximately one-half to two-thirds of the risk of RA 7 .…”

MHC class II alleles associated with Th1 rather than Th17 type immunity drive the onset of early arthritis in a rat model of rheumatoid arthritis

“…A T‐cell‐driven arthritis model that is not dependent on the administration of exogenous Ags is pristane‐induced arthritis (PIA) in the rat . Pristane is a saturated, naturally occurring, hydrocarbon that is used for ascites production and the induction of lupus in mice .…”