ARTHRITIS & RHEUMATISM Vol. 42, No. 12, December 1999, pp 2524–2531 © 1999, American College of Rheumatology IDENTIFICATION OF MULTIPLE LOCI LINKED TO INFLAMMATION AND AUTOANTIBODY PRODUCTION BY A GENOME SCAN OF A MURINE MODEL OF RHEUMATOID ARTHRITIS JEFFREY M. OTTO, GABRIELLA CS-SZABO ´ , JODI GALLAGHER, SONJA VELINS, KATALIN MIKECZ, EDIT I. BUZA ´ S, JILL T. ENDERS, YEFU LI, BJO ¨ RN R. OLSEN, and TIBOR T. GLANT Objective. Proteoglycan-induced arthritis (PGIA) is a murine model of rheumatoid arthritis (RA), both in terms of its pathology and its genetics. PGIA can only be induced in susceptible murine strains and their F 2 progeny. As with RA, the genetics are complex, contain- ing both major histocompatibility complex (MHC)– related and non–MHC-related components. Our goal was to identify the underlying non–MHC-related loci that confer PGIA susceptibility. Methods. We used 106 polymorphic markers to perform simple sequence-length polymorphism analysis on F 2 hybrids of susceptible (BALB/c) and nonsuscep- tible (DBA/2) strains of mice. Because both strains of mice share the H2 d haplotype, this cross permits iden- tification and analysis of non–MHC-related genes. Results. We identified a total of 12 separate quantitative trait loci (QTL) associated with PGIA, which we have named Pgia1 through Pgia12. QTLs associated with the inflammatory symptoms of PGIA were linked to chromosomes 7, 9, 15 (2 separate loci), 16, and 19. QTLs associated with autoantibody produc- tion were identified on chromosomes 1, 2, 7, 8, 10, 11, 16, and 18. QTLs on chromosomes 7 and 16 showed linkage to both inflammation and autoantibody production, suggesting a shared regulatory component in arthritis induction. The first inflammation QTL on chromosome 15 and the autoantibody QTL on chromosome 7 origi- nate from the DBA/2 background, which indicates that as in RA, susceptibility genes can originate from hetero- geneous backgrounds. Conclusion. These data demonstrate the complex- ity of PGIA, where QTLs may be involved in multiple traits or even originate from a genetic background previously determined to be resistant. Rheumatoid arthritis (RA) is a complex disease that affects 1% of the human population. While HLA–DRB genes show high correlation with suscepti- bility to RA (1,2) and HLA–B27 with ankylosing spon- dylitis (3,4), the major histocompatibility complex (MHC) alone is not sufficient or, ultimately, necessary for the development of the disease. Based on the clinical, immunologic, and genetic components of RA, the most appropriate animal models are those that apply cartilage matrix components, such as proteoglycan (PG) (5), type II collagen (6), link protein (7), or cartilage glycoprotein 39 (8), for the systemic immunization of genetically susceptible mice or rats. We have previously reported that PG (aggrecan)– induced arthritis (PGIA) can be produced only in geneti- cally susceptible BALB/c mice (9). BALB/c mice immu- nized with human cartilage PG develop progressive polyarthritis and, later, spondylitis (5). Herein, we report that F 2 hybrids of BALB/c and DBA/2 mice are also susceptible, while F 1 hybrids of BALB/c and DBA/2 mice, both of which contain the H2 d haplotype, are resistant to PGIA. The development of PGIA is based on cross- reactive immune responses between the immunizing hu- man and the mouse self PGs (9–11). To identify non–MHC-related loci linked to PGIA and to investigate the relationship between auto- Supported in part by NIH grants AR-40310 and AR-45652 and by the Coleman Foundation, Chicago, IL. Jeffrey M. Otto, PhD, Gabriella Cs-Szabo ´, PhD, Jodi Gal- lagher, BS, Sonja Velins, MLA, Katalin Mikecz, MD, PhD, Jill T. Enders, BS, Tibor T. Glant, MD, PhD: Rush University at Rush– Presbyterian–St. Luke’s Medical Center, Chicago, Illinois; Edit I. Buza ´s, MD, PhD: Semmelweis Medical University, Budapest, Hun- gary; Yefu Li, MD, PhD: Thomas Jefferson University, Philadelphia, Pennsylvania; Bjo ¨rn R. Olsen, MD, PhD: Harvard Medical School, Boston, Massachusetts. Address reprint requests to Jeffrey M. Otto, PhD, Section of Biochemistry and Molecular Biology, Departments of Biochemistry and Orthopedic Surgery, Rush–Presbyterian–St. Luke’s Medical Cen- ter, 1653 West Congress Parkway, Chicago, IL 60612. Submitted for publication June 22, 1999; accepted in revised form August 10, 1999. 2524