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-Szabó, Jodi Gallagher, Sonja Velins, Katalin Mikecz, E. Búzás, Jill T. Enders, Yefu Li, Björn R. Olsen, Tibor T. Glant

Research output: Contribution to journalArticle

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Abstract

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 F2 progeny. As with RA, the genetics are complex, containing 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 F2 hybrids of susceptible (BALB/c) and nonsusceptible (DBA/2) strains of mice. Because both strains of mice share the H2(d) haplotype, this cross permits identification 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 production 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 originate from the DBA/2 background, which indicates that as in RA, susceptibility genes can originate from heterogeneous backgrounds. Conclusion. These data demonstrate the complexity of PGIA, where QTLs may be involved in multiple traits or even originate from a genetic background previously determined to be resistant.

Original languageEnglish
Pages (from-to)2524-2531
Number of pages8
JournalArthritis and Rheumatism
Volume42
Issue number12
DOIs
Publication statusPublished - Dec 1999

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Autoantibodies
Proteoglycans
Arthritis
Rheumatoid Arthritis
Genome
Inflammation
Major Histocompatibility Complex
Chromosomes, Human, Pair 7
Quantitative Trait Loci
Chromosomes, Human, Pair 16
Chromosomes, Human, Pair 15
Chromosomes, Human, Pair 9
Chromosomes, Human, Pair 2
Chromosomes, Human, Pair 1
Haplotypes
Genes
Pathology

ASJC Scopus subject areas

  • Immunology
  • Rheumatology

Cite this

Identification of multiple loci linked to inflammation and autoantibody production by a genome scan of a murine model of rheumatoid arthritis. / Otto, Jeffrey M.; Cs-Szabó, Gabriella; Gallagher, Jodi; Velins, Sonja; Mikecz, Katalin; Búzás, E.; Enders, Jill T.; Li, Yefu; Olsen, Björn R.; Glant, Tibor T.

In: Arthritis and Rheumatism, Vol. 42, No. 12, 12.1999, p. 2524-2531.

Research output: Contribution to journalArticle

Otto, Jeffrey M. ; Cs-Szabó, Gabriella ; Gallagher, Jodi ; Velins, Sonja ; Mikecz, Katalin ; Búzás, E. ; Enders, Jill T. ; Li, Yefu ; Olsen, Björn R. ; Glant, Tibor T. / Identification of multiple loci linked to inflammation and autoantibody production by a genome scan of a murine model of rheumatoid arthritis. In: Arthritis and Rheumatism. 1999 ; Vol. 42, No. 12. pp. 2524-2531.
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T1 - Identification of multiple loci linked to inflammation and autoantibody production by a genome scan of a murine model of rheumatoid arthritis

AU - Otto, Jeffrey M.

AU - Cs-Szabó, Gabriella

AU - Gallagher, Jodi

AU - Velins, Sonja

AU - Mikecz, Katalin

AU - Búzás, E.

AU - Enders, Jill T.

AU - Li, Yefu

AU - Olsen, Björn R.

AU - Glant, Tibor T.

PY - 1999/12

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N2 - 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 F2 progeny. As with RA, the genetics are complex, containing 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 F2 hybrids of susceptible (BALB/c) and nonsusceptible (DBA/2) strains of mice. Because both strains of mice share the H2(d) haplotype, this cross permits identification 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 production 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 originate from the DBA/2 background, which indicates that as in RA, susceptibility genes can originate from heterogeneous backgrounds. Conclusion. These data demonstrate the complexity of PGIA, where QTLs may be involved in multiple traits or even originate from a genetic background previously determined to be resistant.

AB - 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 F2 progeny. As with RA, the genetics are complex, containing 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 F2 hybrids of susceptible (BALB/c) and nonsusceptible (DBA/2) strains of mice. Because both strains of mice share the H2(d) haplotype, this cross permits identification 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 production 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 originate from the DBA/2 background, which indicates that as in RA, susceptibility genes can originate from heterogeneous backgrounds. Conclusion. These data demonstrate the complexity of PGIA, where QTLs may be involved in multiple traits or even originate from a genetic background previously determined to be resistant.

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