Sex effect on clinical and immunologic quantitative trait loci in a murine model of rheumatoid arthritis

Abstract

Objective. To explore the effect of sex on clinical and immunologic traits in major histocompatibility complex-matched (H-2d) F 2 hybrid mice with proteoglycan (PG)-induced arthritis and to identify how the quantitative trait locus (QTL) on the X chromosome influences the onset QTL of another chromosome.Methods. (BALB/c ؋ DBA/2)F 2 hybrid mice were immunized with cartilage PG, and a genome-wide linkage analysis was performed using >200 simple sequence-length polymorphic markers. The major clinical traits (susceptibility, onset, and severity) were assessed, and PG-specific T and B cell responses, and the production of proinflammatory and antiinflammatory cytokines (tumor necrosis factor ␣, interleukin-1 [IL-1], IL-6, interferon-␥, IL-4, IL-10, and IL-12) were measured in 133 arthritic and 426 nonarthritic female and male F 2 hybrid mice. The major clinical and immunologic traits were linked to genetic loci, and potential linkages among these QTLs and the effect of sex were analyzed.Results. Thirteen QTLs reported in previous studies were confirmed. Binary traits (susceptibility to arthritis) and disease onset were female specific and were identified on chromosomes 3, 7, 10, 11, 13, and X. QTLs for disease severity were mostly male specific and were located on chromosomes 1, 4, 5, 8, 14, 15, and 19. In addition, we identified 4 new QTLs for the onset of arthritis on chromosomes 3, 4, and 11, and 1 new QTL for severity on chromosome 14; all showed a strong gender association. A locus on the X chromosome interacted with a QTL on chromosome 10, and these 2 loci together seemed to control disease incidence and onset. Most of the clinical traits (QTLs) shared common regions with the immunologic traits and frequently showed a locus-locus interaction.Conclusion. Numerous immunologic QTLs overlap with clinical QTLs, thus providing information about possible mechanisms underlying QTL function. Disease susceptibility and onset showed predominant linkage with the female sex, under the control of a QTL on the X chromosome, while the severity QTLs were more strongly linked to the male sex.

Involvement of antibody production quantitative trait loci in the susceptibility to pristane-induced arthritis in the mouse

“…It is the first PIA susceptibility QTL described to date in the mouse and it colocalizes with QTL described for other models of RA, namely Cia5 21 and Pgia26. 22 Recently, evidence was reported for the existence of three QTLs in the Cia5 region. 23 At this time, results do not allow us to conclude that the QTL detected in the present experiment results from the effect of a single gene or the combined effect of multiple genes, as it seems to occur at the Cia5 region, where it has been recently reported that a cluster of genes are differentially expressed during CIA 24 and it will be interesting to investigate if the same occurs in the PIA model.…”

Contribution of genetic studies in rodent models of autoimmune arthritis to understanding and treatment of rheumatoid arthritis

“…Studies in rodent intercrosses identified several arthritis susceptibility, severity and chronicity loci (Table 1). 29,[32][33][34][35][36][37][38][39][40][41][42][43][44][45] The RA genome-wide family-based genetic studies were not designed or structured to address disease severity, histologic damage or the other arthritis-related phenotypes that can be studied in rodents. More recent cohorts have been incorporating severity and outcome parameters in their prospective data collection and will likely have a major role in RA severity genetic association studies.…”

“…24 Similar gender specific effects have been detected in rat and mouse intercrosses or congenic strains. 33,57,80 Sex chromosomes have also been implicated in the regulation of autoimmune arthritis. The Yaa locus in mice unexpectedly reduced CIA severity.…”

Cia27 is a novel non-MHC arthritis severity locus on rat chromosome 10 syntenic to the rheumatoid arthritis 17q22–q25 locus

“…Based on previous observations that certain loci operate in a gender-specific manner, 12,14,15 males and females were first studied separately and then in combined analyses.…”

“…11 Additionally, yet unidentified sex factors appear to regulate the penetrance of certain arthritis-regulatory alleles, making some disease alleles sex-specific. [12][13][14][15][16][17] Little is known about the genetic regulation of disease severity and none of the RA multi-institutional familybased genome-wide screens was designed to address disease severity. These severity genes could have a more significant role in the perpetuation (chronicity) of the inflammatory process and joint damage, and thus could generate better targets for drug development.…”