Genetic origin of lupus in NZB/SWR hybrids: Lessons from an intercross study

Shangkui Xie, Li Li, SoogHee Chang, Ruchi Sharma, Arunan Kaliyaperumal, Syamal K. Datta, Chandra Mohan

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Objective. (SWR x NZB)F1 (or SNF1) hybrid mice succumb to lupus nephritis. A previous analysis of SNF1 x NZB backcross mice revealed the existence of 4 SWR loci (H2 on chromosome 17, Swrl-1 on chromosome 1, Swrl-2 on chromosome 14, and Swrl-3 on chromosome 18) and 2 NZB loci (Nba1 and Lbw2/Sbw2, both on chromosome 4). A second study focusing on SNF1 x SWR backcross offspring uncovered 5 suggestive loci for antinuclear antibody formation, consisting of 3 dominant NZB contributions (Nba4 on chromosome 5, Lbw4 on chromosome 6, and Nba5 on chromosome 7) and 2 recessive SWR contributions (Swrl-1 on chromosome 1 and Swrl-4 on chromosome 10). The present intercross study was executed to replicate the earlier findings, using an independent panel of (SWR x NZB)F2 offspring. Methods. A panel of (NZB x SWR)F2 hybrids were phenotyped (for renal disease, early mortality, and a variety of autoantibodies) and genotyped (using 95 microsatellite primers positioned across all 19 autosomes and the X chromosome). Linkage analysis was conducted using the derived phenotype and genotype data, with the interval-mapping program MapManager. Results. Four suggestive loci were mapped: Swrl-5 on chromosome 1 (peak at 106 cM), linked to hypergammaglobulinemia; an NZB locus on chromosome 5 (Nba4; peak at 15 cM), linked to IgG anti-single-stranded DNA (anti-ssDNA) antibodies, IgG anti-doubled-stranded DNA (anti-dsDNA) antibodies, and glomerulonephritis; an NZB locus on chromosome 13 (Nba6; peak at 28 cM), linked to IgG anti-dsDNA antibodies; and an SWR locus on chromosome 14 (Swrl-2; peak at 30 cM), linked to IgG anti-ssDNA antibodies. Eight additional loci revealed linkage at P < 0.01, of which 7 co-mapped with lupus susceptibility loci previously identified in other models. Conclusion. Considering all 3 mapping studies together, lupus in SWR/NZB hybrids appears to be the epistatic end product of several distinct loci, of which 3 SWR-derived loci (Swrl-1, Swrl-2, and Swrl-3) and 5 NZB-derived loci (Nba1, Nba3, Nba4, Nba5, and Lbw4) have been independently confirmed. The immunologic functions and molecular identities of these loci await elucidation.

Original languageEnglish (US)
Pages (from-to)659-667
Number of pages9
JournalArthritis and rheumatism
Volume52
Issue number2
DOIs
StatePublished - Feb 2005

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

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    Xie, S., Li, L., Chang, S., Sharma, R., Kaliyaperumal, A., Datta, S. K., & Mohan, C. (2005). Genetic origin of lupus in NZB/SWR hybrids: Lessons from an intercross study. Arthritis and rheumatism, 52(2), 659-667. https://doi.org/10.1002/art.20786