title: Identifying a major locus that regulates spontaneous arthritis in IL-1ra-deficient mice and analysis of potential candidates.
abstract: To identify genetic loci that regulate spontaneous arthritis in interleukin-1 receptor antagonist (IL-1ra)-deficient mice, an F2 population was created from a cross between Balb/c IL-1ra-deficient mice and DBA/1 IL-1ra-deficient mice. Spontaneous arthritis in the F2 population was examined and recorded. Genotypes of those F2 mice were determined using microsatellite markers. Quantitative trail locus (QTL) analysis was conducted with R/qtlbim. Functions of genes within QTL chromosomal regions were evaluated using a bioinformatics tool, PGMapper, and microarray analysis. Potential candidate genes were further evaluated using GeneNetwork. A total of 137 microsatellite markers with an average of 12 cM spacing along the whole genome were used for determining the correlation of arthritis phenotypes with genotypes of 191 F2 progenies. By whole-genome mapping, we obtained QTLs on chromosomes 1 and 6 that were above the significance threshold for strong Bayesian evidence. The QTL on chromosome 1 had a peak near D1Mit55 and D1Mit425 at 82·6 cM. It may account for as much as 12% of the phenotypic variation in susceptibility to spontaneous arthritis. The QTL region contained 208 known transcripts. According to their functions, Mr1, Pla2g4a and Fasl are outstanding candidate genes. From microarray analysis, 11 genes were selected as favourable candidates based on their function and expression profiles. Three of those 11 genes, Prg4, Ptgs2 and Mr1, correlated with the IL-1ra pathway. Those genes were considered to be the best candidates.
authors.affiliation: Department of Orthopaedic Surgery - Campbell Clinic and Pathology, University of Tennessee Health Science Center (UTHSC), Memphis, TN 38163, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiao
authors.affiliation: Department of Orthopaedic Surgery - Campbell Clinic and Pathology, University of Tennessee Health Science Center (UTHSC), Memphis, TN 38163, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Jiao
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Orthopaedic Surgery - Campbell Clinic and Pathology, University of Tennessee Health Science Center (UTHSC), Memphis, TN 38163, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xiong
authors.affiliation: Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Shriner
authors.affiliation: Department of Orthopaedic Surgery - Campbell Clinic and Pathology, University of Tennessee Health Science Center (UTHSC), Memphis, TN 38163, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Hasty
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: John
authors.initials: J
authors.lastname: Stuart
authors.affiliation: Department of Orthopaedic Surgery - Campbell Clinic and Pathology, University of Tennessee Health Science Center (UTHSC), Memphis, TN 38163, USA.
authors.forename: Weikuan
authors.initials: W
authors.lastname: Gu
mesh_terms: D000818:Animals; D001168:Arthritis / Q000235:genetics* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D002874:Chromosome Mapping; D019295:Computational Biology; D003433:Crosses, Genetic; D051546:Cyclooxygenase 2 / Q000235:genetics; D004247:DNA / Q000235:genetics; D020869:Gene Expression Profiling; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D015994:Incidence; D053590:Interleukin 1 Receptor Antagonist Protein / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011509:Proteoglycans / Q000235:genetics; D040641:Quantitative Trait Loci; D000099158:Proteoglycan 4
chemical_list: D015415:Biomarkers; D051546:Cyclooxygenase 2; D004247:DNA; D015395:Histocompatibility Antigens Class I; D053590:Interleukin 1 Receptor Antagonist Protein; D015778:Minor Histocompatibility Antigens; D011509:Proteoglycans; C507764:Il1rn protein, mouse; C490628:Mr1 protein, mouse; C498837:Prg4 protein, mouse; D000099158:Proteoglycan 4; C077623:Ptgs2 protein, mouse