PMC:1860061 / 10345-13198 JSONTXT

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We reasoned that since the main candidate gene of Cia2, complement component C5 (Hc), was proven to be essential for CIA development and because the FVB/N strain is C5 deficient [10,25], some small-effect QTL might be masked by Cia2. To exclude the masking effect of C5, we performed linkage analysis with 3 datasets, the first containing all 290 F2 progeny, the second 77 C5+/+ F2 progeny and the third 133 C5+/- F2 progeny. Eight genomic regions were linked to the phenotype of CIA severity (loci 1 to 8, Table 2), with P values varying between 0.043 and 0.003. These eight small-effect QTL were located on chromosomes 5, 6, 7, 10, 11, 16, and 17. Five loci were identified in at least two datasets. Of the eight loci, five had DBA/1 as the susceptibility allele, and three had FVB/N as the susceptibility allele.\nLander and Botstein [26] suggested a LOD score of between 2 and 3 to ensure an overall false positive rate of 5%, which means that using a lower threshold value will prevent false negative QTL at the expense of increasing false positive QTL. Being aware of this, we examined these genomic regions to search whether they, or their syntenic genomic regions on the human genome, have been previously linked to arthritis. Four small-effect QTL overlapped with arthritis QTL on the mouse genome identified previously. Locus 1 and 2 overlap with Cia13 and Cia14, which control severity of CIA in (DBA/1 × BALB/C) F2 progeny [27]. Locus 5 located on chromosome 10 overlaps with Cia8, which was identified in (DBA/1 × B10.Q) F2 progeny [28]. Locus 6 overlaps with Pgia7, which controls susceptibility to proteoglycan-induced arthritis (PGIA) and was identified in (BALB/C × DBA/2) F2 progeny [29]. The syntenic genomic regions of five small-effect QTL on the human genome have been reported to be linked to RA. These are genomic regions 22q11 and 12p13-q24 on chromosome 22 and 12 (the counterparts of locus 2), 12p13-pter on chromosome 12 (the counterpart of locus 3), 21q22-qter and 10q22-23 on chromosome 21 and 10 (the counterparts of locus 5), 17q21-25 on chromosome 17 (the counterpart of locus 6) and 3q29-qter on chromosome 3 (the counterpart of locus 7) 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