Rheumatoid arthritis (RA) is an autoimmune disease, the pathogenesis of which is affected by multiple genetic and environmental factors. To understand the genetic and molecular basis of RA, a large number of quantitative trait loci (QTL) that regulate experimental autoimmune arthritis have been identified using various rat models for RA. However, identifying the particular responsible genes within these QTL remains a major challenge. Using currently available genome data and gene annotation information, we systematically examined RA-associated genes and polymorphisms within and outside QTL over the whole rat genome. By the whole genome analysis of genes and polymorphisms, we found that there are significantly more RA-associated genes in QTL regions as contrasted with non-QTL regions. Further experimental studies are necessary to determine whether these known RA-associated genes or polymorphisms are genetic components causing the QTL effect.

Rheumatoid arthritis (RA),3 one of the most common autoimmune diseases, is characterized by chronic joint inflammation and variable degrees of bone and cartilage erosion. Like other autoimmune diseases, RA has a strong genetic component with a heritability of ∼60% based on twin data (1, 2, 3). To elucidate the genetic and molecular basis of RA, tremendous efforts have been made in the mapping of quantitative trait loci (QTL) associated with the disease. Linkage analysis has identified 52 or more QTL that regulate experimental autoimmune arthritis in rat models for RA, including collagen-induced arthritis, pristane-induced arthritis, oil-induced arthritis, and adjuvant-induced arthritis (4). However, identifying the particular responsible genes within these QTL remains a major challenge. To our knowledge, only one gene, Ncf1, has been confirmed as a causative gene underlying the Pia4 QTL (5). The availability of whole genome sequence and rapid advances in functional annotation of genes offer an opportunity to pinpoint the genetic factors within QTL that are essential for the development of autoimmune arthritis in rats.

We found 52 experimental arthritis QTL identified by linkage studies in rat models by searching the PubMed database for every publication up to January 2008 using the key words “arthritis” and “QTL”. Most data have been summarized by Joe (4). In accordance with accepted linkage criteria, a logarithm of the odds (LOD) score of >4.3 was considered significant, and a LOD score between 2.8 and 4.3 was considered suggestive for linkage (6). Therefore, in this review we only chose those QTL with a peak LOD score of 2.8 or above. For well-defined QTL, we defined the size of the QTL by the QTL region given by authors. For other QTL, the 2-LOD support interval, the chromosomal region in which the QTL is located with a confidence of ∼95%, was used to establish the QTL region (7). The information of QTL is listed in Table I. For the QTL identified by multiple studies, we listed all of them in Table I as they usually have different flanking markers. We are aware that it is possible that we may not collect every relevant publication or QTL and apologize to authors whose work is not included.

Table I.

QTL information for experimental arthritis in ratsa

QTLLODMarkersSearch Region (bp)RAA Genes within QTLRAAP Genes within QTL
Cia2 (8) D1Arb15-D1Arb31 64,146,083–146,714,212 Chrna7, Fcgrt, Ax1, Tgfb1, Gpi, Bax, Il4i1, Zfp36, Xrcc1, Gp49b, Il11, Il16 Zfp36, Xrcc1 
Cia2 (9) D1Rat7-D1Rat35 15,999,443–124,749,065 Chrna7, Fcgrt, Ax1, Tgfb1, Vip, Gpi, Bax, Ccr6, Ctgf, Il4i1, Pdcd5, Zfp36, Xrcc1, Gp49b, Il11 Zfp36, Xrcc1 
Ciaa6 (10) 3.3 D1Rat202-D1Mgh12 181,173,661–247,322,280 Dkk1, Syvn1 (Hrd1), Cd19, Fadd, Pten, Mb12, Htra1, Lip1, Il4ra, Il21r Mb12, Il4ra 
Pia8 (11) 4.7 D1Mit15-D1Rat10 1,595,128–25,271,177 Ctgf  
Pia9 (12) 5.3 ΔD1Rat185 (D1Rat320)-ΔD1Mit13 (D1Rat193) 119,536,685–183,163,338 Serpinh1 (Ra-a47), Nox4, Il16  
Cia7 (13) 4.6 Prlr-D2Mit23 59,681,382–146,659,672 Tnfsf10 (Trail), Crh, Il2, Ank, Il7, Il21, Tenr, Prlr Crh, Il2, Il21, Tenr 
Cia7 (9) 3.2 ΔD2Mit24 (D2Mgh14)-D2Mit23 42866227–146659672 Tnfsf10 (Trail), Il6st (Gp130), Crh, C6, C7, Il2, Ank, Il7, Il21, Tenr, Prlr Crh, Il2, Il21, Tenr 
Cia10* (13) 3.4 D2Mit23-D2Mgh29 146659371–227310008 Il12a (p35), Ptpn22, Tlr2, S100a9, S100a8, Gstm1, S100a4, Adam15, Gstm4, Sh2d2a Ptpn22, Tlr2, Gstm1, Sh2d2a 
Cia11 (14) 5.6 D3Mit9-D3Mgh5 26674019–97524000 Nr4a2 (Nurr1), Cd44, Traf6, Itgav, Hoxd9, Lrp2, Mdk Itgav 
Cia11 (10) 3.5 D3Mit12-D3Mgh6 48033364–50522717   
Aia2 (15) 5.8 D4Arb26-D4Arb30 36592629–73972591 Irf5, Ptn Irf5 
Aia3 (15) 3.9 D4Arb30-ΔD4Arb16 (D4Mit16) 73972454–130228614 Aqp1  
Cia13 (9) 10 D4Mit17-D4Mgh11 134858562–171204531 Cd69, Cxcl12, Cls, Clr, Il17ra, Il17re, Il17rc  
Cia13 (10) 10.8 D4Mit16-D4Rat112 130228505–182386736 Cd69, Cxcl12, Cls, Clr, Il17ra, Il17re, Il17rc  
Cia13 (14) 4.5 D4Mit12-D4Wox12 104,415,993–179,854,843 Cd69, Cxcl12, Cls, Clr, Il17ra, Il17re, Il17rc  
Cia3 (8) 4.8 D4Arb30-D4Arb4 73,972,454–154,937,227 Cxcl12, Aqp1, Il17re, Il17rc  
Cia3 (10) 5.2 D4Wox22-D4Mit16 78,042,682–130,228,614 Aqp1  
Ciaa4* (9) D4Mgh18-D4Mgh11 128,179,958–171,204,531 Cd69, Cxcl12, Cls, Clr, Il17ra, Il17re, Il17rc  
Oia2 (16, 17)  D4Mit24-ΔD4Mgh21 (D4Rat84) 78,039,508–185,398,530 Cd69, Cxcl12, Cls, Clr, Aqp1, Il17ra, Il17re, Il17rc  
Pia2 (18) 3.9 D4Mgh1-D4Rat22 17,617,957–60,974,511 Irf5, Pon1 Irf5 
Pia5 (18) 4.5 D4Rat22-D4Mit16 60,974,347–130,228,614 Aqp1, Ptn  
Pia7 (11) 4.9 ΔD4Arb16 (D4Mit16)-D4Wox16 130,228,505–158,101,973 Cxcl12, Il17ra, Il17re, Il17rc  
Pia7 (19) 5.3 ΔD4Arb16 (D4Mit16)-D4Mgh11 130,228,505–171,204,531 Cd69, Cxcl12, Cls, Clr, Il17ra, Il17re, Il17rc  
Ciaa5* (9) 3.5 D5Wox3-D5Mgh8 99,080,787–149,757,440   
Ciaa5 (10) D5Mit14-ΔD5Wox17 (D5Wox10) 138,304,249–165,073,513 Padi4 Padi4 
Apr2 (20) 3.7 ΔD5Wox17 (D5Wox15)-D5Mgh9 148,718,587–171,801,867 Padi4, Tnfrsf14 Padi4 
Pia3 (18) 4.5 D6Mit1-D6Rat4 98,840,517–144,200,901 Serpina1 (Pi), Fos  
Pia3 (11, 19) 3.8 D6Mgh10-D6Rat4 108,621,345–144,200,901 Serpina1 (Pi), Fos  
Pia12 (19) 3.9 D6Mgh7-D6Wox5 47,039,213–117,362,003 Fos, Prkch, Pik3cg Prkch 
Cia20 (10) 2.9 ΔD6Rat16 (D6Rat19)-D6Wox5 81,682,368–117,362,003 Fos, Prkch Prkch 
Cia4 (8, 21) 5.3 D7Mgh22-D7Arb13 56,589,443–103,063,768 Ifng, Myc Ifng 
Cia8 (21) 5.1 D7Rat33-D7Mgh22 20,547,072–56,589,443   
Pia13 (19) 4.7 D7Mit9-D7Rat74 78,497,123–137,838,801 Myc, Vdr Vdr 
No name* (8) 3.2 D8Arb22-ΔD8Arb17 (D8Rat126) 103,815,825–124,310,006 Myd88  
Cia6 (9) 3.7 D8Mgh4-D8Rat71 86,627,870–127,907,265 Cx3cr1, Myd88  
Pia14 (19) D8Rat21-D8Rat26 79,347,688–87,122,815   
Cia15 (9) 4.5 D9Rat44-D9Arb7 2,948,883–39,821,284 Zap70, Vegfa (Vegf), Col9a1  
Ciaa3 (9) 7.5 D9Rat44-D9Wox19 2,948,883–18,347,743 Vegfa (Vegf 
Ciaa3 (14) 6.5 ΔD9Wox23 (0 bp)-D9Wox19 0–18,347,743 Vegfa (Vegf 
Cia5 (8, 14) 4.9 D10Arb21-ΔD10Arb22 (distal end) 84,263,650–110,718,848 Map3k14 (Nik), Ace, Stat3, Socs3, Tbx21 Ace 
Cia16* (9) 3.5 D10Rat95-D10Rat11 6,380,796–100,633,848 Map3k14 (Nik), Tnfsf13 (April), Ace, Mefv, Ccl2, Stat3, Il4, Ccl3, Ccl5, Cxcl16, Il13, Tp53, I13, Tbs21 Ace, I14, I13 
Oia3 (16, 22)  ΔD10Mit13 (D10Rat92)- ΔD10Mgh1 (D10Rat135) 78,170,545–108,776,963 Map3k14 (Nik), Tnfsf13 (April), Ace, Stat3, Socs3, Tbx21 Ace 
Pia10 (19) 3.1 ΔD10Rat26 (D10Rat27)-D10Rat44 24,731,831–77,091,892 Tnfsf13 (April); Ccl2, Il4, Ccl3,Ccl5, Cxcl16, Il13, Tp53, Il3 Il4, Il3 
 (Table continues    
QTLLODMarkersSearch Region (bp)RAA Genes within QTLRAAP Genes within QTL
Cia2 (8) D1Arb15-D1Arb31 64,146,083–146,714,212 Chrna7, Fcgrt, Ax1, Tgfb1, Gpi, Bax, Il4i1, Zfp36, Xrcc1, Gp49b, Il11, Il16 Zfp36, Xrcc1 
Cia2 (9) D1Rat7-D1Rat35 15,999,443–124,749,065 Chrna7, Fcgrt, Ax1, Tgfb1, Vip, Gpi, Bax, Ccr6, Ctgf, Il4i1, Pdcd5, Zfp36, Xrcc1, Gp49b, Il11 Zfp36, Xrcc1 
Ciaa6 (10) 3.3 D1Rat202-D1Mgh12 181,173,661–247,322,280 Dkk1, Syvn1 (Hrd1), Cd19, Fadd, Pten, Mb12, Htra1, Lip1, Il4ra, Il21r Mb12, Il4ra 
Pia8 (11) 4.7 D1Mit15-D1Rat10 1,595,128–25,271,177 Ctgf  
Pia9 (12) 5.3 ΔD1Rat185 (D1Rat320)-ΔD1Mit13 (D1Rat193) 119,536,685–183,163,338 Serpinh1 (Ra-a47), Nox4, Il16  
Cia7 (13) 4.6 Prlr-D2Mit23 59,681,382–146,659,672 Tnfsf10 (Trail), Crh, Il2, Ank, Il7, Il21, Tenr, Prlr Crh, Il2, Il21, Tenr 
Cia7 (9) 3.2 ΔD2Mit24 (D2Mgh14)-D2Mit23 42866227–146659672 Tnfsf10 (Trail), Il6st (Gp130), Crh, C6, C7, Il2, Ank, Il7, Il21, Tenr, Prlr Crh, Il2, Il21, Tenr 
Cia10* (13) 3.4 D2Mit23-D2Mgh29 146659371–227310008 Il12a (p35), Ptpn22, Tlr2, S100a9, S100a8, Gstm1, S100a4, Adam15, Gstm4, Sh2d2a Ptpn22, Tlr2, Gstm1, Sh2d2a 
Cia11 (14) 5.6 D3Mit9-D3Mgh5 26674019–97524000 Nr4a2 (Nurr1), Cd44, Traf6, Itgav, Hoxd9, Lrp2, Mdk Itgav 
Cia11 (10) 3.5 D3Mit12-D3Mgh6 48033364–50522717   
Aia2 (15) 5.8 D4Arb26-D4Arb30 36592629–73972591 Irf5, Ptn Irf5 
Aia3 (15) 3.9 D4Arb30-ΔD4Arb16 (D4Mit16) 73972454–130228614 Aqp1  
Cia13 (9) 10 D4Mit17-D4Mgh11 134858562–171204531 Cd69, Cxcl12, Cls, Clr, Il17ra, Il17re, Il17rc  
Cia13 (10) 10.8 D4Mit16-D4Rat112 130228505–182386736 Cd69, Cxcl12, Cls, Clr, Il17ra, Il17re, Il17rc  
Cia13 (14) 4.5 D4Mit12-D4Wox12 104,415,993–179,854,843 Cd69, Cxcl12, Cls, Clr, Il17ra, Il17re, Il17rc  
Cia3 (8) 4.8 D4Arb30-D4Arb4 73,972,454–154,937,227 Cxcl12, Aqp1, Il17re, Il17rc  
Cia3 (10) 5.2 D4Wox22-D4Mit16 78,042,682–130,228,614 Aqp1  
Ciaa4* (9) D4Mgh18-D4Mgh11 128,179,958–171,204,531 Cd69, Cxcl12, Cls, Clr, Il17ra, Il17re, Il17rc  
Oia2 (16, 17)  D4Mit24-ΔD4Mgh21 (D4Rat84) 78,039,508–185,398,530 Cd69, Cxcl12, Cls, Clr, Aqp1, Il17ra, Il17re, Il17rc  
Pia2 (18) 3.9 D4Mgh1-D4Rat22 17,617,957–60,974,511 Irf5, Pon1 Irf5 
Pia5 (18) 4.5 D4Rat22-D4Mit16 60,974,347–130,228,614 Aqp1, Ptn  
Pia7 (11) 4.9 ΔD4Arb16 (D4Mit16)-D4Wox16 130,228,505–158,101,973 Cxcl12, Il17ra, Il17re, Il17rc  
Pia7 (19) 5.3 ΔD4Arb16 (D4Mit16)-D4Mgh11 130,228,505–171,204,531 Cd69, Cxcl12, Cls, Clr, Il17ra, Il17re, Il17rc  
Ciaa5* (9) 3.5 D5Wox3-D5Mgh8 99,080,787–149,757,440   
Ciaa5 (10) D5Mit14-ΔD5Wox17 (D5Wox10) 138,304,249–165,073,513 Padi4 Padi4 
Apr2 (20) 3.7 ΔD5Wox17 (D5Wox15)-D5Mgh9 148,718,587–171,801,867 Padi4, Tnfrsf14 Padi4 
Pia3 (18) 4.5 D6Mit1-D6Rat4 98,840,517–144,200,901 Serpina1 (Pi), Fos  
Pia3 (11, 19) 3.8 D6Mgh10-D6Rat4 108,621,345–144,200,901 Serpina1 (Pi), Fos  
Pia12 (19) 3.9 D6Mgh7-D6Wox5 47,039,213–117,362,003 Fos, Prkch, Pik3cg Prkch 
Cia20 (10) 2.9 ΔD6Rat16 (D6Rat19)-D6Wox5 81,682,368–117,362,003 Fos, Prkch Prkch 
Cia4 (8, 21) 5.3 D7Mgh22-D7Arb13 56,589,443–103,063,768 Ifng, Myc Ifng 
Cia8 (21) 5.1 D7Rat33-D7Mgh22 20,547,072–56,589,443   
Pia13 (19) 4.7 D7Mit9-D7Rat74 78,497,123–137,838,801 Myc, Vdr Vdr 
No name* (8) 3.2 D8Arb22-ΔD8Arb17 (D8Rat126) 103,815,825–124,310,006 Myd88  
Cia6 (9) 3.7 D8Mgh4-D8Rat71 86,627,870–127,907,265 Cx3cr1, Myd88  
Pia14 (19) D8Rat21-D8Rat26 79,347,688–87,122,815   
Cia15 (9) 4.5 D9Rat44-D9Arb7 2,948,883–39,821,284 Zap70, Vegfa (Vegf), Col9a1  
Ciaa3 (9) 7.5 D9Rat44-D9Wox19 2,948,883–18,347,743 Vegfa (Vegf 
Ciaa3 (14) 6.5 ΔD9Wox23 (0 bp)-D9Wox19 0–18,347,743 Vegfa (Vegf 
Cia5 (8, 14) 4.9 D10Arb21-ΔD10Arb22 (distal end) 84,263,650–110,718,848 Map3k14 (Nik), Ace, Stat3, Socs3, Tbx21 Ace 
Cia16* (9) 3.5 D10Rat95-D10Rat11 6,380,796–100,633,848 Map3k14 (Nik), Tnfsf13 (April), Ace, Mefv, Ccl2, Stat3, Il4, Ccl3, Ccl5, Cxcl16, Il13, Tp53, I13, Tbs21 Ace, I14, I13 
Oia3 (16, 22)  ΔD10Mit13 (D10Rat92)- ΔD10Mgh1 (D10Rat135) 78,170,545–108,776,963 Map3k14 (Nik), Tnfsf13 (April), Ace, Stat3, Socs3, Tbx21 Ace 
Pia10 (19) 3.1 ΔD10Rat26 (D10Rat27)-D10Rat44 24,731,831–77,091,892 Tnfsf13 (April); Ccl2, Il4, Ccl3,Ccl5, Cxcl16, Il13, Tp53, Il3 Il4, Il3 
 (Table continues    
Table IA.

(Continued)

QTLLODMarkersSearch Region (bp)RAA Genes within QTLRAAP Genes within QTL
Cia12 (14) 4.6 ΔD12Wox5 (0bp)-D12Arb6 0–36,819,134 Flt1 (Vegfr1), Epo, Ncf1 (P47-phoxNcf1 (P47–phox
Cia12 (10) 8.3 D12Rat28-ΔD12Mgh6 (D12Rat19) 16,312,646–37,906,549 Epo, Ncf1 (P47-phoxNcf1 (P47-phox
Cia25 (23) 4.7 D12Wox12-Nos1 20,932,556–39,869,383 Ncf1 (P47-phoxNcf1 (P47-phox
Pia4 (18) 8.4 ΔD12Mit1 (D12Wox12)-D12Mgh5 20,932,556–29,130,304 Ncf1 (P47-phoxNcf1 (P47-phox
Pia4 (12) 8.9 D12Rat72-D12Rat9 23,030,712–24,470,522 Ncf1 (P47-phox) Ncf1 (P47-phox
Pia4 (19) 53.1 D12Wox12-D12Mgh3 20,932,556–25,271,941 Ncf1 (P47-phoxNcf1 (P47-phox
Apr1 (20) 6.1 ΔD12Rat17 (D12Mgh7)-D12Rat22 36,834,562–46,043,557 Hspb8  
Piax* (12) 3.3 D14Rat32-D14Rat25 43,399,833–105,009,477 Lif, Osm, Fgfr3  
Pia6 (18) 4.9 D14Mgh3-D14Wox5 20,165,394–42,600,130 Gc Gc 
Ciaa7 (10) 3.2 D4Rat8-D14Wox12 12,400,909–20,178,280 Gc Gc 
No name* (15) D15Mit6-D15Rat22 47,302,628–80,370,658 Tnfsf11 (Opg1), Htr2a Htr2a 
Pia11 (12) 4.4 D16Rat64-D16Wox8 59,398,217–88,891,349 Gas6  
Cia17 (9) 4.3 D18Mit5-D18Rat82 32,458,819–73,666,556 Dcc, Adrb2, Slc26a2 Adrb2, Slc26a2 
Cia26 (23) 3.6 ΔD18Rat60 (D18Rat13)-ΔD18Mit9 (D18Rat119) 66,720,050–80,564,142 Dcc  
Pia15 (19) 3.4 D18Mgh3-D18Mit6 69,013,304–82,920,522 Dcc  
Cia14* (14) D19Rat13-D19Mit8 24,725,553–45,692,656 Il15, Nqo1  
Aia1 (15) 17.9 D20Arb2-ΔD20Arb8 (D20Rat33) 2,811,409–14,052,767 Tnf, Mif, Tap2, Tap1, Hla-dma, Hla-dmb, Nfkbil1 Tnf, Mif, Tap2, Tap1, Hla-dma, Hla-dmb, Nfkbil1 
Cia1 (8, 14, 15) 78.5 D20Arb2-ΔD20Arb8 (D20Rat33) 2,811,409–14,052,767 Tnf, Mif, Tap2, Tap1, Hla-dma, Hla-dmb, Nfkbil1 Tnf, Mif, Tap2, Tap1, Hla-dma, Hla-dmb, Nfkbil1 
Cia1 (9) 9.4 D20Wox3-D20Rat60 3,660,646–14,605,852 Tnf, Mif, Tap2, Tap1, Hla-dma, Hla-dmb Tnf, Mif, Tap2, Tap1, Hla-dma, Hla-dmb 
Pia1 (11) D20Rat41-D20Rat33 4,740,610–14,052,767 Mif, Tap2, Tap1, Hla-dma, Hla-dmb Mif, Tap2, Tap1, Hla-dma, Hla-dmb 
Pia1 (19) 4.8 D20Wox3-D20Rat33 3,660,646–14,052,767 Tnf, Mif, Tap2, Tap1, Hla-dma, Hla-dmb Tnf, Mif, Tap2, Tap1, Hla-dma, Hla-dmb 
Ciaa1 (9) 39.9 D20Wox3-D20Rat4 3,660,646–12,141,740 Tnf, Tap2, Tap1, Hla-dma, Hla-dmb Tnf, Tap2, Tap1, Hla-dma, Hla-dmb 
Ciaa1 (10) 5.8 ΔD20Mgh4 (0bp)-D20Rat15 0–20,264,413 Tnf, Mif, Tap2, Tap1, Hla-dma, Hla-dmb, Nfkbil1 Tnf, Mif, Tap2, Tap1, Hla-dma, Hla-dmb, Nfkbil1 
Cia18* (9) 3.2 DXRat4-ΔDXWox3 (DXRat66) 23,494,725–31,245,802   
Cia19 (9) 4.5 DXMgh9-ΔDXWox3 (DXRat66) 31,245,802–88,514,169 Ar Ar 
QTLLODMarkersSearch Region (bp)RAA Genes within QTLRAAP Genes within QTL
Cia12 (14) 4.6 ΔD12Wox5 (0bp)-D12Arb6 0–36,819,134 Flt1 (Vegfr1), Epo, Ncf1 (P47-phoxNcf1 (P47–phox
Cia12 (10) 8.3 D12Rat28-ΔD12Mgh6 (D12Rat19) 16,312,646–37,906,549 Epo, Ncf1 (P47-phoxNcf1 (P47-phox
Cia25 (23) 4.7 D12Wox12-Nos1 20,932,556–39,869,383 Ncf1 (P47-phoxNcf1 (P47-phox
Pia4 (18) 8.4 ΔD12Mit1 (D12Wox12)-D12Mgh5 20,932,556–29,130,304 Ncf1 (P47-phoxNcf1 (P47-phox
Pia4 (12) 8.9 D12Rat72-D12Rat9 23,030,712–24,470,522 Ncf1 (P47-phox) Ncf1 (P47-phox
Pia4 (19) 53.1 D12Wox12-D12Mgh3 20,932,556–25,271,941 Ncf1 (P47-phoxNcf1 (P47-phox
Apr1 (20) 6.1 ΔD12Rat17 (D12Mgh7)-D12Rat22 36,834,562–46,043,557 Hspb8  
Piax* (12) 3.3 D14Rat32-D14Rat25 43,399,833–105,009,477 Lif, Osm, Fgfr3  
Pia6 (18) 4.9 D14Mgh3-D14Wox5 20,165,394–42,600,130 Gc Gc 
Ciaa7 (10) 3.2 D4Rat8-D14Wox12 12,400,909–20,178,280 Gc Gc 
No name* (15) D15Mit6-D15Rat22 47,302,628–80,370,658 Tnfsf11 (Opg1), Htr2a Htr2a 
Pia11 (12) 4.4 D16Rat64-D16Wox8 59,398,217–88,891,349 Gas6  
Cia17 (9) 4.3 D18Mit5-D18Rat82 32,458,819–73,666,556 Dcc, Adrb2, Slc26a2 Adrb2, Slc26a2 
Cia26 (23) 3.6 ΔD18Rat60 (D18Rat13)-ΔD18Mit9 (D18Rat119) 66,720,050–80,564,142 Dcc  
Pia15 (19) 3.4 D18Mgh3-D18Mit6 69,013,304–82,920,522 Dcc  
Cia14* (14) D19Rat13-D19Mit8 24,725,553–45,692,656 Il15, Nqo1  
Aia1 (15) 17.9 D20Arb2-ΔD20Arb8 (D20Rat33) 2,811,409–14,052,767 Tnf, Mif, Tap2, Tap1, Hla-dma, Hla-dmb, Nfkbil1 Tnf, Mif, Tap2, Tap1, Hla-dma, Hla-dmb, Nfkbil1 
Cia1 (8, 14, 15) 78.5 D20Arb2-ΔD20Arb8 (D20Rat33) 2,811,409–14,052,767 Tnf, Mif, Tap2, Tap1, Hla-dma, Hla-dmb, Nfkbil1 Tnf, Mif, Tap2, Tap1, Hla-dma, Hla-dmb, Nfkbil1 
Cia1 (9) 9.4 D20Wox3-D20Rat60 3,660,646–14,605,852 Tnf, Mif, Tap2, Tap1, Hla-dma, Hla-dmb Tnf, Mif, Tap2, Tap1, Hla-dma, Hla-dmb 
Pia1 (11) D20Rat41-D20Rat33 4,740,610–14,052,767 Mif, Tap2, Tap1, Hla-dma, Hla-dmb Mif, Tap2, Tap1, Hla-dma, Hla-dmb 
Pia1 (19) 4.8 D20Wox3-D20Rat33 3,660,646–14,052,767 Tnf, Mif, Tap2, Tap1, Hla-dma, Hla-dmb Tnf, Mif, Tap2, Tap1, Hla-dma, Hla-dmb 
Ciaa1 (9) 39.9 D20Wox3-D20Rat4 3,660,646–12,141,740 Tnf, Tap2, Tap1, Hla-dma, Hla-dmb Tnf, Tap2, Tap1, Hla-dma, Hla-dmb 
Ciaa1 (10) 5.8 ΔD20Mgh4 (0bp)-D20Rat15 0–20,264,413 Tnf, Mif, Tap2, Tap1, Hla-dma, Hla-dmb, Nfkbil1 Tnf, Mif, Tap2, Tap1, Hla-dma, Hla-dmb, Nfkbil1 
Cia18* (9) 3.2 DXRat4-ΔDXWox3 (DXRat66) 23,494,725–31,245,802   
Cia19 (9) 4.5 DXMgh9-ΔDXWox3 (DXRat66) 31,245,802–88,514,169 Ar Ar 
a

An asterisk (∗) denotes a QTL with suggestive but not significant, linkage. Delta (Δ) denotes that the marker is not mapped to the assembly in the current Ensembl database; alternatively, we choose a marker near the target marker for Ensembl searching. The information on the distance between those two markers is from Rat Genome Database (rgd.mcw.edu/maps/); RAA gene: RA-associated gene; RAAP gene, gene containing RA-associated polymorphisms either in coding region or in regulatory region.

The 52 arthritis QTL cover 1,486,846,486 bp of genomic sequence, which is roughly 54% of the total rat genome. Every autosome and the X chromosome (Chr), except Chr11, Chr13, and Chr17, contain at least one arthritis QTL. Within the 1,486,846,486-bp genomic sequences, a total of 16,222 genes have been located. The average gene density throughout the whole rat genome except ChrY is about one gene per 99,918 bp. Within the total of 1,486,846,486-bp genomic sequences representing arthritis QTL there is about one gene per 91,656 bp, whereas in the genome region outside of the arthritis QTL regions there is about one gene per 112,145 bp. Overall, the density of genes in QTL regions is higher than that of non-QTL regions; however, not every QTL has a high gene density. QTL located in gene-rich regions include Cia2, Ciaa6, Ciaa5, Apr2, Cia5, Cia16, Oia3, Pia10, Cia12, Pia4, Cia14, Aia1, Cia1, Pia1, and Ciaa1. There is a gene in every 52,795, bp in those genome regions. We also found some QTL located in gene-poor regions, including Cia7, Cia11, Pia2, Pia7, Cia4, Cia8, Pia14, Cia26, Pia15, and Cia19. In those regions, there is a gene in every 160,471 bp. These data suggest that there is no important difference between QTL regions and non-QTL regions relative to gene density.

We conducted a whole genome scan to find the genes that regulate RA in rat genome. First, we obtained the genes for every chromosome and QTL from the Ensembl database (release 48) (www.ensembl.org/index.html), and then we searched PubMed (www.ensembl.org/index.html) and OMIM (Online Mendelian Inheritance in Man; www.ncbi.nlm.nih.gov/sites/entrez) to get a preliminary list of candidate genes associated with arthritis. The search terms were the combination of the symbol of the gene and arthritis. We performed the searching using PGMapper, software newly developed by us and available online at www.genediscovery.org/pgmapper/index.jsp (24). Then, we read the associated literature to determine the connection between those preliminary candidate genes and RA. A gene is considered to be a RA-associated gene if it was associated with RA in at least one of the following studies: 1) functional studies such as knockouts, transgenics, mutagenesis, RNA interference, etc.; 2) association studies; and 3) clinical studies. Through this method, we identified 185 RA-associated genes in the whole rat genome; among them, 124 are located in QTL regions. The catalogue of all RA-associated genes and the relevant literature indicating their candidacy can be found in supplemental table I.4 In total, there are significantly more RA-associated genes in QTL regions than in non-QTL regions. To investigate whether this is also true at the chromosomal level, we examined the distribution of RA-associated genes for every chromosome. Fig. 1 shows the distribution of those genes between QTL and non-QTL regions for each chromosome. We found that the chromosomal distribution of RA-associated genes is complex. The QTL on Chr5, Chr6, Chr10, Chr12, Chr14, and Chr20 cover all RA-associated genes. There are more RA-associated genes in QTL regions than in non-QTL regions on six chromosomes, including Chr1, Chr2, Chr4, Chr7, Chr15, and Chr18. However, fewer RA-associated genes were found in QTL regions than non-QTL regions on Chr3, Chr8, Chr9, Chr16, and Chr19. There is no difference for ChrX. Surprisingly, no QTL have been identified on Chr11, Chr13, and Chr17, although obvious candidate genes exist. The information of genes on ChrY is still not available in the Ensembl database, so all QTL and genes on ChrY are excluded from our analysis. We also found that most RA-associated genes are located in QTL regions on Chr1, Chr2, Chr4, and Chr10. Similarly, there are more QTL identified on these chromosomes, suggesting that these chromosomes may play an important role in the regulation of arthritis. In addition, we also performed a two-tailed paired-sample t test using standard statistical software (SPSS) after excluding the chromosomes without arthritis QTL and the p value was 0.049, indicating that there is a statistically significant difference between the number of RA-associated genes within and outside QTL.

FIGURE 1.

Distribution of RA-associated (RAA) genes between QTL and non-QTL regions on each chromosome.

FIGURE 1.

Distribution of RA-associated (RAA) genes between QTL and non-QTL regions on each chromosome.

Close modal

By comparing the number of genes that contain one or more RA-associated polymorphisms either in coding regions or in regulatory regions between QTL regions and non-QTL regions, we found that most of those genes fall into QTL regions. Among 52 genes containing RA-associated polymorphisms, 35 are located in QTL regions. We also detected the frequency of these genes for every chromosome. Fig. 2 shows the distribution of these genes between QTL and non-QTL regions for each chromosome. The catalogue of all genes containing RA-associated polymorphisms and the references establishing their candidacy can be found in supplemental table I. There was a noticeable difference in the chromosomal distribution of these RA-associated polymorphisms, although the difference between the number of genes containing RA-associated polymorphisms within and outside arthritis QTL did not reach the statistically significant level (p = 0.062). The QTL regions cover all RA-associated polymorphisms on 11 chromosomes, including Chr2, Chr5, Chr6, Chr7, Chr10, Chr12, Chr14, Chr15, Chr18, Chr20, and ChrX. Chr1 has more RA-associated polymorphisms in QTL regions than in non-QTL regions. Excluding ChrY and Chr19, which has no known RA-associated polymorphisms, as well as those three chromosomes that have no known arthritis QTL, only five chromosomes, namely Chr3, Chr4, Chr8, Chr9, and Chr16, have fewer RA-associated polymorphisms in QTL regions than in non-QTL regions. Our data may indicate that the genetic basis of QTL is based on polymorphisms.

FIGURE 2.

Distribution of genes containing RA-associated polymorphisms (RAAP), either in a coding region or a regulatory region, between QTL and non-QTL regions on each chromosome.

FIGURE 2.

Distribution of genes containing RA-associated polymorphisms (RAAP), either in a coding region or a regulatory region, between QTL and non-QTL regions on each chromosome.

Close modal

The direct identification of causative genes underlying QTL has been slow and remains a major bottleneck in fully understanding the genetic contribution to rheumatoid arthritis. Using currently available genome data and gene annotation information, we systematically examined RA-associated genes and polymorphisms within and outside QTL over the whole rat genome. By the whole genome analysis of genes and polymorphisms, we found that there are significantly more RA-associated genes or polymorphisms in QTL regions as contrasted with non-QTL regions. However, a substantial number are not in QTL regions. Because some QTL have only a small effect on disease and because QTL identified by linkage analysis usually cover large regions of genomic sequence and include hundreds of genes, identification of specific genes remains difficult. One interesting question raised by our investigation is whether those known RA-associated genes or polymorphisms within QTL regions constitute the genetic basis of the QTL effect. Candidates must be carefully investigated in more directed experiments to establish their roles in the regulation of QTL. In general, we found multiple RA-associated genes or polymorphisms existing in a single QTL. Thus, another important question is whether those QTL are caused by a single, large-effect gene or by a series of genes, each of small effect. We should be able to answer this question with the advance of fine mapping technologies that can effectively refine the map location of identified QTL. Actually, some QTL have been dissected into subregions by fine mapping, such as Cia5 (25) and Oia3 (22) on chromosome 10, indicating that it is possible that some of those QTL are composed of several linked subloci.

Our analysis indicated that chromosomal distribution of RA-associated genes or polymorphisms is complex. Although for most of chromosomes there are more RA-associated genes or polymorphisms in QTL regions than in non-QTL regions, some chromosomes still have fewer RA-associated genes or polymorphisms in QTL regions than in non-QTL regions. There were even no QTL detected in Chr11, Chr13, and Chr17 despite the existence of obvious candidate genes. This may be because of the following. First, methods for QTL mapping cannot detect all QTL, especially some small-effect QTL, because of small sample size, small phenotypic variance, sparse marker coverage. Second, gene annotation is still in progress. The map location and/or function of many genes is currently unknown in the rat. For example, two well-known RA-associated genes in human, FCRL3 (26) and SLC22A4 (27), are still not mapped to the current Ensembl rat assembly and thus we cannot obtain the exact location of homologues of these two genes in the rat genome. Third, because direct effects on arthritis regulation may not yet be recognized for many genes, some arthritis-associated genes may be missing from the gene list collected by our investigation. There may be unknown RA-causative genes or polymorphisms in the QTL regions. Fourth, the association of some genes or polymorphisms with RA was detected in human or other species. This may not be true for the rat. The same gene or polymorphism may have different influence on the same phenotype in different ethnic groups or species. Some RA-associated genes or polymorphisms identified by human studies may have no role in the regulation of arthritis in the rat and cannot be a cause of rat QTL. Fifth, the putative contribution of some RA-associated genes or polymorphisms in the regulation of arthritis may not be true, as it cannot be replicated or confirmed by other independent studies. In addition, some genes may only have an indirect role in the pathogenesis of arthritis and cannot be considered as genetic factors underlying the QTL effect.

This investigation is the first attempt to explore the genetic and molecular basis of QTL of experimental autoimmune arthritis at a genome-wide scale. Our data indicated that the nature of QTL may be based on polymorphisms either in coding regions or in regulatory regions of genes. Those polymorphisms may cause the changes in expression and/or function of relevant genes that can account for the QTL effect. Moreover, some rare alleles and/or haplotypes appear to play important roles in the initiation and/or development of RA or other autoimmune disorders and may be important candidates underlying the QTL (28, 29, 30, 31, 32, 33). In addition, some RA-associated genes identified from knockouts or transgenics may have important roles in the pathogenesis of RA but have only little opportunity to be the genetic factors causing the QTL effect. Those genes are not polymorphic in the population under investigation, so they may not be able to contribute to the phenotypic variance in quantitative traits.

The authors have no financial conflict of interest.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1

This work was funded by National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant AR51190 (to W.G.).

3

Abbreviations used in this paper: RA, rheumatoid arthritis; Chr, chromosome; LOD, logarithm of the odds; QTL, quantitative trait locus.

4

The online version of this article contains supplemental material.

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