Human Molecular Genetics, 2001, Vol. 10, No. 18 1901-1906
© 2001 Oxford University Press
High resolution linkage and association mapping identifies a novel rheumatoid arthritis susceptibility locus homologous to one linked to two rat models of inflammatory arthritis
1Arthritis Rheumatism Campaign Epidemiology Research Unit, University of Manchester, Manchester M13 9PT, UK, 2Department of Medicine, Rheumatology Unit, Karolinska Hospital, Stockholm, Sweden and 3Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden
Received April 17, 2001; Revised and Accepted June 25, 2001.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONPATIENTS AND METHODSREFERENCES |
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Rheumatoid arthritis (RA) is an oligogenic autoimmune disease but, to date, linkage and association to major histocompatibility complex (MHC) has been the only consistent finding in genetic studies. However, MHC is estimated to contribute only 30–40% of the total genetic component to disease susceptibility. Studies in animal models of inflammatory arthritis have identified a number of putative vulnerability loci but the homologous regions in the human genome have not previously been investigated as candidate RA susceptibility loci. We have investigated linkage to five regions homologous to those identified in animal models of inflammatory arthritis in RA affected sibling pair (ASP) families. Linkage to 17q22 syntenic to a susceptibility locus common to two experimental rat models was detected in 200 RA ASP families and replicated in a further 100 RA ASP families. Linkage to additional markers mapping to the area has refined the extent of linkage to a 4 cM region. Association to one of the markers (D17S807) was demonstrated in this cohort using extensions of the transmission disequilibrium test. Association to two 2-marker haplotypes including this marker was detected in an independent cohort of single-case RA families, thus narrowing the region harbouring the aetiological mutation to
1 cM. This is the first time that an arthritis susceptibility locus mapped in experimental animal models of disease has been used to identify a novel RA susceptibility locus in humans. The difficult task of identifying a disease mutation from a linkage result should, in this case at least, be facilitated by the combined use of animal and human based investigations. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONPATIENTS AND METHODSREFERENCES |
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Rheumatoid arthritis (RA) is a chronic disabling condition characterized by inflammation of synovial joints, with a prevalence of up to 1% in the population. Family and twin studies suggest that the genetic component to RA susceptibility approaches 60% (1). Association and linkage with RA have consistently been reported to human leukocyte antigen (HLA) in different populations but HLA has been estimated to account for only one-third of the total genetic susceptibility component (2). It is expected that a number of other genetic susceptibility factors exist, each making a smaller genetic contribution than HLA—the challenge now is to identify these. Ultimately, this may give new insights into pathways involved in disease pathogenesis and lead to the identification of novel therapeutic targets.
Identification of candidate arthritis susceptibility genes or regions can arise from several routes including results of whole genome scans (WGS), expression studies or targeting genes involved in a pathway which contributes to disease pathogenesis. In an alternative strategy, it is possible that animal models of inflammatory arthritis can provide an important insight as to which candidate genes or regions should be studied. This strategy has proved valuable in the investigation of a number of human autoimmune diseases but has not previously been applied to the investigation of arthritic disease. For example, regions homologous to loci identified in animal models of multiple sclerosis (MS), systemic lupus erythematosus (SLE) and type 1 insulin dependent diabetes mellitus (IDDM) have subsequently been shown to be linked to disease in humans (3–5).
There is no spontaneous model of RA in rats or mice although arthritis can be induced in susceptible rodent strains using immunostimulatory adjuvants, with or without joint-specific antigens, to produce a variety of models. For example, oil-induced arthritis (OIA) is induced in susceptible rat strains using the adjuvant oil, Freund’s incomplete adjuvant (FIA). Mycobacterium butyricum or Mycobacterium tuberculosis suspended in FIA can induce adjuvant-induced arthritis (AIA) in susceptible rat strains. In both AIA and OIA, the arthritis has an abrupt onset and is self-limiting. Collagen-induced arthritis (CIA) can be induced in rats or mice using either homologous or heterologous collagen II, resulting in chronic or acute arthritis, respectively. Pristane is a well-defined mineral oil which acts as a non-immunogenic adjuvant. Intradermal injection of pristane into the base of the tail induces an erosive and deforming arthritis (pristane-induced arthritis, PIA) which can run a relapsing/remitting, acute or chronic course in susceptible rat strains (6). In all these models, the arthritis induced is erosive, symmetrical and histologically similar to RA. In addition, in the PIA model, Rheumatoid factor is present (reviewed in 7).
WGS of the progeny of crosses between a variety of arthritis-prone and arthritis-resistant strains have been highly successful in identifying a large number of putative arthritis susceptibility regions in different animal models (8–22). Regions in the human genome homologous to these loci in animal models can be identified from homology databases. We have therefore investigated whether these homologous regions may be linked to human RA.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONPATIENTS AND METHODSREFERENCES |
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Linkage analysis
Two adjacent microsatellite markers (D17S807 and D17S795) mapping to 17q22, syntenic to the OIA 3/CIA 5 locus in rat models of inflammatory arthritis, showed evidence of linkage in single-point analysis of 200 RA affected sibling pair (ASP) families (LOD 1.00, P = 0.025 and LOD = 1.21, P = 0.015, respectively) (Table 1). Linkage to these two markers was replicated in a further 100 RA ASP families (LOD = 1.87, P = 0.003 and LOD = 0.50, P = 0.09, respectively). Table 2 shows the evidence for linkage to these two markers for the combined data set of 300 ASP families. Linkage to three additional microsatellite markers around the peak of linkage was investigated in the original cohort of 200 families and the results of single-point linkage analysis confirm linkage in this region (Table 3). The results of multi-point linkage analysis using Mapmaker/sibs are shown in Figure 1. The maximum multi-point LOD score was 2.4.
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No evidence of linkage was demonstrated to the other chromosome regions investigated, 12p13, 8q24 and 22q13, 7p15 and 7q21 in the first 200 RA ASP families using either single- (Table 2) or multi-point analysis (data not shown).
Family-based association study:
The data from these RA ASP families was also investigated for association to markers showing evidence of linkage using a combined extended transmission disequilibrium test (ETDT) and sibship transmission disequilibrium test (sibTDT) approach, to maximize the number of subjects included, and association to D17S807 was demonstrated (P = 0.02).
Association to all of the five microsatellite markers spanning the peak of linkage on chromosome 17q23 in RA ASP families was then investigated in an independent cohort of nuclear families with one affected proband, using transmission disequilibrium test (TDT)-based methods. Evidence for association was found for two 2-marker haplotypes involving the microsatellite markers D17S1821 and D17S807 (
2 d.f. 10.84, corrected P-value = 0.014). This association corresponded to the peak of linkage in the RA ASP families.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONPATIENTS AND METHODSREFERENCES |
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We have found evidence for both linkage and association to chromosome 17q22 in ASP families with RA. Association and linkage to haplotypes of two markers close to the peak of linkage in ASP families has been confirmed in an independent data set of single-case families. No evidence of linkage was detected to four other regions investigated; 12p13, 8q24 and 22q13, 7p15 and 7q21–q22, homologous to Oia2, Cia 4, Aia 2 and Pia 4, respectively.
This is the first study to demonstrate linkage to RA with regions syntenic to areas identified in animal models of inflammatory arthritis. Work in other oligogenic autoimmune diseases, including SLE, IDDM and MS, has shown that targeting candidate regions identified in animal models in this way is an efficient method of identifying susceptibility loci for the human form of disease (3–5).
Chromosome 17q21–q25 was selected as a candidate region for investigation because evidence of linkage was detected to the syntenic region in two animal models of inflammatory arthritis, OIA and CIA, in rats (8,9). It was hypothesized that regions linked to more than one animal model of arthritis were more likely to contain true arthritis-susceptibility genes. There are a number of lines of evidence to support the hypothesis that this region of chromosome 17q22 contains a RA susceptibility allele. Firstly, the strength of the LOD score suggests that the linkage result is unlikely to have resulted from a type I error. Secondly, the linkage has been replicated in independent sets of RA ASP families. Thirdly, the association has also been replicated in an independent cohort of single-case families. Fourthly, WGS of ASP families with psoriasis have detected evidence of linkage to this region and the evidence for linkage appears stronger in those families with joint involvement (23). A number of strong candidate genes, including intracellular adhesion molecule 2 (ICAM2) and platelet endothelial cell adhesion molecule-1 (PECAM1) map to this locus. Finally, a WGS of US RA ASP families has also demonstrated linkage to the region (24). Linkage in US RA ASP families extended over a considerable distance with the peak of linkage mapping 15 cM from the peak of linkage and association in the current study. Interestingly, evidence from experiments in rats made congenic for the Oia 3 locus on an arthritis-resistant background strain suggest that the Oia 3 locus may harbour more than one arthritis susceptibility gene. The peak of linkage in the current study corresponds to the central region of the Oia 3 locus that harbours a susceptibility gene predisposing to arthritis-development in both male and female rats (25). In support of this, no effect of stratification by sex on the strength of linkage was detected in our data set (data not shown). In contrast, the peak of linkage in the US study appears to correspond more closely to the telomeric portion of the Oia 3 locus (24,25). In the current study, additional markers have been used to refine the peak of linkage to a 4 cM region of chromosome 17q22. The evidence for association to the marker D17S807 or haplotypes involving this marker narrows down the region harbouring the putative disease susceptibility gene to a manageable size for the next stage of investigation: high density mapping using single nucleotide polymorphism (SNP) markers.
Although no evidence of linkage was detected to four other regions investigated homologous to Oia 2, Cia 4, Aia 2 and Pia 4, respectively, the study had insufficient power to exclude a gene of modest effect mapping to these areas. Important genetic effects can occur as a result of genes with a very modest genetic contribution if the population frequency of alleles is high (26). Animal models are not an exact reflection of the situation in RA and some have features more in keeping with the seronegative arthritides. For example, rats with AIA may develop balanitis, urethritis, keratitis, conjunctivitis, iridocyclitis and diarrhoea, which are more in keeping with Reiters syndrome (7). It may be then that some loci syntenic to those identified in animal models of arthritis will subsequently be shown to be linked to other forms of arthritis in humans but not RA.
In summary, we report the identification of an RA susceptibility locus mapping to 17q22. Work is now underway to construct a dense map of SNP markers to investigate association with genes mapping to this region in order to identify the aetiological mutation.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONPATIENTS AND METHODSREFERENCES |
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Study design
Linkage to regions homologous to five loci linked to animal models of arthritis was investigated initially in 200 ASP families from the ARC National Repository. Regions showing evidence of linkage were then investigated in an independent set of 100 RA ASP families to try to replicate the linkage. In the next stage, markers mapping to confirmed regions of linkage were then investigated for association in the RA ASP families. Following this, additional markers mapping to regions of interest were investigated for linkage in the RA ASP families to better define the peak of linkage. Finally, all markers showing evidence of linkage to a region were investigated for association in an independent cohort of single-case RA families.
Candidate loci
Five loci, homologous to regions showing linkage in animal models of inflammatory arthritis, were selected for investigation. These areas were prioritized because they fulfilled one or more of the following criteria: (i) the regions showed linkage in more than one animal model of arthritis; (ii) the region harboured a strong candidate gene; or (iii) there was evidence that either the animal locus or the homologous locus in humans was linked to autoimmune disease.
Oia 2. ‘Oia 2’ maps to rat chromosome 4 (8). The Oia 2 locus co-localizes with a susceptibility locus in murine and rat models of CIA (10,11) and with a locus associated with susceptibility to PIA (12). The OIA 2 locus is of particular interest because genes which map close to the OIA 2 locus in rats map to 12p13 in humans. This region has been implicated in two RA WGS (24,27). It also harbours a number of candidate genes including tumour necrosis factor receptor 1.
Cia 4. The CIA susceptibility locus, ‘Cia 4’, maps to rat chromosome 7 (9). It co-localizes with susceptibility loci to mouse models of CIA (13) and proteoglycan-induced arthritis (14). Genes which map close to CIA 4 map predominantly to two areas of the human genome: 8q24 and 22q13. The region 8q24 harbours a strong RA candidate susceptibility gene, the proto-oncogene, c-myc.
Aia 2. Genes mapping close to the Aia 2 locus in rats map to 7p15 in humans (15). This region has been linked to a number of human autoimmune diseases (28,29).
Pia 4. The Pia 4 locus on rat chromosome 12 (16) co-localizes with a susceptibility locus for CIA (11). The homologous region in the human genome is 7q21–q22 and the homologous region in mice has been linked to IDDM (30). The region also harbours a number of candidate RA susceptibility genes.
Oia 3. The Oia 3 locus on rat chromosome 10 co-localizes with a CIA susceptibility locus, Cia 5 (8,9). The homologous region in the human genome is 17q21–q25 and it is highly conserved with rat chromosome 10. In humans the region has been linked to MS (29) and psoriasis (23).
For each of these five loci, the homologous region in the human genome had either already been identified (Oia 2, Cia 4, Aia 2, Pia 4) or was identified using rat/mouse human homology databases (Oia 3). Thirty-three microsatellite markers, with an average spacing of 3.7 cM, spanning these regions of interest in the human genome were identified from Genethon database (Table 1).
ASP families
DNA was available from 300 ASP families in the ARC National Repository (www.http://arc.man.ac.uk) (31). ASP families were recruited from all areas of the UK by direct referral from consultant rheumatologists, direct recruitment at clinics by metrologists and by self-referral following a media campaign. Patients were assessed by trained metrologists using standardized questionnaires and examination and all cases satisfied the 1987 ACR criteria (32) modified for genetic studies (33). For the purposes of the current study, two separate sets of families were identified—a test group and a replication group. The first set of 200 ASP families, comprising 696 individuals, was used for initial investigation of linkage. DNA from both parents was available for 34 families and from one parent in a further 42 families. Where parental DNA was not available, DNA from other siblings was obtained where possible. Fifty-one families contained three siblings, 52 contained four siblings, four contained five siblings and one family each contained six, seven and eight siblings. In some cases, a single family contained multiple ASPs. The remaining families consisted of ASPs only. This data set had previously been used to test for linkage to markers throughout the genome. As part of the analysis for that study, these families were investigated for inconsistencies of sibships using the software ‘RELATIVE’ (34). Three half-sibs and one unrelated sibling were discovered and these individuals were removed from further analyses. The second set of 100 ASP families, comprising 261 individuals, was used as a replication data set for any positive linkages detected in the first 200 families. DNA from both parents was available in five cases and from one parent in one case. Eleven families contained three siblings, four contained four siblings and one family each contained five and six siblings. The remaining families consisted of ASP only.
Nuclear families for family-based association study
DNA was available from 152 nuclear families with one affected offspring from the ARC National Repository. DNA was available from both parents in 149 cases and from one parent only in the three remaining cases.
Microsatellite genotyping
Semi-automated analysis of microsatellite genotypes was performed using a PE Applied Biosystems 377 DNA sequencer with Genescan analysis (version 2.1 and 3.1) and Genotyper software (version 1.1.1 or 2) as described previously (35). Forward polymerase chain reaction (PCR) primers were fluorescently labelled with either 6-FAM, HEX or TET attached to the 5' end during synthesis. PCRs were performed in a total reaction volume of 10 µl, containing 50 ng of DNA, 10 pmol of each primer, 4 nmol of each of the four deoxynucleotide triphosphates, 0.04 U Taq Polymerase (Bioline) in 1–3 mM MgCl2 buffer. The mixture was overlaid with a drop of liquid paraffin and subjected to 35 cycles of denaturation (95°C), primer annealing and extension. Reactions for each marker were performed separately. Panels of PCR products were combined into a single pool before electrophoresis such that all PCR products in a panel for a single person could be loaded into a single lane of a gel. Electrophoresis was performed on 0.2 mm 4% polyacrylamide gels run for 2 h at 3000 V with a running temperature of 51°C. PCR products from two reference samples were included on every gel to monitor any gel–gel variation.
Statistical analysis
Genotype data were initially analysed using Genetic Analysis Software (GAS) (Alan Young, Oxford) in order to check for genotype inconsistencies and inheritance problems. ‘PEDCHECK’ (36) was also used as an additional check to identify genotyping errors.
1. Linkage analysis. Single-point linkage analysis was performed using SPLINK (version 1.05, David Clayton, MRC Biostatistics Unit, Cambridge). This is a maximum-likelihood program which uses the data files produced by GAS to estimate the probability that two siblings share 2, 1 or 0 alleles identical-by-descent. Information from other siblings was used to infer parental genotypes when this information was not directly available and internally generated allele frequencies were used when information from other siblings was unavailable.
Multi-point linkage analysis was performed using Mapmaker/sibs (37). This program uses information from other markers to infer linkage across a region. Again, it is a maximum-likelihood method that uses allele frequencies generated by SPLINK to infer parental genotypes when this information is not directly available.
2. Family-based association analysis. The TDT is a test of association in the presence of linkage (38). Preferential transmission from a heterozygous parent to affected offspring is assessed. The ETDT, which is a modification of the TDT that allows the analysis of the effect of multiple alleles, was used in single-point linkage analysis (39). SibTDT allows information from siblings to be used to infer parental genotypes when this information is not available and was combined with the ETDT to assess association in the RA ASP families (40). ‘TRANSMIT’ (David Clayton, MRC Biostatistics Unit, Cambridge), a maximum-likelihood method of TDT, was used for 2-marker haplotype analysis. This program was used for to test for association with haplotypes involving adjacent markers using a moving window approach.
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ACKNOWLEDGEMENTS |
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This work was funded by the Arthritis Rheumatism Campaign. A.B. is in receipt of a Clinical Research Fellowship from the Medical Research Council (UK).
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FOOTNOTES |
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+ To whom correspondence should be addressed at: ARC-EU, Stopford Building, University of Manchester, UK. Tel: +44 161 275 5037; Fax: +44 161 275 5043; Email: abarton@fs1.ser.man.ac.uk
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REFERENCES |
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1 MacGregor, A.J., Snieder, H., Rigby, A.S., Koskenvuo, M., Kaprio, J., Aho, K. and Silman, A.J. (2000) Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum., 43, 30–37.[ISI][Medline]
2 Deighton, C.M., Walker, D.J., Griffiths, I.D. and Roberts, D.F. (1989) The contribution of HLA to rheumatoid arthritis. Clin. Genet., 36, 178–182.[ISI][Medline]
3 Kuokkanen, S., Sundvall, M., Terwilliger, J.D., Tienari, P.J., Wikstrom, J., Holmdahl, R., Pettersson, U. and Peltonen, L. (1996) A putative vulnerability locus to multiple sclerosis maps to 5p14-p12 in a region syntenic to the murine locus Eae2. Nat. Genet., 13, 477–480.[ISI][Medline]
4 Tsao, B.P., Cantor, R.M. and Kalunian, K.C. (1997) Evidence for linkage of a candidate chromosome 1 region to human systemic lupus erythematosus. J. Clin. Invest., 99, 725–731.[ISI][Medline]
5 Nistico, L., Buzzetti, R., Pritchard, L.E., Van der Auwera, B., Giovannini, C., Bosi, E., Larrad, M.T., Rios, M.S., Chow, C.C., Cockram, C.S. et al. (1996) The CTLA-4 gene region of chromosome 2q33 is linked to and associated with type I diabetes. Hum. Mol. Genet., 5, 1075–1080.
6 Vingsbo, C., Sahlstrand, P., Brun, J.G., Jonsson, R., Saxne, T. and Holmdahl, R. (1996) Pristane-induced arthritis in rats – a new model for rheumatoid arthritis with a chronic disease course influenced by both major histocompatibility complex and non-major histocompatibility complex genes. Am. J. Pathol., 149, 1675–1683.[Abstract]
7 Goldings, E.A. and Jasin, H.E. (1993) Arthritis and autoimmunity in animals. In McCarty, D.J. and Koopman, W.J. (eds), Arthritis and Allied Conditions, Lea and Febiger, Philadelphia, pp. 525–541.
8 Lorentzen, J.L., Glaser, A., Jacobsson, L., Galli, J., Fakhrai-Rad, H., Klareskog, L. and Luthman, H. (1998) Identification of rat susceptibility loci for adjuvant-oil-induced arthritis. Proc. Natl Acad. Sci. USA, 95, 6383–6387.
9 Remmers, E.F., Longman, R.E., Du, Y., O’Hare, A., Cannon, G.W., Griffiths, M.M. and Wilder, R.L. (1996) A genome scan localizes five non-MHC loci controlling collagen-induced arthritis in rats. Nat. Genet., 14, 82–85.[ISI][Medline]
10 Griffiths, M.M., Wang, J., Joe, B., Dracheva, S., Kawahito, Y., Shepard, J.S., Reese, V.R., McCall-Vining, S., Hashiramoto, A., Cannon, G.W. et al. (2000) Identification of four new quantitative trait loci regulating arthritis severity and one new quantitative trait locus regulating autoantibody production in rats with collagen-induced arthritis. Arthritis Rheum., 43, 1278–1289.[ISI][Medline]
11 McIndoe, R.A., Bohlman, B., Chi, E., Schuster, E., Lindhardt, M. and Hood, L. (1999). Localization of non-MHC collagen-induced arthritis susceptibility loci in DBA/1j mice. Proc. Natl Acad. Sci. USA, 96, 2210–2214.
12 Nordquist, N., Olofsson, P., Vingsbo-Lundberg, C., Petterson, U. and Holmdahl, R. (2000) Complex genetic control in a rat model for rheumatoid arthritis. J. Autoimmun., 15, 425–432.[ISI][Medline]
13 Yang, H.-T., Jirholt, J., Svensson, L., Sundvall, M., Jansson, L., Pettersson, U. and Holmdahl, R. (1999) Identification of genes controlling collagen-induced arthritis in mice: striking homology with susceptibility loci previously identified in the rat. J. Immunol., 163, 2916–2921.
14 Otto, J.M., Cs-Szabo, G., Gallagher, J., Velins, S., Mikecz, K., Buzas, E.I., Enders, J.T., Li, Y., Olsen, B.R. and Glant, T.T. (1999) Identification of multiple loci linked to inflammation and autoantibody production by a genome scan of a murine model of rheumatoid arthritis. Arthritis Rheum., 42, 2524–2531.[ISI][Medline]
15 Kawahito, Y., Cannon, G.W., Gulko, P.S., Remmers, E.F., Longman, R.E., Reese, V.R., Wang, J., Griffiths, M.M. and Wilder, R.L. (1998) Localisation of quantitative trait loci regulating adjuvant-induced arthritis in rats: Evidence for genetic factors common to multiple autoimmune diseases. J. Immunol., 161, 4411–4419.
16 Vingsbo-Lundberg, C., Nordquist, N., Olofsson, P., Sundvall, M., Saxne, T., Petterson, U. and Holmdahl, R. (1998) Genetic control of arthritis onset, severity and chronicity in a model for rheumatoid arthritis in rats. Nat. Genet., 20, 401–404.[ISI][Medline]
17 Jirholt, J., Cook, A., Emahazion, T., Sundvall, M., Jansson, L., Nordquist, N., Pettersson, U. and Holmdahl, R. (1998) Genetic linkage analysis of collagen-induced arthritis in the mouse. Eur. J. Immunol., 28, 3321–3328.[ISI][Medline]
18 Furuya, T., Salstrom, J.L., McCall-Vining, S., Cannon, G.W., Joe, B., Remmers, E.F., Griffiths, M.M. and Wilder, R.L. (2000) Genetic dissection of a rat model for rheumatoid arthritis: significant gender influences on autosomal modifier loci. Hum. Mol. Genet., 9, 2241–2250.
19 Carlson, B.C., Jansson, A.M., Larsson, A., Bucht, A. and Lorentzen, J.C. (2000) The endogenous adjuvant squalene can induce a chronic T-cell mediated arthritis in rats. Am. J. Pathol., 156, 2057–2065.
20 Dracheva, S.V., Remmers, E.F., Gulko, P.S., Kawahito, Y., Longman, R.E., Reese, V.R., Cannon, G.W., Griffiths, M.M. and Wilder, R.L. (1999) Identification of a new quantitative trait locus on chromosome 7 controlling disease severity of collagen-induced arthritis in rats. Immunogenetics, 49, 787–791.[ISI][Medline]
21 Gulko, P.S., Kawahito, Y., Remmers, E.F., Reese, V.R., Wang, J., Dracheva, S.V., Ge, L., Longman, R.E., Shepard, J.S., Cannon, G.W. et al. (1998) Identification of a new non-major histocompatibility complex genetic locus on chromosome 2 that controls disease severity in collagen-induced arthritis in rats. Arthritis Rheum., 41, 2122–2131.[ISI][Medline]
22 Otto, J.M., Chandrasekeran, R., Vermes, C., Mikecz, K., Finnegan, A., Rickert, S.E., Enders, J.T. and Glant, T.T. (2000) A genome scan using a novel genetic cross identifies new susceptibility loci and traits in a mouse model of rheumatoid arthritis. J. Immunol., 165, 5278–5286.
23 Samuelsson, L., Enlund, F., Torinsson, A., Yhr, M., Inerot, A., Enerback, C., Wahlstrom, J., Swanbeck, G. and Martinsson, T. (1999) A genome-wide search for genes predisposing to familial psoriasis by using a stratification approach. Hum. Genet., 105, 523–529.[ISI][Medline]
24 Jawaheer, D., Seldin, M.F., Amos, C.I., Chen, W.V., Shigeta, R., Monteiro, J., Kern, M., Criswell, L.A., Albani, S., Nelson, J.L. et al. (2001) A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases. Am. J. Hum. Genet., 68, 927–936.[ISI][Medline]
25 Holm, B.C., Xu, H.W., Jacobsson, L., Larsson, A., Luthman, H. and Lorentzen, J.C. (2001) Rats made congenic for Oia3 on chromosome 10 become susceptible to squalene-induced arthritis. Hum. Mol. Genet., 10, 565–572.
26 Risch, N. and Merikangas, K. (1996) The future of genetic studies of complex human diseases. Science, 273, 1516–1517.[ISI][Medline]
27 Cornelis, F., Faure, S., Martinez, M., Prud’homme, J.F., Fritz, P., Dib, C., Alves, H., Barrera, P., de Vries, N., Balsa, A. et al. (1998) New susceptibility locus for rheumatoid arthritis suggested by genome-wide linkage study. Proc. Natl Acad. Sci. USA, 95, 10746–10750.
28 Jacob, H.J., Petterson, A., Wilson, D., Mao, Y., Lenmark, A. and Lander, E.S. (1992) Genetic dissection of autoimmune type I diabetes in the BB rat. Nat. Genet., 2, 56–60.[ISI][Medline]
29 Sawcer, S., Jones, H.B., Feakes, R., Gray, J., Smaldon, N., Chataway, J., Robertson, N., Clayton, D., Goodfellow, P.N. and Compston, A. (1996) A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22. Nat. Genet., 13, 464–468.[ISI][Medline]
30 Ghosh, S., Palmer, S.M., Rodrigues, N.R., Cordell, H.J., Hearne, C.M., Cornall, R.J., Prins, J.B., McShane, P., Lathrop, G.M., Peterson, L.B. et al. (1993) Polygenic control of autoimmune diabetes in nonobese diabetic mice. Nat. Genet., 4, 404–409.[ISI][Medline]
31 Worthington, J., Ollier, W.E.R., Leach, M.K., Smith, I., Hay, E.M., Thomson, W., Pepper, L., Carthy, D., Farhan, A., Martin, S. et al. (1994) The Arthritis and Rheumatism Council’s National Repository of family material: pedigrees from the first 100 rheumatoid arthritis families containing affected sibling pairs. Br. J. Rheumatol., 33, 970–976.
32 Arnett, F.C., Edworthy, S.M., Bloch, D.A., McShane, D.J., Fries, J.F., Cooper, N.S., Healey, L.A., Kaplan, S.R., Liang, M.H., Luthra, H.S. et al. (1988) The American Rheumatism association revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum., 31, 315–324.[ISI][Medline]
33 MacGregor, A.J., Bamber, S. and Silman, A.J. (1994) A comparison of the performance of different methods of disease classification for rheumatoid arthritis. Results from an analysis from a nationwide twin study. J. Rheumatol., 21, 1420–1426.[ISI][Medline]
34 Goring, H.H. and Ott, J. (1997). Relationship estimation in affected sib pair analysis of late-onset diseases. Eur. J. Hum. Genet., 5, 69–77.[Medline]
35 John, S., Myerscough, A., Marlow, A., Hajeer, A., Silman, A., Ollier, W. and Worthington, J. (1998) Linkage of cytokine genes to rheumatoid arthritis. Evidence of genetic heterogeneity. Ann. Rheum. Dis., 57, 361–365.
36 O’Connell, J.R. and Weeks, D.E. (1998) PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am. J. Hum. Genet., 63, 259–266.[ISI][Medline]
37 Kruglyak, L. and Lander, E.S. (1995) Complete multipoint sib-pair analysis of qualitative and quantitative traits. Am. J. Hum. Genet., 57, 439–454.[ISI][Medline]
38 Speilman, R.S., McGinnis, R.E. and Ewens, W.J. (1993) Transmission test for linkage disequilibrium: The insulin gene region and insulin dependent diabetes mellitus (IDDM). Am. J. Hum. Genet., 52, 506–516.[ISI][Medline]
39 Sham, P.C. and Curtis, D. (1995) An extended transmission disequilibrium test (TDT) for multi-allele marker loci. Ann. Hum. Genet., 59, 323–336.[ISI][Medline]
40 Speilman, R.S. and Ewens, W.J. (1998) A sibship test for linkage in the presence of association: the sib transmission/disequilibrium test. Am. J. Hum. Genet., 62, 450–458.[ISI][Medline]
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  T. T. Glant, S. Szanto, A. Vegvari, Z. Szabo, K. Kis-Toth, K. Mikecz, and V. A. Adarichev Two Loci on Chromosome 15 Control Experimentally Induced Arthritis through the Differential Regulation of IL-6 and Lymphocyte Proliferation J. Immunol., July 15, 2008; 181(2): 1307 - 1314. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-C. Zhang, S. Mori, F. Date, H. Furukawa, and M. Ono A non-major histocompatibility locus determines tissue specificity in the pathogenic process underlying synovial proliferation in a mouse arthropathy model Ann Rheum Dis, February 1, 2007; 66(2): 242 - 245. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Parsons, H. J. Mroczkowski, F. E.A. McGuigan, O. M.E. Albagha, S. Manolagas, D. M. Reid, S. H. Ralston, and R. J. S. Reis Interspecies synteny mapping identifies a quantitative trait locus for bone mineral density on human chromosome Xp22 Hum. Mol. Genet., November 1, 2005; 14(21): 3141 - 3148. [Abstract] [Full Text] [PDF]
|
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M. Brenner, H.-C. Meng, N. C. Yarlett, B. Joe, M. M. Griffiths, E. F. Remmers, R. L. Wilder, and P. S. Gulko The Non-MHC Quantitative Trait Locus Cia5 Contains Three Major Arthritis Genes That Differentially Regulate Disease Severity, Pannus Formation, and Joint Damage in Collagen- and Pristane-Induced Arthritis J. Immunol., June 15, 2005; 174(12): 7894 - 7903. [Abstract] [Full Text] [PDF]
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|
 P. Serrano-Fernandez, S. M. Ibrahim, D. Koczan, U. K. Zettl, and S. Moller In silico fine-mapping: narrowing disease-associated loci by intergenomics Bioinformatics, April 15, 2005; 21(8): 1737 - 1738. [Abstract] [Full Text] [PDF]
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 M. A. Gonzalez-Gay, J. Llorca, E. Sanchez, M. A. Lopez-Nevot, M. M. Amoli, C. Garcia-Porrua, W. E. R. Ollier, and J. Martin Inducible but not endothelial nitric oxide synthase polymorphism is associated with susceptibility to rheumatoid arthritis in northwest Spain Rheumatology, September 1, 2004; 43(9): 1182 - 1185. [Abstract] [Full Text] [PDF]
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|
 A. Barton, J. A. Woolmore, D. Ward, S. Eyre, A. Hinks, W. E. R. Ollier, R. C. Strange, A. A. Fryer, S. John, C. P. Hawkins, et al. Association of protein kinase C alpha (PRKCA) gene with multiple sclerosis in a UK population Brain, August 1, 2004; 127(8): 1717 - 1722. [Abstract] [Full Text] [PDF]
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 S. N. Twigger, J. Nie, V. Ruotti, J. Yu, D. Chen, D. Li, J. Mathis, V. Narayanasamy, G. R. Gopinath, D. Pasko, et al. Integrative Genomics: In Silico Coupling of Rat Physiology and Complex Traits With Mouse and Human Data Genome Res., April 1, 2004; 14(4): 651 - 660. [Abstract] [Full Text] [PDF]
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 A. Schulz, D. Standke, L. Kovacevic, M. Mostler, P. Kossmehl, M. Stoll, and R. Kreutz A Major Gene Locus Links Early Onset Albuminuria with Renal Interstitial Fibrosis in the MWF Rat with Polygenetic Albuminuria J. Am. Soc. Nephrol., December 1, 2003; 14(12): 3081 - 3089. [Abstract] [Full Text] [PDF]
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|
 A.-K. Siegel, M. Planert, S. Rademacher, A. P. Mehr, P. Kossmehl, M. Wehland, M. Stoll, and R. Kreutz Genetic Loci Contribute to the Progression of Vascular and Cardiac Hypertrophy in Salt-Sensitive Spontaneous Hypertension Arterioscler. Thromb. Vasc. Biol., July 1, 2003; 23(7): 1211 - 1217. [Abstract] [Full Text] [PDF]
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