ࡱ> Root Entry FmVData 9u1TabletWordDocument,j)  !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'(+-./01236789:;<=>?*Lhijklmnopqrstuvwxyz{|}~3 0TableKsRoot Entry FrVData x1TabletWordDocument~  !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~inked and HLA-unlinked loci. This interaction interactaction could either result in an additive effect (that is, the penetration of the disease as represented by the sum of the penetrations contributed by two or more loci) or multiplicatively (that is, the penetration of the disease as the product of the penetration contributed by two or more loci). The HLA class I molecules can be classified into supertypes associated with overlapping peptide-binding motifs and repertoires. Within the HLA-B locus more than 250 alleles were identified, therefore the number of possible combinations is exceeding 35,000 (38). While the risk for specific HLA allele in spondyloarthropaties may vary from one population group to another, the association of HLA-B27, and SpA has been well known for over 25 years. However, genetic family studies in Caucasians indicate that HLA-B27 contributes only about 16% of the total genetic risk for AS, and that the genes on chromosome 6 in the HLA as a whole, including HLA-B27 itself, account for about half of the genetic variability for AS (39). The association between HLA-B7 and jSpA, antigen antigene that share several structural similarities with HLA-B27 antigen antigene, is less clear. The region of amino acid positions 63-71 in HLA-B27 appears to participate in the formation of at least three distinct epitopes shared by HLA-B27 and HLA-B7 identified as ME1, GSP5.3 and GS145.2, respectively (40). Beside binding specific peptides and presenting them to T cells, those epitopes, and particularly ME1, are critical factors in determining allele-specific alteration in gram-negative bacterial invasion and susceptibility for reactive arthritis (41). We and others have found previously the increased occurrence of HLA-B7 CREG antigen in both children and adults with SpA in various populations (2, 11, 42-46), while others did not (47, 48). It is of interest that the HLA-B*0702 allele (the only subtype found) is present in 9.67%, and the HLA-B*2705 allele (the most common one) is present in 6.00% of the general Croatian population, respectively (49, 50). In our study we found a significant relative risk of HLA-B*0702 (RR=2.61) for developing jSpA (in 18 patients), that was even more emphasized in combination with HLA-B*27 specificity 05/02 (RR=14.82) found in 6 patients (Figure 1). Prominent clinical features in those 24 patients included hip involvement, presence of enthesitis and sacroilitis, all very typical clinical features of jSpA. Similar findings were noted in adult patients in France (38). It is of interest that none of the patients studied were either HLA-B27 or HLA-B7 homozygouse. MICA class I chain-related genes are located 46.4 kilobases centromeric from HLA-B, and are highly polymorphic (Figure 1). A strong association of the MICA-A4 microsatellite allele with adult SpA was found in the Jappanese and Italian populations (51, 52). However, the strong linkage disequilibrium between HLA-B and MICA microsatellite alleles was observed in the Croatian population as well, as in other populations (53, 54). In the present study, the statistically significant higher frequency of the MICA-A4 microsatellite allele in the patient group was also found to be a result of linkage disequilibrium between MICA and HLA-B genes. Therefore, our data suggest that the MICA gene does not play a major or additional role in the susceptibility to jSpA in Croatian children. On the other hand, the association with D6S273 microsatellite allele was clearly not a result of the linkage disequlibrium with HLA-B27. The D6S273 microsatellite locus, located in the HSP70b2 region close to the TNF-a and TNF-b genes, BAT2 and mismatch repair gene MSH5, has a dinucleotide repeat motif (CA) with allele size ranging from 128bp to 142bp (55). Polymorphism at the level of D6S273 microsatellite loci was previously studied in the Croatian population. The most frequent alleles found at the D6S273 locus were D6S273-134 and D6S273-136 microsatellite alleles. That study confirmed the irregularity in distribution of microsatellite alleles in different populations with the predominance of two or three alleles on these two investigated microsatellite loci (56). It was previously found that the D6S273-138 allele provides an additional risk in RA susceptibility, as well as IDDM (24, 25). Previous population studies reported an association between the D6S273-128 allele and rheumatoid arthritis in Singaporean Chinese, while a study on D6S273 polymorphism in patients with Addison's disease demonstrated a relationship with the D6S273-140 allele (26, 27). In our study relative risk for the D6S273-134 allele was 2.68, while relative risk for the phenotype combination of B*07/B*27; D6S273-134 was 26.83. In contrast to the MICA-A4 allele we found no linkage disequilibrium between HLA-B*27 specificity and D6S273-134 allele (LD=-0.5). These findings might imply that a gene surrounding this location is causally related to jSpA. The HLA class III region carries many genes with immune response-related functions, and the presence of polymorphism in these genes raises the possibility that genetic liability is conferred by the entire cluster (haplotype) instead of a single susceptibility gene. This possibility was already reported in Crohn's disease (57). Furthermore, D6S273 was found to be a part of the minihaplotype in RA patients who were responders to anti-TNF-a therapy, suggesting that the D6S273 microsatellite allele may be part of a larger haplotype that may affect response to therapy (58). No data on the possible role of D6S273 polymorphism and response to therapy in jSpA patients is currently available. The use of genetic markers for association analysis of disease, especially complex and multifactorial diseases like jSpA, has been suggested to have several limitations, one of which is that this method tends to give rise to type I and type II errors (59, 60). In this respect, it appears necessary to increase the number of jSpA patients from a widened selection of ethnic backgrounds. In addition, various independent statistical methods for association analysis, such as linkage disequilibrium mapping, haplotype analysis, the exact test of the Hardy-Weinberg equilibrium, the haplotype relative risk test, and the transmission disequilibrium test would also be useful in increasing our understanding of the pathogenesis of this disease. In addition, the general problem of analysis of microsatellites is the likelihood that the instability of a microsatellite locus associated with a specific disease is not necessarily associated with an identical instability in a related disease. The latter argument is supported by the fact that 50 - 10000 microsatellites are located throughout the human genome (HYPERLINK "http://www.rheuma21st.com/archives/cutting_genomics_rheumatology.html#62"61). In conclusion, our data show that phenotype extended HLA-B*27/HLA-B*07;and D6S273-134 haplotype is associated with increased susceptibility to juvenile spondyloarthropathies in the Croatian children. Further studies are necessary for comparison of our findings as well as important in illumination of the role of D6S273 microsatellite in association with jSpA. Future studies might be useful in confirming our results in different populations. NEMA SMISLA I NEPOTREBNO JE REFERENCES: 1. Espinoza LR, Cuellar ML. Clinical aspects of the spondyloarthropathies. In: Lopez-Larrea C, editor. HLA-B27 in the development of spondyloarthropathies. Austin (TX): Landes; 1996. p. 1-16. 2. Harjacek M, Miller LC, Tucker LB, Chikanza IC, Schaller JG. HLA-B7 in association with seronegative spondlyloarthropathy. Arthritis Rheum 1996; 39: S54. 3. harjacek M, Ostojic J, Grubic Z. HLA B*0702 is strongly associated with spondyloarthropathies in Croatian children. In Arthritis Rheum 2001; 44: S239. 4. Sampaio-Barros PD, Conde RA, Donadi EA, Kraemer MH, Persoli L, Coimbra IB, Costallat LT, Samara AM, Bertolo MB. Undifferentiated spondyloarthropathies in Brazilians: importance of HLA-B27 and the B7-CREG alleles in characterization and disease progression. J Rheumatol 2003; 30: 2632-2637. 5. Khan MA, Kushner I, Braun WE. A subgroup of ankylosing spondylitis associated with HLA-B7 in American blacks. Arthritis Rheum 1978; 21: 528-530. 6. HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Cedoz+JP%22%5BAuthor%5D"Cedoz JP, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Wendling+D%22%5BAuthor%5D"Wendling D, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Viel+JF%22%5BAuthor%5D"Viel JF. The B7 cross reactive group and spondyloarthropathies: an epidemiological approach. J Rheumatol 1995; 22: 1884-1890. 7. Marsh SGE, Albert ED, Bodmer WF, Bontrop RE, Dupont B, Erlich HA, Hansen JA, Mach B, Mayr WR, Parham P, Petersdorf EW, Sasazuki T, Schreuder GMTh, Strominger JL, Svejgaard A, Terasaki PI. Nomenclature for factors of the HLA system. Human Immunology 2002; 63: 1213-1268 8. Sims AM, Wordsworth BP, Brown MA. Genetic susceptibility to ankylosing spondylitis. Curr Mol Med 2004; 4: 13-20. 9. HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10728740&query_hl=19&itool=pubmed_docsum"Martinez-Borra J, Gonzalez S, Lopez-Larrea C. Genetic factors predisposing to spondylarthropathies. Arthritis Rheum 2000; 43: 485-492. 10. Grubi Z, Kerhin-Brklja i V, Peri P, e uk-Jeli i E, }unec R, Kaatelan A. HLA-B27 subtypes in Croatian patients with ankylosing spondylitis. Scan J Rheum 2001; 30: 51-52. 11. Harja ek M, Ostoji J, Grubi Z. HLA B*0702 is strongly associated with spondyloarthropathies in Croatian children. Arthritis Rheum 2001; 44: S239. 12. HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Gruen+JR%22%5BAuthor%5D"Gruen JR, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Weissman+SM%22%5BAuthor%5D"Weissman SM. Human MHC class III and IV genes and disease associations. HYPERLINK "javascript:AL_get(this,%20'jour',%20'Front%20Biosci.');"Front Biosci 2001; 6: 960-972. 13. Zake LN, Cimdina I, Rumba I, Dabadghao P, Sanjeevi CB. Major Histocompatibility Complex class I chain related (MIC) A gene, TNFa microsatellite alleles and TNFB alleles in juvenile idiopathic arthritis patients from Latvia. Human Immunology 2002; 63: 418-423. 14. Forre A, Smerdel A. Genetic epidemiology of juvenile idiopathic arthritis. Scandinavian Journal of Rheumatology 2002; 31: 123-128. 15. Mok JW, Lee YJ, Kim JY, Lee EU, Song YW, Park MH, Park KS. Association of MICA polymorphism with Rheumatoid Arthritis patients in Koreans. Human Immunology 2003; 64: 1190-1194. 16. Hassan AB, Nikitina-Zake L, Padyukov L, Karlsson G, Gupta M, Lundberg IE, Sanjeevi CB. MICA4/HLA-DRB1*04/TNF1 haplotype is associated with mixed connective tissue disease in Swedish patients. Human Immunology 2003; 64: 290-296. 17. Park YS, Sanjeevi CB, Robies D, Rewers M, Gottlieb PA, Fain P, Eisenbarth GS. Additional association of intra-MHC genes, MICA and D6S273, with Addison's disease. Tissue Antigens 2000; 60: 155-163. 18. Kim TH, Uhm WS, Inman RD. Pathogenesis of ankylosing spondylitis and reactive arthritis. Curr Opin Rheumatol 2005; 17: 400-405. 19. Colbert RA. The immunobiology of HLA-B27: variations on a theme. Curr Mol Med 2004; 4: 21-30. 20. Sims AM, Wordsworth BP, Brown MA. Genetic susceptibility to ankylosing spondylitis. Curr Mol Med. 2004; 4:13-20. 21. HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10728740&query_hl=12&itool=pubmed_DocSum"Martinez-Borra J, Gonzalez S, Lopez-Larrea C. Genetic factors predisposing to spondylarthropathies. Arthritis Rheum 2000; 43: 485-492. 22. Zhang G, Luo J, Bruckel J, Weisman MA, Schumacher HR et al. Genetic studies in familial ankylosing spondylitis susceptibility. Arthritis Rheum 2004; 50: 2246-2254. 23. HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9336417&query_hl=17&itool=pubmed_docsum"Brown MA, Kennedy LG, MacGregor AJ, Darke C, Duncan E, Shatford JL, Taylor A, Calin A, Wordsworth P. Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment. Arthritis Rheum 1997; 40: 1823-1928. 24. Singal DP, Li J, Ye M, Lei K. D6S273 microsatellite polymorphism and susceptibility to rheumatoid arthritis. Tissue Antigens 1998; 52: 353-8. 25. Valdes AM, Wapelhorst B,. Concannon P, Erlich HA et al. Extended DR3-D6S273-HLA-B haplotypes are associated with increased susceptibility to type 1 diabetes in US Caucasians. Tissue Antigens 2005; 65: 115-119. 26. Yu HX, Ren EC, Chan SH. Associations of HLA microsatellites with rheumatoid arthritis in Singaporean Chinese. Tissue Antigens 2003; 62: 133-138. 27. HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Park+YS%22%5BAuthor%5D"Park YS, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Sanjeevi+CB%22%5BAuthor%5D"Sanjeevi CB, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Robles+D%22%5BAuthor%5D"Robles D, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Yu+L%22%5BAuthor%5D"Yu L, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Rewers+M%22%5BAuthor%5D"Rewers M, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Gottlieb+PA%22%5BAuthor%5D"Gottlieb PA, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Fain+P%22%5BAuthor%5D"Fain P, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Eisenbarth+GS%22%5BAuthor%5D"Eisenbarth GS. Additional association of intra-MHC genes, MICA and D6S273, with Addison's disease. Tissue Antigens 2002; 60: 155-163. 28. Mizuki N, Ota M, Kimura M, Ohno S, Ando H, Kasuyama Y, Yamazaki M. Triplet repeat polymorphism in the transmembrane region of the MICA gene: A strong association of six GCT repetitions with Behcet disease. Proc Natl Acad Sci USA 1997; 94: 1298-1303. 29. Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, et al. International League of Associations for Rheumatology. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004; 31:390-392. 30. HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12022342&query_hl=19&itool=pubmed_docsum"Burgos-Vargas R, Rudwaleit M, Sieper J. The place of juvenile onset spondyloarthropathies in the Durban 1997 ILAR classification criteria of juvenile idiopathic arthritis. International League of Associations for Rheumatology. J Rheumatol 2002; 29: 869-874. 31. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16: 1215. 32. Bunce M, Barnardo MC, Procter J, Marsh SG, Vilches C, Welsh KI. High resolution HLA-C typing by PCR-SSP: identification of allelic frequencies and linkage disequilibria in 604 unrelated random UK Caucasoids and a comparison with serology. Tissue Antigens 1997; 50: 100-111. 33. Olerup O, Zetterquist H. HLA-DR typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours: an alternative to serological DR typing in clinical practice including donor-recipient matching in cadaveric transplantation. Tissue Antigens 1992; 39: 225-235. 34. HLA 2004: Immunobiology of the Human MHC. Proceedings of the 13th International Histocompatibility Workshop and Congress. (Hansen JA and Dupont B, eds), Volume I & II, IHWG Press, Seattle, WA, 2004. 35. Svejgaard A, Ryder LP: HLA and disease associations: detecting the strongest. Tissue Antigens 1994; 43: 18-27. 36. Woolf B. On estimating he relation between blood group ad disease. Ann Hum Genet 1955; 19: 251-253. 37. Imanishi T, Akaza T, Kimura A, Tokunaga K, and Gojobori T (1992) Allele and haplotype frequencies for HLA and complement loci in various ethnic groups. In HLA1991 Vol. 1 (K. Tsuji et al. ed.), 1065-1220, Oxford University Press, Oxford. 38. HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Sette+A%22%5BAuthor%5D"Sette A, Sidney J. Nine major HLA class I supertypes account for the vast preponderance of HLA-A and -B polymorphism. HYPERLINK "javascript:AL_get(this,%20'jour',%20'Immunogenetics.');"Immunogenetics 1999; 50: 201-212. 39. Khan MA. Genetic aspects of ankylosing spondylitis. Best Practice & Research Clin Rhumatol 2002; 16: 675-690. 40. HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22el%2DZaatari+FA%22%5BAuthor%5D"Zaatari FA, Taurog JD. In vitro mutagenesis of HLA-B27: single and multiple amino acid substitutions at consensus B27 sites identify distinct monoclonal antibody-defined epitopes. Human Immunology 1992; 33: 243-248. 41. Kapasi K, Inman RD. ME1 epitope of HLA-B27 confers class I-mediated modulation of gram-negative bacterial invasion. J Immunol 1994; 153: 833-840. 42. Harjacek M, Miller LC, Tucker LB, Chikanza IC, Schaller JG. HLA-B7 in association with seronegative spondlyloarthropathy. Arthritis Rheum 39: 9: S54. 43. Khan MA. B7-CREG and ankylosing spondylitis. Br J Rheumatol. 1983; 22: 129-133. 44. HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Cedoz+JP%22%5BAuthor%5D"Cedoz JP, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Wendling+D%22%5BAuthor%5D"Wendling D, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Viel+JF%22%5BAuthor%5D"Viel JF. The B7 cross reactive group and spondyloarthropathies: an epidemiological approach. J Rheumatol 1995; 22: 1884-1890. 45. HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Sampaio%2DBarros+PD%22%5BAuthor%5D"Sampaio-Barros PD, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Conde+RA%22%5BAuthor%5D"Conde RA, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Donadi+EA%22%5BAuthor%5D"Donadi EA, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Kraemer+MH%22%5BAuthor%5D"Kraemer MH. Undifferentiated spondyloarthropathies in Brazilians: importance of HLA-B27 and the B7-CREG alleles in characterization and disease progression.HYPERLINK "javascript:AL_get(this,%20'jour',%20'J%20Rheumatol.');"J Rheumatol 2003; 0: 2632-2637. 46. HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Haberhauer+G%22%5BAuthor%5D"Haberhauer G, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Broll+H%22%5BAuthor%5D"Broll H. Cross-reacting HLA-B alleles as genetic markers of HLA-B27 negative ankylosing spondylitis. J Rheumatol 1986; 45: 260-262. 47. HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Vargas%2DAlarcon+G%22%5BAuthor%5D"Vargas-Alarcon G, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Londono+JD%22%5BAuthor%5D"Londono JD, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Hernandez%2DPacheco+G%22%5BAuthor%5D"Hernandez-Pacheco G, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Pacheco%2DTena+C%22%5BAuthor%5D"Pacheco-Tena C, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Castillo+E%22%5BAuthor%5D"Castillo E et al. Effect of HLA-B and HLA-DR genes on susceptibility to and severity of spondyloarthropathies in Mexican patients. Ann Rheum Dis 2002; 61: 714-717. 48. HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Boyer+GS%22%5BAuthor%5D"Boyer GS, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Templin+DW%22%5BAuthor%5D"Templin DW, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Bowler+A%22%5BAuthor%5D"Bowler A, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Lawrence+RC%22%5BAuthor%5D"Lawrence RC et al. Class I HLA antigens in spondyloarthropathy: observations in Alaskan Eskimo patients and controls. HYPERLINK "javascript:AL_get(this,%20'jour',%20'J%20Rheumatol.');"J Rheumatol 1997; 24: 500-506. 49. Grubic Z, Kerhin-Brkljacic V, Peric P, Cecuk-Jelicic E, Zunec R, Kastelan A. HLA-B27 subtypes in Croatian patients with ankylosing spondylitis. Scand J Rheumatol. 2001; 30: 51-2. 50. Grubic Z, Zunec R, Cecuk-Jelicic E, Kerhin-Brkljacic V, Kastelan A. Polymorphism of HLA-A, -B, -DRB1, -DQA1 and -DQB1 haplotypes in a Croatian population. Eur J Immunogenet 2000; 27: 47-51. 51. HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Tsuchiya+N%22%5BAuthor%5D"Tsuchiya N, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Shiota+M%22%5BAuthor%5D"Shiota M, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Moriyama+S%22%5BAuthor%5D"Moriyama S, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Ogawa+A%22%5BAuthor%5D"Ogawa A et al. MICA allele typing of HLA-B27 positive Japanese patients with seronegative spondylarthropathies and healthy individuals: differential linkage disequilibrium with HLA-B27 subtypes. HYPERLINK "javascript:AL_get(this,%20'jour',%20'Arthritis%20Rheum.');"Arthritis Rheum. 1998; 41: 68-73. 52. HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10990233&query_hl=14&itool=pubmed_docsum"Ricci-Vitiani L, Vacca A, Potolicchio I, Scarpa R, Bitti P et al. MICA gene triplet repeat polymorphism in patients with HLA-B27 positive and negative ankylosing spondylitis from Sardinia. J Rheumatol 2000; 27: 2193-2197. 53. Martinez N, Grubi Z, e uk-Jeli i E, }unec R, `tingl K, Kerhin-Brklja i V. TNFa and MICA microsatellite alleles in HLA extended haplotypes. Genes and Immunity 2004; 5: S57. 54. Grimaldi M, Clayton J, Pontaotti P, Cambon-Thomsen A, Crouau-Roy B. New highly polymorphic microsatellite marker in linkage disequlibrium with HLA-B. Human Immunology 1996; 51: 89-94. 55. Gourrad PA, Mano S, Barnetche T, Carrington M, Inoko H, Cambon-Thomsen A. Integration of microsatellite characteristics in the MHC region: a literature and sequence based analysis. Tissue Antigens 2004; 64: 543-555. 56. HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Grubic+Z%22%5BAuthor%5D"Grubic Z, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Moghaddam+PH%22%5BAuthor%5D"Moghaddam PH, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Giphart+MJ%22%5BAuthor%5D"Giphart MJ, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Zunec+R%22%5BAuthor%5D"Zunec R, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Cecuk%2DJelicic+E%22%5BAuthor%5D"Cecuk-Jelicic E, HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Kastelan+A%22%5BAuthor%5D"Kastelan A. Distribution of alleles at two microsatellite loci (D6S273 and TNFa) in Croatian population. Coll Antropol 1999; 23: 87-90. 57. Rioux JD, Daly MJ, Silverberg MS, Lindblad K. Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat Genet 2001; 29: 223-8. 58. Martinez A, Salido M, Bonilla G, Pascual-Salcedo D, Fernandez-Arquero M, de Miguel S, et al. Association of the major histocompatibility complex with response to infliximab therapy in rheumatoid arthritis patients. Arthritis Rheum 2004; 50: 10771082. 59. Kidd, KK. Associations of disease with genetic markers: Dj vu all over again. Am J Med Genet 1993; 48: 71-73. 60. Hodge, SE. What association analysis can and cannot tell us about the genetics of complex disease. Am J Med Genet 1994; 5: 318-323 61. Weissenbach J, Gyapay G, Dib C, Vignal A, Morisette J. A second-generation linkage map of the human genome. Nature 1993; 359: 794-801.     PAGE  PAGE 1  DEFUVXZfgln|ƶwe"hfhFzH*OJQJ\mHsHhfhFzOJQJ\mHsH"hr*hFz6OJQJ\mHsHhFzOJQJ\mHsHhr*hFzOJQJ\mHsHh hFzOJQJ\mHsHhFzOJQJmHsH"hr*hFz5OJQJ\mHsHhFz5OJQJmHsHhFz5>*OJQJmHsH'EFVYZgm\@@$x$If]a$gdFzl\zkd$$Ifl0zz t064 l4al$x$If]a$gdFzlW4 $]a$gdFzxxxmnhh$x$If]a$gdFzlzkd$$Ifl0zz t064 l4alhh$x$If]a$gdFzlzkdJ$$Ifl0zz t064 l4alhh$x$If]a$gdFzlzkd$$Ifl0zz t064 l4alhh$x$If]a$gdFzlTzkdx$$Ifl0zz t064 l4alhh$x$If]a$gdFzlzkd$$Ifl0zz t064 l4alhh$x$If]a$gdFzlzkd$$Ifl0zz t064 l4alb{μzmaO=Oa"hfhFz5OJQJ\mHsH"hr*hFz5OJQJ\mHsHhFzOJQJmHsHhFz5OJQJmHsHhFz5>*OJQJmHsH"hM_hFz>*OJQJ\mHsH#hr*hFzOJQJ\aJmHsHhfhFzOJQJmH sH #hfhFzOJQJ\aJmHsH&hfhFzH*OJQJ\aJmHsHhFzOJQJ\mHsHhr*hFzOJQJ\mHsHhh$x$If]a$gdFzlzkd=$$Ifl0zz t064 l4al xx_CCC$x$If]a$gdFzlW4x$If]gdFzlW4 $]a$gdFzzkd$$Ifl0zz t064 l4al  +,789FGRS[`bmnoz{|~Ƹyky`yN#hiJhFzCJOJQJ\mHsH *hFzOJQJ\ *h hFzOJQJ\hiJhFzOJQJ\hFzOJQJ\hFzOJQJmHsH#hahFzCJOJQJ\mHsHhahFzOJQJ\hFzCJOJQJmHsH&hhFz5CJOJQJ\mHsH"hhFz5OJQJ\mHsH&hhFz5OJQJ\aJmHsH,89kdk$$Iflֈ}!%n t04 l4aP$x$If]a$gdFzlW49GJLNPRx$If]^gdFzlT$x$If]a$gdFzlT$x$If]a$gdFzlRSo:$x$If]a$gdFzlkd$$$Iflֈ}!%n t04 l4aPortvxzx$If]^gdFzl\$x$If]a$gdFzl\z{:$x$If]a$gdFzlkd$$Iflֈ}!%n t04 l4aPx$If]^gdFzl$x$If]a$gdFzl             ڱã曗̋Ëy#hiJhFzCJOJQJ\mHsHhiJhFzOJQJ\hFzhFzOJQJhiJhFzH*OJQJ\#hahFzCJOJQJ\mHsHhFzOJQJ\ *h hFzOJQJ\hahFzOJQJ\hFzCJOJQJmHsHhFzOJQJmHsH/:$x$If]a$gdFzlkd$$Iflֈ}!%n t04 l4aPx$If]^gdFzl$x$If]a$gdFzl:$x$If]a$gdFzlkdO$$Iflֈ}!%n t04 l4aP$$If]a$gdFzl$If]^gdFzl$If]gdFzl :$x$If]a$gdFzl\kd $$Iflֈ}!%n t04 l4aP      $$If]a$gdFzl\$If]^gdFzl\  > :$x$If]a$gdFzlTkd $$Iflֈ}!%n t04 l4aP  6 < = > ? @ A B C D E F G H I d k l m n o p q r s t u v w x   : @ \ Ͻ浱򠒀oooo hLhFzOJQJaJmHsH#hLhFzH*OJQJaJmHsHhFzOJQJaJmHsH hfhFzOJQJaJmHsHhFzhFzOJQJ#hiJhFzCJOJQJ\mHsHhiJhFzH*OJQJ\hFzOJQJ\hiJhFzOJQJ\hFzCJOJQJmHsH)> @ B D F H $$If]a$gdFzl$If]^gdFzlH I m :$x$If]a$gdFzlTkdz $$Iflֈ}!%n t04 l4aPm o q s u w $$If]a$gdFzl$$If]^a$gdFzl$If]^gdFzlw x y :... $]a$gdFzkd3 $$Iflֈ}!%n t04 l4aP\ ]      D E n o | } ξέΠvvvvvviYhhFz5CJ\mH sH hFz5CJ\mH sH hFzOJQJmH sH hFz5>*CJH*mH sH hfhFz5>*CJmH sH hFz5>*CJmH sH !hhFz5>*CJ\mH sH  *h]hFz5CJmH sH hFz>*CJmH sH  hLhFzOJQJaJmHsH)hfhFzB*OJQJaJmHphsH     $dx$If]a$gdFzl $x$If]a$gdFzl ]gdFz   )kd $$Ifl$֞ _ p#wT,-- t04 la    ( 1 8 = D $dx$If]a$gdFzl $dx$If]a$gdFzl D E )kd $$Iflv֞ _ p#wT,-- t04 laE F L P Z b i n $dx$If]a$gdFzl n o )kd$$Ifl֞ _ p#wT,-- t04 lao p q r s t u | $dx$If]a$gdFzl | } )kd&$$Ifl֞ _ p#wT,-- t04 la} $dx$If]a$gdFzl  )kd0$$Iflv֞ _ p#wT,-- t04 la $dx$If]a$gdFzl  Q ) ]gdFzkd:$$Ifl֞ _ p#wT,-- t04 la ' + < = Q R i  ? A c e f ͼ{l{l{aQaFhFz5CJmH sH  *h)hFz>*CJmH sH hFz>*CJmH sH hfhFzOJQJmH sH hFzOJQJmH sH hfhFz5OJQJmH sH hFz5OJQJmH sH hFzCJmH sH hFz5>*CJ\mH sH !hhFz5>*CJ\mH sH hhFz5CJ\mH sH ! *h]hFz5CJ\mH sH ! *h]hFz5CJ\mH sH Q R b i o x ~ $x$If]^a$gdFzl $x$If]`a$gdFzl  ]^ T7$x$If]`a$l kd`$$IflrB&04 lal 7kd$$IflrB&04 lal$x$If]^a$l     7kd$$IflrB&04 lal$x$If]^a$l   & 2 > ? 7kd$$IflrB&04 lal$x$If]^a$l ? @ A e gWf'(,$]`a$gdFz$ n]`a$gdFz$ n@]`a$gdFz$ n@1$7$8$H$`a$gdFz$ n]`a$gdFz]]gdFz ]^ f m o p HKøzkzkz_zkzkPz_zh hFzB*OJQJph3f *h=hFzOJQJhfhFzB*OJQJphhFzOJQJhfhFzCJOJPJQJhfhFz6CJOJQJhFz6CJOJQJh(~hFz>*CJmH sH jh(~hFzUhFz!hthFz5>*CJ\mH sH hFz>*CJmH sH hi#'hFz5CJmH sH hthFz5CJmH sH "(56T !"-.<BCJfguwdWhfhFzOJQJaJ $ *h=hFzB*OJQJaJ ph *h=hFzOJQJaJ h/hFzOJQJaJ!hfhFzB*OJQJaJ phh/hFzOJQJaJ hFzOJQJaJ hfhFz5OJQJ *h=hFzOJQJ *h=hFzOJQJhFzOJQJhfhFzB*OJQJphhfhFzOJQJ"  2?LM` efg*DǸǪǃwhw]ǸwhfhFzOJQJhfhFzOJQJmHsHhFzOJQJmHsH#hFzB*OJPJQJnH ph# tH )hfhFzB*OJPJQJnH phtH hFzOJPJQJnH tH hfhFzB*OJQJphhFzOJQJh/hFzOJQJaJhfhFzOJQJaJ h/hFzOJQJaJ hFzOJQJaJ DN5ELTW^efn146Xorvw1ɾɾɲɦɲɦɚɾɃrrrar *h=hFzB*OJQJph3f *h=hFzB*OJQJph *h=hFzOJQJhGhFzOJQJhFzOJQJmH sH  *h=hFzOJQJ *h=hFzOJQJhfhFzOJQJhFzOJQJhfhFzOJQJmHsHhFzOJQJmHsH%hfhFzB*OJQJmHphsH&1HIVcdfgQSTXrcXMXhNhFzOJQJh/hFzOJQJhGhFzOJQJmHsH/ *h=hFz7B*OJQJaJmHphsH%hfhFzB*OJQJmHphsHhFzOJQJmHsHhfhFz5>*OJQJ *h=hFzOJQJ *h=hFzOJQJh $hFzB*OJQJph3fhfhFzOJQJhfhFzB*OJQJphhFzOJQJ),-MNPWXYbcMQX񨝎phU%hfhFzB*OJQJmH phsH hFzOJQJhfhFzB*OJQJphh/hFzOJQJmH sH hNhFzOJQJmH sH hNhFzOJQJh/hFzOJQJhNhFzOJQJmHsHhFzOJQJmHsH *h=hFzOJQJmHsH%hfhFzB*OJQJmHphsHh/hFzOJQJmHsHXYgnoruv,-e8>@JL! $ ] ` y 崤Ñvvn_n_nhfhFzB*OJQJphhFzOJQJh/hFzOJQJmH sH hFzOJQJmH sH %h $hFzB*OJQJmH ph3fsH  *h=hFzOJQJmH sH hNhFzOJQJmH sH %hfhFzB*OJQJmH phsH hfhFzOJQJmH sH h/hFzOJQJmH sH hFzOJQJmH sH #y z o!p!!""+".":"@"x"y"""""""""#V#_#p#r#u#v############$$$ $¯¯ ¯¯¯¯¯¯¯…yyy *hVhFzOJQJh/hFzOJQJ *hVhFzOJQJmH sH hfhFzOJQJmH sH %hfhFzB*OJQJmH phsH hFzOJQJmH sH hFz *h=hFzOJQJmH sH hfhFzOJQJhFzOJQJhGhFzOJQJ/ $ $$$p$u$x$%R&T&&&&&&&r'~''(.(x,y,,,,,,ķĥj֥_SDSSj:*hFzOJQJUjhFzOJQJUhfhFzOJQJ)hfhFzB*OJPJQJnH ph# tH  hfhFzOJPJQJnH tH )hfhFzB*OJPJQJnH phtH #hFzB*OJPJQJnH ph# tH hfhFzOJPJQJhFzOJPJQJhFzOJQJh/hFzOJQJmH sH h/hFzOJQJhfhFzB*OJQJph,,-- --------- -,-5-------?.....ͱͱͱͱͣ|o`N" *h=hFzOJQJ\mH sH hFz5OJQJ\mH sH hVhFzOJQJaJ *hVhFzOJQJaJ *hFzOJQJaJ *hVhFzOJQJaJhfhFz5CJOJQJ *hVhFzOJQJnH tH hFzOJQJnH tH hfhFzOJQJnH tH  *hVhFzOJQJnH tH  *hVhFzOJQJhFzOJQJ,...{/001m245#6C7kkk"$ & 0` P@1$7$8$H$a$gdFz$ & 0` P@1$7$8$H$a$gdFz$a$gdFz $1$7$8$H$a$]gdFz $]a$gdFz&$ & 0` P@1$7$8$H$]a$gdFz ...{//00#0$0%00&11m2o2p2q22;zh\hEh,jhFzB*OJPJQJUnH phtH hFzB*OJQJph#hFzB*OJPJQJnH phtH 1hEihFzB*OJPJQJmH ,nH phsH ,tH hVhFz;CJOJQJhFzCJOJQJhFz;CJOJQJhFzOJQJhEihFzOJQJmHsHhFzOJPJQJnH tH &hfhFz5CJOJQJ\mH sH h=hFzOJQJ\mH sH 22223333333333444%4&444555ϽϽr`RF`hFzOJQJmH sH hFzOJPJQJnH tH #h ;hFzOJPJQJ\nH tH 2j .hFzB*OJPJQJUnH phtH 2j,hFzB*OJPJQJUnH phtH ,jhFzB*OJPJQJUnH phtH #hFzB*OJPJQJnH phtH ,jhFzB*OJPJQJUnH phtH 2jA+hFzB*OJPJQJUnH phtH 556"6#6$6&6'6666668(9l9*:9:::I:J:M:ѻwыѬkcXLck7)hfhFzB*OJPJQJnH phtH h ;hFzOJQJ\hIhFzOJQJhFzOJQJhFzOJQJmH sH &jl/hFzB*OJQJUph jhFzB*OJQJUphhEihFz5OJQJmH ,sH ,hEihFzOJQJmH ,sH ,+hEihFzOJPJQJ\mH ,nH sH ,tH %hEihFzB*OJQJmH ,phsH ,hFzB*OJQJphhFz5OJPJQJnH tH C7d9J:<!==]>E?@@@mAB5C&$ & 0` P@1$7$8$H$]a$gdFz $]a$gdFz"$ & 0` P@1$7$8$H$a$gdFz$a$$5$7$8$9DH$]a$gdFz M:N:O::::::::h;i;j;u;v;;;;;;<<<!<"<-<.<Īēyē_SDSDh ;hFzOJQJmH sH hFzOJQJmH sH 2j3hFzB*OJPJQJUnH phtH 2jL2hFzB*OJPJQJUnH phtH ,jhFzB*OJPJQJUnH phtH 2j0hFzB*OJPJQJUnH phtH #hFzB*OJPJQJnH phtH ,jhFzB*OJPJQJUnH phtH #hFzB*OJPJQJnH phtH .<6<7<C<D<O<P<*=+=5=6===============g>h>y>z>>>>>>>>>>>M?N?Z?[?e?f?o?p?{?|?????@@@@@OAʼʪ#hFzB*OJPJQJnH phtH hFzOJPJQJnH tH hFzB*OJQJphhGzhFzOJQJmH sH h ;hFzOJQJmH sH hFzOJQJmH sH :OApAqArABBB2B3B4BBB%C&C)C*C/C1C5C9C:CCCC0D1DDn`n`n`nF2j6hFzB*OJPJQJUnH phtH hFzOJPJQJnH tH  hIhFzOJPJQJnH tH (hEihFzOJPJQJmHnH sHtH #hFzB*OJPJQJnH phtH 2j4hFzB*OJPJQJUnH phtH ,jhFzB*OJPJQJUnH phtH hEihFzOJQJmH ,sH ,1hEihFzB*OJPJQJmH ,nH phsH ,tH DDDDDDD(E)EJEMEEEEEE F FFF F"FG?GFGGGIGJGGGGGGGGfH͎ͯuuWu6WuWuWu@j8hNhFzB*OJPJQJU_HaJ nH phtH :jhNhFzB*OJPJQJU_HaJ nH phtH 1hNhFzB*OJPJQJ_HaJ nH phtH @j7hNhFzB*OJPJQJU_HaJ$nH phtH :jhNhFzB*OJPJQJU_HaJ$nH phtH 1hNhFzB*OJPJQJ_HaJ$nH phtH 1hfhFzB*OJPJQJ_HaJ$nH phtH fHgHhHpHqHsHtHHHHHHHHIIIIIIIJJJ$J%J'JfE@jy>hNhFzB*OJPJQJU_HaJ nH phtH @j=hNhFzB*OJPJQJU_HaJ nH phtH @j;hNhFzB*OJPJQJU_HaJ nH phtH 1hNhFzB*OJPJQJ_HaJ nH phtH :jhNhFzB*OJPJQJU_HaJ nH phtH @jX:hNhFzB*OJPJQJU_HaJ nH phtH 'J(JJJJJJJJ?K@KAKNKOKPKKKKKKKKKKɨɇnXXXIhfhFzOJQJmH sH +hFzB*OJPJQJ_HaJ nH phtH 1hNhFzB*OJPJQJ_HaJ$nH phtH @jAAhNhFzB*OJPJQJU_HaJ nH phtH @j?hNhFzB*OJPJQJU_HaJ nH phtH 1hNhFzB*OJPJQJ_HaJ nH phtH :jhNhFzB*OJPJQJU_HaJ nH phtH KKKKKKKKKKKKL L LLLLMMMMNNNNNOOKRMRPRQRɷɠueUhIhFz6CJOJQJaJhFzCJOJPJQJnH tH  hfhFzOJPJQJnH tH 2jBhFzB*OJPJQJUnH phtH ,jhFzB*OJPJQJUnH phtH #hFzB*OJPJQJnH phtH hFzB*CJOJQJph3hFzOJPJQJnH tH hGzhFzOJQJmH sH hFzOJQJmH sH  QRSSSS1SySzSSSSSSTTTǮzcWI?7IhFzOJQJhFzCJ OJQJhFzOJPJQJnH tH hFzOJQJmH sH -hfhFzB*OJPJQJ_HnH phtH 4hfhFz6B*OJPJQJ_HaJnH phtH 1hfhFzB*OJPJQJ_HaJnH phtH 1hfhFzB*OJPJQJ_HaJnH phtH  hfhFzOJPJQJnH tH $hIhFzOJPJQJ_HnH tH (hIhFzOJPJQJ_HaJnH tH STNVV+XX[YY[<_`dgvh8ilPnop$5$7$8$9DH$]a$gdFz$a$gdFz $]a$gdFz$]a$"$ & 0` P@1$7$8$H$a$gdFz $1$7$8$H$a$TTTlUmUnUuUvUUUUU)V*V+V9V:VNVVVҡҡw[wwO8,jhFzB*OJPJQJUnH phtH hFzOJQJmH sH 7jEhfhFzOJPJQJU_HaJ nH tH 1jhfhFzOJPJQJU_HaJ nH tH  hfhFzOJPJQJnH tH (hfhFzOJPJQJ_HaJ nH tH 7j+DhfhFzOJPJQJU_HaJ$nH tH 1jhfhFzOJPJQJU_HaJ$nH tH (hfhFzOJPJQJ_HaJ$nH tH VPWQWRW\W]WXXXYTYUYZY_YgYYYӼtlt[F1F(hIhFzOJPJQJ_HaJ$nH tH (hIhFzOJPJQJ_HaJ nH tH  hIhFzOJPJQJnH tH hFzOJQJhIhFzOJQJhEihFzOJQJmHsH(hEihFzOJPJQJmHnH sHtH 1hEihFzB*OJPJQJmHnH phsHtH ,jhFzB*OJPJQJUnH phtH 2jmFhFzB*OJPJQJUnH phtH #hFzB*OJPJQJnH phtH YYYYYYYYY8Z9Z:ZBZCZEZFZZZZZZZZ_[`[īď٫vZvvv>7jJhIhFzOJPJQJU_HaJ nH tH 7jAIhIhFzOJPJQJU_HaJ nH tH 1jhIhFzOJPJQJU_HaJ nH tH 7jGhIhFzOJPJQJU_HaJ$nH tH 1jhIhFzOJPJQJU_HaJ$nH tH (hIhFzOJPJQJ_HaJ$nH tH (hIhFzOJPJQJ_HaJ nH tH "hFzOJPJQJ_HaJ nH tH `[a[h[i[j[[[[[t\u\v\\\\\]]]]]]]ѼqUqq97jMhIhFzOJPJQJU_HaJ nH tH 7j LhIhFzOJPJQJU_HaJ$nH tH 1jhIhFzOJPJQJU_HaJ$nH tH 0hEihFzOJPJQJ_HaJ$mH ,nH sH ,tH 0hEihFzOJPJQJ_HaJ mH ,nH sH ,tH (hIhFzOJPJQJ_HaJ$nH tH (hIhFzOJPJQJ_HaJ nH tH 1jhIhFzOJPJQJU_HaJ nH tH ]]]]]]]]7^8^9^C^D^F^^^___&_'_-_˲疲hS7hShS7jQhIhFzOJPJQJU_HaJ nH tH (hIhFzOJPJQJ_HaJ nH tH 1jhIhFzOJPJQJU_HaJ nH tH (hIhFzOJPJQJ_HaJ$nH tH 7jJPhIhFzOJPJQJU_HaJ nH tH 1jhIhFzOJPJQJU_HaJ nH tH 7jNhIhFzOJPJQJU_HaJ nH tH 0hEihFzOJPJQJ_HaJ mH ,nH sH ,tH -_._0_1_6_9_<_?_@_A________^`_```g`h`i``ȵـٜٜdٜO(hIhFzOJPJQJ_HaJ$nH tH 7jShIhFzOJPJQJU_HaJ nH tH 7jRhIhFzOJPJQJU_HaJ nH tH 1jhIhFzOJPJQJU_HaJ nH tH %hIhFzB*CJ OJQJaJ ph3 hIhFzOJPJQJnH tH (hIhFzOJPJQJ_HaJ nH tH "hFzOJPJQJ_HaJ nH tH `````xayazaaaaabbb b!b#b$bbε΀gKggg7jVhIhFzOJPJQJU_HaJ nH tH 1jhIhFzOJPJQJU_HaJ nH tH 7j\UhIhFzOJPJQJU_HaJ$nH tH 1jhIhFzOJPJQJU_HaJ$nH tH 0hEihFzOJPJQJ_HaJ$mH ,nH sH ,tH 0hEihFzOJPJQJ_HaJ$mH ,nH sH ,tH 0hEihFzOJPJQJ_HaJ mH ,nH sH ,tH bbbbbbbZc[c\cjckcmcnccccdd dzddddʱʱʱʱʱʱyʱʱdR=R(hIhFzOJPJQJ_HaJ nH tH "hFzOJPJQJ_HaJ nH tH (hIhFzOJPJQJ_HaJ$nH tH 7j*[hIhFzOJPJQJU_HaJ nH tH 7jYhIhFzOJPJQJU_HaJ nH tH 0hEihFzOJPJQJ_HaJ mH ,nH sH ,tH 1jhIhFzOJPJQJU_HaJ nH tH 7j:XhIhFzOJPJQJU_HaJ nH tH ddddddddd$e%e&e.e/e1e2eeeeeeeeLf뫖zaEaaa7j]hIhFzOJPJQJU_HaJ nH tH 1jhIhFzOJPJQJU_HaJ nH tH 7j\hIhFzOJPJQJU_HaJ$nH tH (hIhFzOJPJQJ_HaJ$nH tH 1jhIhFzOJPJQJU_HaJ$nH tH (hfhFzOJPJQJ_HaJ nH tH "hFzOJPJQJ_HaJ nH tH (hIhFzOJPJQJ_HaJ nH tH LfMfNfVfWfYfZfffffffZg[ggggggggggʵʵʵʵʵkOkk=="hFzOJPJQJ_HaJ nH tH 7j'bhIhFzOJPJQJU_HaJ nH tH 1jhIhFzOJPJQJU_HaJ nH tH (hIhFzOJPJQJ_HaJ$nH tH 7j`hIhFzOJPJQJU_HaJ nH tH (hIhFzOJPJQJ_HaJ nH tH 1jhIhFzOJPJQJU_HaJ nH tH 7j[_hIhFzOJPJQJU_HaJ nH tH gggghhShkhlhohphuhzhhi,i-i0i1i7i8i;iׯjM"ɻQU\<q.H/tsJvĭǢ-c0m\(3EO1bQ-<H)3蝗o7=2x꾉,%$:Cqc3IWE<$6)\M?w|nPFUJm4X:M2kHo$(7L~{A1?j0;YWhCwŶFębbÞﷵ"kܵ~0{#sT?ͧ @/b,?w"}͉HWEawWs{"L훟RӖ+=^_X{WNi߄=aTb>rg#bw=ts/\ !Fυ7b_cOc73 soQnS>]1w^&oK~]>c_CrU s_{|MZ32droE1.OtaWۢ?Cl!(ĺZPjG!yAtK~?Xs̘v)v[!T,O~^`y!C2|Ƅ%1 񞱅1[vkf?|ŒŒ%%%-K~%Œ%ڒ_m7X,E|ВXku '֢ZΌL(k:@@Oܧqm@qU<}7풜 mzgؾ hPPuMxo?Ue=3ɱ;~}/7aO x#} gVߒq~"#??o]#G =uV`{X:qy5۽v.x9(vt@CQP\ճ/v}mNPPBb؝q}*-{A{A/sl,jx]0r1[fCIj 4 N$(γl_E^Hc?3 tʳt z tt>̾A Ym, ٛOl^"챙^l^nbKg'DmK͓iZ~utٛNZK:ѹzwkFz]zpѻ.uֲ]frr[e60-b쒅ѫn{,~?gYR9Ou`,Am񻙟}gjk&uOi¡x\ ~UԜ/Q枈| T咯iqVO}WvSx"|OxlPh]UOE[/_B"7s.T:0PP($cP#9*=Gd[y?M|k'h?;) *:7qݓ6S ??/ggw.y> 7c2:O)OS+mY~ݲkeW!h^)eocq1JcUa+Qx8GU#6Q73wraEc5~)C+w\pXfú"0eaYyWïJgY6ΞS%ID151Ǯc|6f㫟8?j᫓4/~_XHvfײ|no=,+&>QAs^1s=VozoMv&GQRy+)e#c׬-V1M7vMuڦ%6 ,AKH$$4"bK)JbCoE!6I[_ *QE؇.TB$of۽cw{dorrΙ{7sflw}w^[/$SguSm7Oo?YQN𸒻0ʰRך~{ I[1*#&ʧ|֛ 21-k7$qmt vV -s wW"pAwgxpX}8pz)AW 7|=UΑV]SԹ|5/p`9-9kzQHuq:T\ JNU>;wypzJmgY3}I6v[=CkkJ$!7!c4 7|]u3FKfj.T;\k1tMIY N΅I$}&$U>TcT#5}B?R wg>eVW,#w 7|]1O2Wվ@E !鶊2 NV@hkM' mBü}#XQ~eoZOR#{IM,몋.E]dYG􂐤uqz:x /ffwMW'7as~j*Pz1yZ`VH= ㆯ.Ck#zM@DŽK_=*N<+8eXG Hnz8iQ"}ҭF/aaθ:V{hjc]]7 }ㆯ2Ĩ }&tI_*NL+8eX}GQ;%M .q|t,V02z2LU븷~& fS>=' K_r6UPLB@z]*> m.E\bλlBK>voyW 1m7/Q8 ތx;=qN0"mw{x\D%v':awJB-UDC xeF;2mb*,[6֘6G'{TM  WUj:h~U툽-`fhDS&jU K@Y3۴[~i1oɦb/ j@0CB6;${ش[= oԦbҚSu37J0~^̈́O:5 B#.9)sE?+5%|M].:?qN7lȳrUnE碷et`orڈ[0~DCG?)::= ߅*kNDyK  yK http://www.rheuma21st.com/archives/cutting_genomics_rheumatology.html62cDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Cedoz+JP%22%5BAuthor%5DgDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Wendling+D%22%5BAuthor%5DaDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Viel+JF%22%5BAuthor%5D}DyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10728740&query_hl=19&itool=pubmed_docsumcDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Gruen+JR%22%5BAuthor%5DiDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Weissman+SM%22%5BAuthor%5DDyK yK pjavascript:AL_get(this,%20'jour',%20'Front%20Biosci.');}DyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10728740&query_hl=12&itool=pubmed_DocSum{DyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9336417&query_hl=17&itool=pubmed_docsumaDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Park+YS%22%5BAuthor%5DiDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Sanjeevi+CB%22%5BAuthor%5DcDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Robles+D%22%5BAuthor%5D[DyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Yu+L%22%5BAuthor%5DcDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Rewers+M%22%5BAuthor%5DiDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Gottlieb+PA%22%5BAuthor%5D_DyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Fain+P%22%5BAuthor%5DmDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Eisenbarth+GS%22%5BAuthor%5D}DyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12022342&query_hl=19&itool=pubmed_docsumaDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Sette+A%22%5BAuthor%5DDyK yK pjavascript:AL_get(this,%20'jour',%20'Immunogenetics.');qDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22el%2DZaatari+FA%22%5BAuthor%5DcDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Cedoz+JP%22%5BAuthor%5DgDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Wendling+D%22%5BAuthor%5DaDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Viel+JF%22%5BAuthor%5DyDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Sampaio%2DBarros+PD%22%5BAuthor%5DcDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Conde+RA%22%5BAuthor%5DeDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Donadi+EA%22%5BAuthor%5DgDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Kraemer+MH%22%5BAuthor%5DDyK yK njavascript:AL_get(this,%20'jour',%20'J%20Rheumatol.');kDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Haberhauer+G%22%5BAuthor%5DaDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Broll+H%22%5BAuthor%5DwDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Vargas%2DAlarcon+G%22%5BAuthor%5DgDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Londono+JD%22%5BAuthor%5D}DyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Hernandez%2DPacheco+G%22%5BAuthor%5DsDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Pacheco%2DTena+C%22%5BAuthor%5DgDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Castillo+E%22%5BAuthor%5DcDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Boyer+GS%22%5BAuthor%5DgDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Templin+DW%22%5BAuthor%5DcDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Bowler+A%22%5BAuthor%5DiDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Lawrence+RC%22%5BAuthor%5DDyK yK njavascript:AL_get(this,%20'jour',%20'J%20Rheumatol.');gDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Tsuchiya+N%22%5BAuthor%5DcDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Shiota+M%22%5BAuthor%5DgDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Moriyama+S%22%5BAuthor%5DaDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Ogawa+A%22%5BAuthor%5DDyK yK vjavascript:AL_get(this,%20'jour',%20'Arthritis%20Rheum.');}DyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10990233&query_hl=14&itool=pubmed_docsumcDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Grubic+Z%22%5BAuthor%5DkDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Moghaddam+PH%22%5BAuthor%5DgDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Giphart+MJ%22%5BAuthor%5DaDyK yK http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?dSummaryInformation(tDocumentSummaryInformation8lCompObjXObjectPoolsQsQ Heading 8$$dh@&a$5CJ OJQJDA@D Default Paragraph FontZi@Z  Table Normal :V 4 l4a _H(k@(No List PB@P Body Text$dha$B*CJ OJQJphhC@h Body Text Indent$dh`a$CJOJQJmHsHu4 @4 Footer  !.)@!. Page Number`Q@2` Body Text 3$kdh]ka$>*CJOJQJmHsHuRR@BR Body Text Indent 2hdx^h<Z@R< Plain Text OJ QJ aJ<P@b< Body Text 2 dx0U@q0 Hyperlink>*B*RYR  Document Map-DM OJ QJ aJp@p  Table Grid7:V0dh L             L F z z z z z z=j  L ?HDEFVYZgmn,/0|}!#%'(8:<>@BCcjlnprsGNOViw   &08?DKLUYdnv~&,678HXhyz I j k l p u z   ' 2 M &,0&,0YBYYYBYYYBYYYBYYYBYYYBYYYBYYYBYYYBYY& &,0Y   $  YYYY$YYYYYYY$YYYYYYY$YYYYYYY$YYYY,0,0,0$,0,0YY,0,0,0$,0,0YY,0,0,0$,0,0YY,0,0,0$,0,0Y&,0&,0&Y`&,0Y| T U UYYLE |TUU|TUU4|TUU-a|TUU|TUU ! &ox &,0[Y[YvYYYY [Yv    [YvYYYYY[YvYYYYY&,0&,0&,0&,0&,0&,0#,0{z}zz}z}z} z} z} z}z}z}z}zz}zz}z}z}nx #z}#z}{z}zz}z} z}z}zz}z}&,0&,0&,0y0&0EFVYZgmn,/0<|}!#%'(8:<>@BCcjlnprsGNOViw   &08?DKLUYdnv~i&,678HXhyz  I j k l p u z        % & ' 2 3 4 5 6 7 8 9 : ; < = > ? @ A B C D E F G H I J M 0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0ˀ0ˀ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˀ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˀ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˀ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˀ0ˠ0ˠ0ˀ0ˀ0ˀ0ˀ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˀ0ˀ0ˀ0ˀ0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@@0@0@0@0@0@0@000pˀ@0 00000000000000000000000 EFVYZgmn,/0<}!#%'(8:<>@BCcjlnprsGNOViw   &08?DKLUYdnv~&,68HXhyz j k l p u z  M _chcrqt_ _chcrqt_ _chcrqt_ _chcrqt_  = 0l8 0l8 PPP 08 08 +Q)q*N02>PPP02>08 08  *:****08 08 y}kD08 08 Ƅ}E&08 08 ӁGۜu09 09 0H#嶌0 9 0 9  H0*ܢy綊0&9 0&9 0&9 0&9 0&9 0&9 0&9 0&9  @0+ܟu源沂@0J: @0J: @0J: @0J: @0J: @0J:  @<ܟt纑綋D@0d: @0d: @0d: @0d: @0d: @0d: llڸ湎嶋屁V@0: @0: @0: @0: @0: @0:  @0峆}ۇ?`@0: @0: @0: @0: @0: @0: aۼڐOՀ9ڍJe@0: @0: @0: @0: @0: @0: ^zv+Ճ=ۍJ\@0: @0: @0: @0: @0: @0: [yu,8ՆB`4@0(; @0(; @0(; @0(; @0(; @0(; Zxq&y0U$N@0T; @0T; @0T; @0T; @0T; @0T; P ߋuV-  wC$ 0; 0; 0; 0; 0; @0; @0; @0; @0; @0; @0; @0; @0; @0#= @0#= @0#= @0#= @0#= @0#= @0#= @0#= @0#= @0Z= @0Z= @0Z= @0Z= @0Z= @0Z= @0Z= @0Z= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0$> @0$> @0$> @0$> @0$> @0$> @0$> @0$> @0$> @0T> 0T> 0T> @0T> @0T> @0T> @0T> @0T> @0T> @0T> @0T> @0T> @0T> @0T>  @0@0? @0? @0? @0? @0?  @0@0? @0? @0? @0? @0?  @0 0?0 0 0  @0+A @0+A @0+A0 0  @0DA @0DA3+A 3+A 3+A 3+A 3+A 3+A 3+A 3+A  @0YA  @0YA  @0YA  @0YA  @0YA  @0YA  @0YA  @0YA  @0YA  @0YA 0 0  0?07 $$$' \ f D1Xy $,.25M:.<OADFfH'JKQRTVY`[]-_`bdLfg=ijlnqXtvu-wRFLM\fg?HKRZ_lstuvwxyz{|~m9Roz  > H m w   D E n o | } Q  ? ,C75CSpxx@MMM8N:Ng@BCDEFGIJLMNOPQSTUVWXY[\]^`abcdefghijkmnopqr}xAL  '!!lYZ,"$?\ƏjJ@2Y(  HB X@ C DHB Y@ C DB S  ?LML Y>S>tX>S>t DFUVXZfgijln .167@ACD]_}~;=DFrs{}'8B?@FGHIpq<@im% )  5 M DFUVXZfgln +,.0;={}'8BFGim%,4J Q  5 M :::::EFVYZgmn,/0<}!#%'(8:<>@BCcjlnprsOViw   &08?KLUYdnv~&,678HXhyzk l p u z   M ")01@d! _ p#qh= *h= $a$gd= $a$gd= Kyt= h=CJ h=CJ$^a$gd='#v353#vN5N#v353#vN5N#vO5O#v252#v5#v5#v5yt=^`gd=$^a$gd=$^a$gd= h=H*D VXgijl 016@BC]^j}jm{|(8Ccsqstuv  $LMN[b]_ghipq&,67yz     * 3 8 : H I Q R i j k l o p t u y z      / 0 4 5 J K L p @qdp @qdq @qdp @q @p @q$Fq*Fp @q dp @qRFp @qXFp @qdp @q @qdqvFqFqdqFqFqFqFqGqGq(Gq.Gq:@q0Gq2Gq:GqMq@MpNMqPMqVMpXMqZMq^Mq`MqbMqdMqfMphMqjMpxMqzMqMpMqMpMqMpMqMqMqMqMpMqMqMqMpMpMpMqMqMqMpMqMpMqMpNqNp Nq NpNqNpNq Np*Nq,Np6Np8Np:Np@p`@p@pd@qgp@p@p@p@p@Unknown GTimes New Roman5Symbol3 Arial;HelveticaC MArialMTArialIM Times-BoldTimesKM Times-RomanTimesyMTimesNewRomanPS-ItalicMTTimes New Roman3Times7CourierC Lucida Grande h|޳ QkK:!4d9 G2qPIABSTRACTMiroslav HarjacekMiroslav Harjacek FMicrosoft Word DocumentNB6WWord.Document.8 ՜.+,0< hp   N獫票楧栮捯洀鉭曮㞱Û뜰⠲쎔딁烊皭〼፥ᙼ䕸忤઱9   ABSTRACT Title Oh+'0D   < H T `lt|' ABSTRACT.2Miroslav HarjacekNormalMiroslav Harjacek10Microsoft Word 11.2@NZ@g@ܐ Q@VQGPICTd ,, MSWD ,Times 2-.( $   N-( 1-)  ,  Helvetica-(]Table 1 1ac ): ) Demographic -(]c-)haracteristics- Q(]j -)o-)f- Q) -)t-)h-)e- Q) -)study-) -)p-)a-)tients- Q) -)w-)'i-) th- Q)0 -)jSpA-@ )r -\(  -+uNo. of -)p-)atients-)   v-(,80-@ )8  111v -(Male/-){F-)emal-)me-@ ) -@ )    v-(50)8/)30-)8  1UW1UW1UWv -( Age at ons-)e-)t- Q) -)--)m-))ean-)T -) ()ra-)-n-)ge)- Q)I -)y-)ear-)Is-@z) -@ )   v-(11.6 (-)3-)-)18)-)I  -( Disease d-)u-)rati-)Fo-)n)-) -)m-))ean-)T -) ()ra-)-n-)ge-)8)-) mo-)Tn-)ths-@ )C   v-)29 (2-)s--)134)-)e  -(Fo-);r-)m- Q)* -)of-)* -)dis-)@e-)as)5e (j# 2-+   v-@ (  -(n )*Undife-)r-)entia-)mt-) ed- Q)8 -)jSpA-)i   v-(n4)8-@ )  -( )*jAS-@ )M   v-(2-@ )  -(T )*ReA-)a   v-(T30-@ )8  -(Positiv)e family history*-(   v-(25-@ )8  111v -(# 2+Fifty-G)_ -)pat-)Fi-) ents- )_ -)(-)4)8-G) -)wit-)=h-G) -)u-)ndif-)Qe-)rentia-)~t-) e-)d-G) -)jSpA)i,-) -)and- Q)T -)2-) -)with- Q)Y -)jA-),S-) )- ) -)f-) ullfiled-G) -)ILAR-G)o -)c-)riter-)Wi-) a- ) -)f-) or-G)- -)t-) he-G)8 -)ErA)S (} enthesitis)--)r-)elat-)Qe-)d-) -)art-);h-)ritis-=)N -)(34,-=)W -)35-=)8 -))-)E-) rA)2;-=) -)jAS )b-=) -)juvenile ankylosi-(}}n-)g-) -) spondylitis;-) -)ReA-=)a -)--)react-)pi-) ve- Q)5 -( arthritis; )* )!-) his-)Nt-) ory- Q)F -)o-)f) r-)h-)eu-)8m-))atic- Q)N -)disease-) -)i-) n-) th-)8e-) first- Q)_ -)de-)8g-)re-)-e-) relati-){v-)e-@ )  ! ! ! !  ! ! !  ! ! !  ! ! !  ! ! !  ! ! !  ! ! !  ! ! !  ! ! !l@0@0@0@0@0SummaryInformation(tDocumentSummaryInformation8lCompObjXObjectPoolsQsQ**); **In the same group of patients we found six patients with the phenotype HLA-B*07/B*27 while only one healthy subject showed this phenotype (8.11% vs. 0.06%, p=0.0036; OR=14.82)sub of jSpA patients and matched controls1 \fbffflggggûh=OJQJh=0JmHnHu!hh=5>*CJ\mH sH h=h=>*CJmH sH $h=h=>*B*CJmH phsH a xjbjbtttttttttj %bbb : d &Q&Q&Q8^QSnTT"TTTVVVaaaaaaa,qRt~a VV@VVVa[bbTTn[[[Vb@T Ta[ d @bbbbVa[[ [T Y&QY[[n0n[t[t[[ D6D6Table 1: Demographic characteristics of the study patients with jSpA No. of patients74Male/Female 46/28Age at onset -mean (range) years 11.6 (3-18)Disease duration- mean (range) months29 (2-134)Form of diseaseErA#45jAS2ReA27Positive family history*25#ErA enthesitis-related arthritis; jAS juvenile ankylosing spondylitis; ReA -reactive arthritis; * - history of rheumatic disease in the first degree relative Table 2: Pattern of joint involvement of the 74 study patients PATIENTSHIPS (n)KNEES (n)ENTH. (n)SUBT. J. (n)SI. J. (n )B*0702 (n=26)103525B*2705 (n=27); B*2702 (n=4)179884B*07 and B*27 negative (n=17)75926B*07/B*27 (n=6)30222B*27/MICA-A4/D6S273-134 (n=13)a 53524B*07/B*27/MICA-A4/D6S273-134 (n=5)30022B*0702/MICA-A4/D6S273-134 (n=5)b20022B*0702/MICA-A5.1/D6S273-134 (n=16)c72315 ENTH enthesitis; SUBT. J: - subtalar joints; SI. J. - Sacroiliac joints a - one patient was lost for follow-up; b - two patients were lost for follow-up; c - one patient was lost to follow-up and two patients in this group had jAS with typical clinical features Table 3. Selected allele frequencies in patients with jSpA and controls MarkerSignificant allelejSpA (n=74)Controls (n=169)ppcRR (EF)HLA-B*2731 19 (0.11)<0.000010.00025.69 (0.42)*070226 29 (0.17)0.003560.07122.61(0.35)MICAA443 55 (0.33)0.000320.00162.88 (0.58)D6S27313457 94 (0.56)0.002510.017572.68 (0.77) Table 43. Phenotype frequencies of MICA-A4 and D6S273 alleles in HLA-B27 positive and -B27 negative groups Microsatellite alleleB*27 positiveB*27 negative patients (N=31)controls (N=19)patients (N=43)controls (N=150)MICA-A431 (100%)17 (89.47%)12 (27.91%)40 (26.67%)D6S273-13419 (61.29%)7 (36.84%)30 (69.77%)70 (46.67%) MALO SAM REDIZAJNIRALA OVU TABLICU! Figure 2: Histogram illustrating relative risk of jSpA conferred by selected alleles alone or in combination  4. DISCUSION The data reported in herein have several implications. One of the major findings of this study is the striking association of HLA-B*2705, HLA-B*0702 and D6S273-134 alleles with an increased risk of developing jSpA in the Croatian children. To our knowledge, the current study represents the first attempt to compare HLA-B specificities HLA-A-B haplotypic association with MICA and D6S273 microsatellites in children with jSpA. The contribution of the HLA region to this relative risk depends on the model of interaction between the HLA-lLL L LLLL.L>L@LLLLLMXMZMMMMMMMʺvfVfVfVJVh"hFz5mH sH h"hFz5>*CJmH sH h"hFz5>*CJmH sH h+hFzCJ!h+hFz5>*CJ\mH sH h+hFz>*CJmH sH h+hFz5CJmH sH hFzhFz>*CJmH sH hFzhFz>*CJH*mH sH hFz>*CJmH sH hFzOJQJmH sH hFzhFzH*OJQJmH sH hfhFzOJQJmH sH !#445678"@MPMZMjMzMMMMMM n$If]gdFzl MMkdns$$Iflִ/ >%SRnnR t09!6    4 l4aMMMMMN NN N,N8N n$If]gdFzl M8N:NN@N^^`` `bb@bd d"d$dfff\fIJweUGh=h=>*CJmH sH h=h=>*CJ\mH sH #h+h=OJQJ\aJmHsHhr*h=OJQJ\mHsHh=>*CJmH sH h=5>*CJmH sH h=OJQJh=0JmHnHu"hr*h=5OJQJ\mHsHhFzOJQJhFz0JmHnHuh+hFz>*CJmH sH h+hFzmH sH hFzhFz5>*CJmH sH 8N:NkdQt$$Iflִ/ >%SRnnR t09!6    4 l4aM:N*CJOJQJmHsHuRR@BR Body Text Indent 2hdx^h<Z@R< Plain Text OJ QJ aJ<P@b< Body Text 2 dx0U@q0 Hyperlink>*B*RYR  Document Map-DM OJ QJ aJp@p  Table Grid7:V0dh I             I F z z z z z z=j I ?HDEFVYZgmn,/0|}!#%'(8:<>@BCcjlnprsGNOViw   &08?DKLUYdnv~&,678HXhyz I j k l s    $ / J &,0&,0YBYYYBYYYBYYYBYYYBYYYBYYYBYYYBYYYBYY& &,0Y   $  YYYY$YYYYYYY$YYYYYYY$YYYYYYY$YYYY,0,0,0$,0,0YY,0,0,0$,0,0YY,0,0,0$,0,0YY,0,0,0$,0,0Y&,0&,0&Y`&,0Y| T U UYYLE |TUU|TUU4|TUU-a|TUU|TUU ! &ox &,0[Y[YvYYYY [Yv    [YvYYYYY[YvYYYYY&,0&,0&,0R@R Normaldh$CJOJPJQJ_HmH nHsH tHJ@J Heading 1$@&5OJQJmHsHuR@R Heading 2$<@&56CJOJQJaJP@P Heading 4$<@&5CJOJQJaJH@H Heading 5 <@&56CJaJF@F Heading 7 <@& OJQJaJP@P Heading 8$$dh@&a$5CJ OJQJDA@D Default Paragraph FontZi@Z  Table Normal :V 4 l4a _H(k(No List PB@P Body Text$dha$B*CJ OJQJphhC@h Body Text Indent$dh`a$CJOJQJmHsHu4 @4 Footer  &,0&,0&,0r |, |, |,X r |, |,{,r |, |,{,r |, |,{,r |, |,{,r |, |,{,r |, |,{,r |, |,{,&,0&,0y0&0EFVYZgmn,/0<|}!#%'(8:<>@BCcjlnprsGNOViw   &08?DKLUYdnv~i&,678HXhyz  I j k l s        " # $ / 0 1 2 3 4 5 6 7 8 9 : ; < = > ? @ A B C D E F G J 0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0ˀ0ˀ0@0ˀ0000000000000000000000 00 00 0000000000000000000000000ˀ0ˀ0@@0@0@0@0@0@0@000pˀ@0 00000000000000000000000 EFVYZgmn,/0<}!#%'(8:<>@BCcjlnprsGNOViw   &08?DKLUYdnv~&,68HXhyz k l   J _chcrqt_ _chcrqt_ _chcrqt_ _chcrqt_  = 0l8 0l8 PPP 08 08 +Q)q*N02>PPP02>08 08  *:****08 08 y}kD08 08 Ƅ}E&08 08 ӁGۜu09 09 0H#嶌0 9 0 9  H0*ܢy綊0&9 0&9 0&9 0&9 0&9 0&9 0&9 0&9  @0+ܟu源沂@0J: @0J: @0J: @0J: @0J: @0J:  @<ܟt纑綋D@0d: @0d: @0d: @0d: @0d: @0d: llڸ湎嶋屁V@0: @0: @0: @0: @0: @0:  @0峆}ۇ?`@0: @0: @0: @0: @0: @0: aۼڐOՀ9ڍJe@0: @0: @0: @0: @0: @0: ^zv+Ճ=ۍJ\@0: @0: @0: @0: @0: @0: [yu,8ՆB`4@0(; @0(; @0(; @0(; @0(; @0(; Zxq&y0U$N@0T; @0T; @0T; @0T; @0T; @0T; P ߋuV-  wC$ 0; 0; 0; 0; 0; @0; @0; @0; @0; @0; @0; @0; @0; @0#= @0#= @0#= @0#= @0#= @0#= @0#= @0#= @0#= @0Z= @0Z= @0Z= @0Z= @0Z= @0Z= @0Z= @0Z= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0$> @0$> @0$> @0$> @0$> @0$> @0$> @0$> @0$> @0T> 0T> 0T> @0T> @0T> @0T> @0T> @0T> @0T> @0T> @0T> @0T> @0T> @0T>  @0@0? @0? @0? @0? !.)@!. Page Number`Q@2` Body Text 3$kdh]ka$>*CJOJQJmHsHuRR@BR Body Text Indent 2hdx^h<Z@R< Plain Text OJ QJ aJ<P@b< Body Text 2 dx0U@q0 Hyperlink>*B*RYR  Document Map-DM OJ QJ aJp@p  Table Grid7:V0dh n             n F z z z z z z='0 n ?HlDEFVYZgmn,/0|}!#%'(8:<>@BCcjlnprsGNOViu $.6=BIJSWblt|!"29?HNXYZjz%k     & , - . 1 I T o &,0&,0YBYYYBYYYBYYYBYYYBYYYBYYYBYYYBYYYBYY& &,0Y   $  YYYY$YYYYYYY$YYYYYYY$YYYYYYY$YYYY,0,0,0$,0,0YY,0,0,0$,0,0YY,0,0,0$,0,0YY,0,0,0$,0,0Y&,0&,0&Y`&,0Y| T U UYYLE |TUU|TUU4|TUU-a|TUU|TUU ! &z}&,0[Y[YvYYYY [Yv    [YvYYYYY[YvYYYYY&,0&,0&,0&,0&,0&,0#,0{z}zz}z}z} z} z} z}z}z}z}zz}zz}z}z}nx #z}#z}{z}zz}z} z}z}zz}z}&,0&,0&,0y0&0EFVYZgmn,/0<|}!#%'(8:<>@BCcjlnprsGNOViu $.6=BIJSWblt|!"29?HNXYZjz%&k     & , - . / 1 2 4 7 : = G H I T U V W X Y Z [ \ ] ^ _ ` a b c d e f g h i j k l o 0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0ˀ0ˀ0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0ˀ0ˀ0ˀ0ˀ0ˠ0ˠ0ˠ0ˀ0ˠ0ˀ0ˀ0ˠ0ˀ0ˀ0ˠ0ˀ0ˠ0ˀ0ˠ0ˠ0ˀ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˠ0ˀ0ˀ0@0@0@0@0@0@0@0@000pˀ@0 000000000000000@0?  @0@0? @0? @0? @0? @0?  @0 0?0 0 3 Oy00Oy00h ?Oy00Oy00Oy00 @  @0000000 EFVYZgmn,/0<}!#%'(8:<>@BCcjlnprsGNOViu $.6=BIJSWblt|!"29?HNXZjz&     & , - . / o _chcrqt_ _chcrqt_ _chcrqt_ _chcrqt_  = 0l8 0l8 PPP 08 08 +Q)q*N02>PPP02>08 08  *:****08 08 y}kD08 08 Ƅ}E&08 08 ӁGۜu09 09 0H#嶌0 9 0 9  H0*ܢy綊0&9 0&9 0&9 0&9 0&9 0&9 0&9 0&9  @0+ܟu源沂@0J: @0J: @0J: @0J: @0J: @0J:  @<ܟt纑綋D@0d: @0d: @0d: @0d: @0d: @0d: llڸ湎嶋屁V@0: @0: @0: @0: @0: @0:  @0峆}ۇ?`@0: @0: @0: @0: @0: @0: aۼڐOՀ9ڍJe@0: @0: @0: @0: @0: @0: ^zv+Ճ=ۍJ\@0: @0: @0: @0: @0: @0: [yu,8ՆB`4@0(; @0(; @0(; @0(; @0(; @0(; Zxq&y0U$N@0T; @0T; @0T; @0T; @0T; @0T; P ߋuV-  wC$ 0; 0; 0; 0; 0; @0; @0; @0; @0; @0; @0; @0; @0; @0#= @0#= @0#= @0#= @0#= @0#= @0#= @0#= @0#= @0Z= @0Z= @0Z= @0Z= @0Z= @0Z= @0Z= @0Z= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0= @0$> @0$> @0$> @0$> @0$> @0$> @0$> @0$> @0$> @0T> 0T> 0T> @0T> @0T> @0T> @0T> @0T> @0T> @0T> @0T> @0T> @0T> @0T>  @0@0? @0? @0? @0? @0?  @0@0? @0? @0? @0? @0?  @0 0?0 0 0  @0+A @0+A @0+A0 0  @0DA @0DA3+A 3+A 3+A 3+A 3+A 3+A 3+A 3+A @0YA  @0YA  @0YA  @0YA  @0YA  @0YA  @0YA @0YA @0YA @0YA 0 0  0?07 $$$' \ f D1Xy $,.25M:.<OADFfH'JKQRTVY`[]-_`bdLfg=ijlnqXtvu-wRFLM$d?HKRZ_lstuvwxyz{|~m9Roz  > H m w   D E n o | } Q  ? ,C75CSpxx@MMM8N:N$d@BCDEFGIJLMNOPQSTUVWXY[\]^`abcdefghijkmnopqr}xAn  '!!lYZ,"$?\ƏjJ@2Y(  HB X@ C DHB Y@ C DB S  ?JKn Y>S>tX>S>t DFUVXZfgijln .167@ACD]_}~;=DFrs{}'8B?@FGHIpq<@imGK2 W o DFUVXZfgln +,.0;={}'8BFGim?GNVls2 W o ::::EFVYZgmn,/0<}!#%'(8:<>@BCcjlnprsOViu $.6=IJSWblt|!"9?HNXYZjz    & , - 0 o ")01@d! xh= *h= Kyt= h=CJ$^a$gd='#v353#vN5N#v353#vN5N#vO5O#v252#v5#v5#v5yt=^`gd=$^a$gd=$^a$gd= h=H*0 VXgijl 016@BC]^j}jm{|(8Ccsqs"JKLY` ?HNXY$%',-.04LUZ\jkst            % & + , - . 0 1 2 Q R V W l m n p @qdp @qdq @qdp @q @p @q$Fq*Fp @q dp @qRFp @qXFp @qdp @q @qdqvFqFqdqFqFqFqFqGqGq(Gq.Gq:@q0Gq2Gq:GqMq@MpNMqPMqVMpXMqZMq^Mq`MqbMqdMqfMphMqjMpxMqzMqMpMqMpMqMpMqMqMqMqMpMqMqMqMpMpMpMqMqMqMpMqMpMqMpNqNp Nq NpNqNpNq Np*Nq,Np6Np8Np:Np@p`@p@pd@q dp@p@p@p@p@Unknown GTimes New Roman5Symbol3 Arial;HelveticaC MArialMTArialIM Times-BoldTimesKM Times-RomanTimesyMTimesNewRomanPS-ItalicMTTimes New Roman3Times7CourierC Lucida Grande h|γ QkK:!4d9 G2qPIABSTRACTMiroslav HarjacekMiroslav Harjacek0 @20 3? @0 0?07 $$$' \ f D1Xy $,.25M:.<OADFfH'JKQRTVY`[]-_`bdLfg=ijlnqXtvu-wRFLM\fj@k?HKRZ_lstuvwxyz{|~m9Roz  > H m w   D E n o | } Q  ? ,C75CSpxx@MMM8N:N2jHj^jjjjj:k@k@BCDEFGIJLMNOPQSTUVWXY[\]^`abcdefghijkmnopqr}xAI  '!!lYZ,"$?\ƏjJ@2Y(  HB X@ C DHB Y@ C DB S  ?LMI Y>S>tX>S>t DFUVXZfgijln .167@ACD]_}~;=DFrs{}'8B?@FGHIpq<@im% ) 2 J DFUVXZfgln +,.0;={}'8BFGim%,4J Q s ~  2 J :::::EFVYZgmn,/0<}!#%'(8:<>@BCcjlnprsOViw   &08?KLUYdnv~&,678HXhyzk l s   J ")01@ l l d! l l @{o_)h= *h= $a$gd= $a$gd= Kyt= h=CJ h=CJ$^a$gd='#v353#vN5N#v353#vN5N#vO5O#v252#v5#v5#v5yt=^`gd=$^a$gd=$^a$gd= h=H*L VXgijl 016@BC]^j}jm{|(8Ccsqstuv  $LMN[b]_ghipq&,67yz     * 3 8 : H I Q R i j k l s    , - 1 2 G H I p @qdp @qdq @qdp @q @p @q$Fq*Fp @q dp @qRFp @qXFp @qdp @q @qdqvFqFqdqFqFqFqFqGqGq(Gq.Gq:@q0Gq2Gq:GqjpHjpJjpTjp^jp`jpvjpjpjpjpjpjpjpjpjpjpjpkp.kp:kp@p`@p@pd@qjHj{Y4$$ Sx$  &#$/Ifa$gd=l! Sx$  &#$/Ifgd=lkd9u$$Ifl0 HJ j t 6  064 l4aHjJjTj^j{Y4$$ Sx$  &#$/Ifa$gd=l! Sx$  &#$/Ifgd=lkdu$$Ifl0 HJ j t 6  064 l4a^j`jvjj{Y4$$ Sx$  &#$/Ifa$gd=l! Sx$  &#$/Ifgd=lkdv$$Ifl0 HJ j t 6  064 l4ajjjj{Y4$$ Sx$  &#$/Ifa$gd=l! Sx$  &#$/Ifgd=lkdv$$Ifl0 HJ j t 6  064 l4ajjjj{Y4$$ Sx$  &#$/Ifa$gd=l! Sx$  &#$/Ifgd=lkdw$$Ifl0 HJ j t 6  064 l4ajjjjjjjjk,k.k8kk@kh=OJQJh=0JmHnHu hfh=OJQJaJmH sH hfh=OJQJaJmH sH jjjj{Y4$$ Sx$  &#$/Ifa$gd=l! Sx$  &#$/Ifgd=lkdsw$$Ifl0 HJ j t 6  064 l4ajk.k:k{Y4$$ Sx$  &#$/Ifa$gd=l! Sx$  &#$/Ifgd=lkdw$$Ifl0 HJ j t 6  064 l4a:kL@LLLLLMXMZMMMMMMMʺvfVfVfVJVh"hFz5mH sH h"hFz5>*CJmH sH h"hFz5>*CJmH sH h+hFzCJ!h+hFz5>*CJ\mH sH h+hFz>*CJmH sH h+hFz5CJmH sH hFzhFz>*CJmH sH hFzhFz>*CJH*mH sH hFz>*CJmH sH hFzOJQJmH sH hFzhFzH*OJQJmH sH hfhFzOJQJmH sH @MPMZMjMzMMMMMM n$If]gdFzl MMkdns$$Iflִ/ >%SRnnR t09!6    4 l4aMMMMMN NN N,N8N n$If]gdFzl M8N:NN@N^^`` `bb@bd d"d$dfff\fIJweUGh=h=>*CJmH sH h=h=>*CJ\mH sH #h+h=OJQJ\aJmHsHhr*h=OJQJ\mHsHh=>*CJmH sH h=5>*CJmH sH h=OJQJh=0JmHnHu"hr*h=5OJQJ\mHsHhFzOJQJhFz0JmHnHuh+hFz>*CJmH sH h+hFzmH sH hFzhFz5>*CJmH sH 8N:NkdQt$$Iflִ/ >%SRnnR t09!6    4 l4aM:NjFjJjRjTj\j`jtjvj~jjûvivivXGXGXGXGXGXG hfh=OJQJaJmH sH hfh=OJQJaJmH sH h=5OJQJmH sH hfh=5OJQJmH sH #hfh=5OJQJaJmH sH #hfh=5OJQJaJmH sH !h+h=5>*CJ\mH sH h=OJQJh=0JmHnHu!hh=5>*CJ\mH sH h=h=>*CJmH sH $h=h=>*B*CJmH phsH HB Y@ C DB S  ?PQt Y>S>tX>S>t DFUVXZfgln .1GHdfACJLxy#->HEFLMNOvw BFosMQ8 ] u DFUVXZfgln +,.0AC#->HLM osEMT\ry8 ] u ::::EFVYZgmn,/0B#%')+-.>@BDFHIiprtvxyU\o{     *4<COPY]hrz'(?ENT^_`p     ! & , 2 3 6 u ")01@ ffd! ff}Jh= *h= Kyt= h=CJ$^a$gd='#v353#vN5N#v353#vN5N#vO5O#v252#v5#v5#v5yt=^`gd=$^a$gd=$^a$gd= h=H*|  01Gdeqps#.>Iiy wy!(PQR_fENT^_    !*+-2346:R[`bpqyz       ! % & + , 1 2 3 4 6 7 8 W X \ ] r s t p @q @p @q$Fq*Fp @qRFp @qXFp @q @q^FqFqFqFqFqGqGq(Gq.Gq:@q0Gq2Gq:GqMq@MpNMqPMqVMpXMqZMq^Mq`MqbMqdMqfMphMqjMpxMqzMqMpMqMpMqMpMqMqMqMqMpMqMqMqMpMpMpMqMqMqMpMqMpMqMpNqNp Nq NpNqNpNq Np*Nq,Np6Np8Np:Np@p`@p@pd@q4d9 G3qPIABSTRACTMiroslav HarjacekMiroslav Harjacek FMicrosoft Word DocumentNB6WWord.Document.8 ՜.+,0< hp   N獫票楧栮捯洀鉭曮㞱Û뜰⠲쎔딁烊皭〼፥ᙼ䕸忤઱9   ABSTRACT Title Oh+'0   < H T `lt|' ABSTRACTMiroslav HarjacekNormalMiroslav Harjacek8Microsoft Word 11.2@2~@g@ܐ Q@܊VQGpPICThd ,, MSWD ,Times 2-.( $   N-( 1-)  ,  Helvetica-(]Table 1 1ac ): ) Demographic -(]c-)haracteristics- Q(]j -)o-)f- Q) -)t-)h-)e- Q) -)study-) -)p-)a-)tients- Q) -)w-)'i-) th- Q)0 -)jSpA-@ )r -\(  -+uNo. of -)p-)atients-)   v-(,74-@ )8  111v -(Male/-){F-)emal-)me-@ ) -@ )    v-(46/28-)~  1UW1UW1UWv -( Age at ons-)e-)t- Q) -)--)m-))ean-)T -) ()ra-)-n-)ge)- Q)I -)y-)ear-)Is-@z) -@ )   v-(11.6 (-)3-)-)18)-)I  -( Disease d-)u-)rati-)Fo-)n)-) -)m-))ean-)T -) ()ra-)-n-)ge-)8)-) mo-)Tn-)ths-@ )C   v-)29 (2-)s--)134)-)e  -(Fo-);r-)m- Q)* -)of-)* -)dis-)@e-   !#45678")as)5e (j# 2-+   v-@ (  -(n )*Undife-)r-)entia-)mt-) ed- Q)8 -)jSpA-)i   v-(n45-@ )8  -( )*jAS-@ )M   v-(2-@ )  -(T )*ReA-)a   v-(T27-@ )8  -(Positiv)e family history*-(   v-(25-@ )8  111v -(# 2+Fou-)Wr-)ty-G)' -)seve-)jn-) -)pati-)Qe-)nts-G)C -)(4-)-5-) -)with u-)n-)dife-)Qr-)entia-)mte-)(d-G) -)jSpA)i,-) -)an-)8d-) -)2 with )jAS-)M)-) -)fullfil-)de-)d-G) -)ILAR-)o -)c-)riter-)Wi-) a-G) -)f-) or-)- -(}the-=)F -)ErA-=)S -) enthesitis)--)r-)elat-)Qe-)d-) -)art-);h-)ritis-=)N -)(34,-=)W -)35))IE-)!r-)A)!;-=) -)jAS )b-=) -)!juvenile ankylosing spondylitis; (}R-)$e-)A-)! -)-(reactive-) -) art-);h-)ritis;- Q)\ -)* )!-) history-) -) of)* -)r-)he-)8u-)matic- Q)x -)dis-)@ea-)6se- Q)5 -)in-)' -)the- Q)F -)f-)i-) rst- Q)8 -)de-)8g-)r-)e-)e- Q) -)rel-)8a-)tive-@ )N  ! ! ! !  ! ! !  ! ! !  ! ! !  ! ! !  ! ! !  ! ! !  ! ! !  ! ! !)r-)he-)8u-)matic- Q)x -)dis-)@ea-SummaryInformation(4DocumentSummaryInformation8lCompObjXObjectPoolsQsQ80 (0.42) (0.35) (0.58) (0.77)3 a xjbjbtttttttd8 %bbb : d &Q&Q&Q8^QRklTT"TTTVVVQaSaSaSaSaSaSa,aoRq~a VV@VVVaU[bbTT%lU[U[U[Vb@T TQaU[ d @bbbbVQaU[U[ U[T gT&Q}YU[U[;l0klU[1rU[1rU[U[ D6D6Table 1: Demographic characteristics of the study patients with jSpA No. of patients74Male/Female 46/28Age at onset -mean (range) years 11.6 (3-18)Disease duration- mean (range) months29 (2-134)Form of diseaseErA#45jAS2ReA27Positive family history*25#ErA enthesitis-related arthritis; jAS juvenile ankylosing spondylitis; ReA -reactive arthritis; * - history of rheumatic disease in the first degree relative Table 2: Pattern of joint involvement of the 74 study patients PATIENTSHIPS (n)KNEES (n)ENTH. (n)SUBT. J. (n)SI. J. (n )B*0702 (n=26)103525B*2705 (n=27); B*2702 (n=4)179884B*07 and B*27 negative (n=17)75926B*07/B*27 (n=6)30222B*27/MICA-A4/D6S273-134 (n=13)a 53524B*07/B*27/MICA-A4/D6S273-134 (n=5)30022B*0702/MICA-A4/D6S273-134 (n=5)b20022B*0702/MICA-A5.1/D6S273-134 (n=16)c72315 ENTH enthesitis; SUBT. J: - subtalar joints; SI. J. - Sacroiliac joints a - one patient was lost for follow-up; b - two patients were lost for follow-up; c - one patient was lost to follow-up and two patients in this group had jAS with typical clinical features Table 3. Selected allele frequencies in patients with jSpA and controls MarkerSignificant allelejSpA (n=74)Controls (n=169)ppcRR (EF)HLA-B*2731 19 (0.11)<0.000010.00025.69 (0.42)*070226 29 (0.17)0.003560.07122.61(0.35)MICAA443 55 (0.33)0.000320.00162.88 (0.58)D6S27313457 94 (0.56)0.002510.017572.68 (0.77) Table 43. Phenotype frequencies of MICA-A4 and D6S273 alleles in HLA-B27 positive and -B27 negative groups Microsatellite alleleB*27 positiveB*27 negative patients (N=31)controls (N=19)patients (N=43)controls (N=150)MICA-A431 (100%)17 (89.47%)12 (27.91%)40 (26.67%)D6S273-13419 (61.29%)7 (36.84%)30 (69.77%)70 (46.67%) MALO SAM REDIZAJNIRALA OVU TABLICU! Figure 2: Histogram illustrating relative risk of jSpA conferred by selected alleles alone or in combination  4. DISCUSION The data reported in herein have several implications. One of the major findings of this study is the striking association of HLA-B*2705, HLA-B*0702 and D6S273-134 alleles with an increased risk of developing jSpA in the Croatian children. To our knowledge, the current study represents the first attempt to compare HLA-B specificities HLA-A-B haplotypic association with MICA and D6S273 microsatellites in children with jSpA. The contribution of the HLA region to this relative risk depends on the model of interaction between the HLA-lLL L LLLL.L>L@LLLLLMXMZMMMMMMMʺvfVfVfVJVh"hFz5mH sH h"hFz5>*CJmH sH h"hFz5>*CJmH sH h+hFzCJ!h+hFz5>*CJ\mH sH h+hFz>*CJmH sH h+hFz5CJmH sH hFzhFz>*CJmH sH hFzhFz>*CJH*mH sH hFz>*CJmH sH hFzOJQJmH sH hFzhFzH*OJQJmH sH hfhFzOJQJmH sH @MPMZMjMzMMMMMM n$If]gdFzl MMkdns$$Iflִ/ >%SRnnR t09!6    4 l4aMMMMMN NN N,N8N n$If]gdFzl M8N:NN@N^^`` `bb@bIJh=>*CJmH sH h=5>*CJmH sH h=OJQJh=0JmHnHu"hr*h=5OJQJ\mHsHhFzOJQJhFz0JmHnHuh+hFz>*CJmH sH h+hFzmH sH hFzhFz5>*CJmH sH 8N:NkdQt$$Iflִ/ >%SRnnR t09!6    4 l4aM:N%SRnnR t09!6    4 l4aMMMMMN NN N,N8N n$If]gdFzl M8N:NN@NhFzOJQJhFz0JmHnHuh+hFz>*CJmH sH h+hFzmH sH hFzhFz5>*CJmH sH 8N:NkdQt$$Iflִ/ >%SRnnR t09!6    4 l4aM:N*CJ\mH sH hFzhFzCJ\mH sH !hFzhFz>*CJH*\mH sH hFzhFz>*CJ\mH sH -jhFz5>*CJU_HmHnHsHtH!hFzhFz5>*CJH*mH sH hFz5>*CJmH sH "hr*hFz5OJQJ\mHsHhFzOJQJhFz0JmHnHu#hfhFzOJQJ\aJmHsH#h+hFzOJQJ\aJmHsHhr*hFzOJQJ\mHsH OR*# * OR=Odds ratio; # EF=etiological fraction 1