Recently, single nucleotide polymorphisms (SNPs) assist in determining the exact prognosis of patients, which in turn leads to the selection of a specific therapy based on specific genetic variations [25-30]. Numerous linkage and association studies, as well as the analysis of murine models, have provided ample evidence for a genetic basis for SLE. Genetic susceptibility to SLE results from the combined actions of multiple alleles, each of them conferring a modest incremental risk. There is evidence that susceptibility alleles that are associated with a greater disease severity also are associated with lupus nephritis. There also is evidence for a set of kidney-specific genes that are likely to amplify or to sensitize to the autoimmune pathology [31].
This study provides a useful method for the further study of genes in patients with SLE.
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Table1. Comparison of IL-10 genotype distributions, allele frequencies and carriage rates observed in SLE patients and healthy control subjects.
All the p values represent chi-square test results.
SLE patients Controls P OR
IL-10 N=119 (%) n=100 (%) (95% CI) Genotype
AA 66(55.5) 40 (40) 0.007 A/C 48 (40.3) 45 (45)
CC 5 ( 4.2) 15 (15) Allelic frequencies
A 180(75.6) 125 (62.5) 0.003 1.210 (1.063~1.377)
C 58(24.4) 75 (37.5) 0.650
(0.488~0.865) Carriage rate
A 114(95.8) 85 (85.0) 0.077 1.164 (0.981~1.382)
C 53(44.5) 60 (60.0) 0.767
(0.571~1.030) All the p values represent chi-square test results.
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Table 2. Relationship between IL-10 genotype and clinical signs and findings in patients with SLE
AA
involvement 27 (40.9%)
24
Table 3 Relationship between IL-10 genotype and renal involvement in patients with SLE
AA A/C CC Total P value
n(%) n(%) n(%) n(%) Hematuria 5(62.5) 2(25) 1(12.50) 8(100) 0.322 Hypertension 6(54.5) 3(27.3) 2(18.2) 11(100) 0.126
Serum Cr 1.39 3.39 0.82 0.495
Table 4 Relationship between IL-10 genotype and proteinuria in patients with SLE
25
參考文獻
1. Llorente, L., W. Zou, Y. Levy, Y. Richaud-Patin, J. Wijdenes, J.
Alcocer-Varela, B. Morel-Fourrier, J. C. Brouet, D. Alarcon-Segovia, P.
Galanaud, et al. Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus. J. Exp. Med.
1995; 181:839.
2. Mongan, A. E., S. Ramdahin, R. J. Warrington.Interleukin-10 response abnormalities in systemic lupus erythematosus. Scand. J. Immunol.1999;
46:406.
3. Lacki, J. K., W. Samborski, S. H. Mackiewicz.Interleukin-10 and interleukin-6 in lupus erythematosus and rheumatoid arthritis, correlations with acute phase proteins. Clin. Rheum. 1997; 16:275.
4. Llorente, L., Y. Richaud-Patin, R. Fior, J. Alcocer-Varela, J. Wijdenes, B. M. Fourrier, P. Galanaud, D. Emilie. . In vivo production of interleukin-10 by non-T cells in rheumatoid arthritis, Sjogren’s syndrome, and systemic lupus erythematosus: a potential mechanism of B lymphocyte hyperactivity and autoimmunity .Arthritis Rheum. 1994; 37:1647.
5. Howard M, O'Garra A, Ishida H, de Waal Malefyt R, de Vries J.
Biological properties of interleukin 10. J Clin Immunol.1992; 12: 239-47.
6. Chernoff AE, Granowitz EV, Shapiro L, Vannier E, Lonnemann G, Angel JB, Kennedy JS, Rabson AR, Wolff SM, Dinarello CA.A randomized, controlled trial of IL-10 in humans. Inhibition of inflammatory cytokine
26
production and immune responses. J Immunol.1995; 154:5492-9.
7. Te Velde, A. A., R. de Waal Malefijt, R. J. Huijbens, J. E. de Vries, C.
G. Figdor. IL-10 stimulates monocyte Fc R surface expression and cytotoxic activity: distinct regulation of antibody-dependent cellular cytotoxicity by IFN- , IL-4, and IL-10. J. Immunol. 1992; 149:4048.
8. Lalani, I., K. Bhol, A. R. Ahmed. Interleukin-10: biology, role in inflammation and autoimmunity .Ann .Allergy Asthma Immunol. 1997;
79:469.
9. Llorente, L., W. Zou, Y. Levy, Y. Richaud-Patin, J. Wijdenes,
J.Alcocer-Varela, B. Morel-Fourrier, J. C. Brouet, D. Alarcon-Segovia, P.
Galanaud, et al. Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus. J.
Exp. Med. 1995; 181:839.
10. Tan, E. M., A. S. Cohen, J. F. Fries, A. T. Masi, D. J. McShane, N. F.
Rothfield, J. G. Schaller, N. Talal, R. J. Winchester. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum.1982;
25:1271.
11. Eskdale J, Kube D, Tesch H, Gallagher G. Mapping of the human IL10 gene and further characterization of the 5' flanking sequence.
Immunogenetics. 1997; 46(2):120-8.
12. Bienvenu J, Doche C, Gutowski MC, Lenoble M, Lepape A, Perdrix JP.
Production of pro-inflammatory cytokines and cytokines involved in the TH1/TH2 balance is modulated by pentoxifylline. J. Cardiovasc Pharmacol.
1995; 25 Suppl 2:80-4.
13. Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ,
Hutchinson IV.An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet. 1997 Feb; 24(1): 1-8.
27
14. Lazarus, M, Hajeer, AH, Turner, D, Sinnott, P, Worthington, J, Ollier, WE, & Hutchinson, IV: Genetic variation in the interleukin 10 gene promoter and systemic lupus erythematosus. J Rheumatol 1997; 24:2314 2317
15. Mok, CC, Lanchbury, JS, Chan, DW, & Lau, CS: Interleukin-10
promotor polymorphisms in Southern Chinese patients with systemic lupus erythematosu. Arthritis Rheum 1998; 41:1090 1095
16. Gibson, AW, Edberg, JC, Wu, J, Westendom, RG, Huizinga, TW, &
Kimberly, RP: Novel single nucleotide polymorphism in the distal IL-10 promotor affect IL-10 production and enhance the risk of systemic lupus erythematosus. J Immunol. 2001;166: 3915 3922.
17. Lim S, Crawley E, Woo P, Barnes PJ. Haplotype associated with low interleukin-10 production in patients with severe asthma .Lancet. 1998 Jul 11;
352(9122):113.
18. Borish L, Aarons A, Rumbyrt J, Cvietusa P, Negri J, Wenzel S.
Interleukin-10 regulation in normal subjects and patients with asthma. J Allergy Clin Immunol. 1996 Jun; 97(6):1288-96.
19. Grove J, Daly AK, Bassendine MF, Gilvarry E, Day CP. Interleukin 10 promoter region polymorphisms and susceptibility to advanced alcoholic liver disease. Gut.
2000 Apr; 46(4):540-5.
20. Guseva I. A., Omarbekova Zh., Myakotkin V.A. Polymorphism of FcgRIIIA-158F/V and promotion region of IL-10 genes in systemic lupus erythematosus in Kazakhs Therapeutic Archives No 5 2003 : 36
21. Eskdale, J., G. Gallagher, C. L. Verweij, V. Keijsers, R. G. Westendorp, T. W. Huizinga. 1998. Interleukin 10 secretion in relation to human IL-10 locus haplotypes. Proc. Natl. Acad. Sci. USA 1998; 5:9465.
22. Mehrian, R., Jr. F. P. Quismorio, G. Strassmann, M. M. Stimmler, D. A.
Horwitz, R. C. Kitridou, W. J. Gauderman, J. Morrison, C. Brautbar, C. O.
Jacob. Synergistic effect between IL-10 and bcl-2 genotypes in determining
28
susceptibility to systemic lupus erythematosus. Arthritis Rheum.1998;
41:596.
23. Eskdale, J., J. McNicholl, P. Wordsworth, B. Jonas, T. Huizinga, M.
Field, G. Gallagher.Interleukin-10 microsatellite polymorphisms and IL-10 locus alleles in rheumatoid arthritis susceptibility. Lancet 1998; 352:1282.
24. Keijsers, V., C. L. Verweij, R. G. J. Westendorp, F. C. Breedveld, T. W.
J. Huizinga.IL-10 polymorphisms in relation to production and rheumatoid arthritis. Arthritis Rheum. 1997; 40: (Suppl. 9):S179.
25. Lazarus, M., A. H. Hajeer, D. Turner, P. Sinnott, J. Worthington, W. E.
Ollier, I. V. Hutchinson. Genetic variation in the interleukin 10 gene promoter and systemic lupus erythematosus. J. Rheum.1997; 24:2314.
26.Mok, C. C., J. S. Lanchbury, D. W. Chan, C. S. Lau.Interleukin-10 promoter polymorphisms in Southern Chinese patients with systemic lupus erythematosus. Arthritis Rheum. 1998; 41:1090.
27. Eskdale, J., P. Wordsworth, S. Bowman, M. Field, G. Gallagher.
Association between polymorphisms at the human IL-10 locus and systemic lupus erythematosus. Tissue Antigens 1997; 49:635.
28. Crawley, E., R. Kay, J. Sillibourne, P. Patel, I. Hutchinson, P. Woo.
Polymorphic haplotypes of the interleukin-10 5' flanking region determine variable interleukin-10 transcription and are associated with particular
phenotypes of juvenile rheumatoid arthritis. Arthritis Rheum. 1999; 42:1101.
29. D’Alfonso, S., M. Rampi, D. Bocchio, G. Colombo, R. Scorza-Smeraldi,
29
P. Momigliano-Richardi .Systemic lupus erythematosus candidate genes in the Italian population: evidence for a significant association with interleukin-10.
Arthritis Rheum. 2000; 43:120.
30. Pratt RE, Dzau VJ.Genomics and hypertension Concepts, potentials, and opportunities. Hypertension 1999; 33:238-47.
31. Morel L. Genetics of Human Lupus Nephritis. Seminars in nephrology 2007; 27: 2-11.