中国汉族男性人群IL-12B+1188A/C基因多态性与痛风的易感性研究
摘要
目的探讨中国汉族男性群体的白细胞介素(IL)-12B＋1188A/C位点的多态性是否与痛风的易感性有关。
方法采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)检测377例痛风患者和576名健康对照者的IL-12B+1188A/C位点的基因多态性分布,并进行基因型-表型相关性分析。
结果IL-12B+1188位点AA和AC基因型频率与痛风易感性相关(P<0.001)。痛风组A等位基因频率高于正常对照组(P<0.001,OR=1.404,95%CI=1.165-1.691)。基因型-表型分析显示IL-12B+1188A/C和血清甘油三酯水平具有相关性(P=0.001)。
结论中国汉族男性人群中IL-12B+1188位点(A/C)基因多态性与原发性痛风易感性相关联,说明此位点在痛风发病过程中起重要作用。
Objective:To investigate whether the IL12+1188A/C polymorphism are associated with susceptiblLity to gout in a Chinese Han male population.
Methods:377gout cases and576controls were included in our study. Genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Hardy-Weinberg was used to verify the representativeness of the sample. Comparisons between the groups were performed with x2test and t-test. In addition, we performed analysis of genotype-phenotype.
Results:There was a clear link between the IL-12+1188AA and AC genotypic and A allelic frequencies between gout cases and controls (P<0.001, df=2). The A allele of IL-12B+1188appeared to be the risk allele for predisposition to gout (P<0.001, OR=1.404,95%CI=1.165-1.691). Genotype-phenotype analysis among gout patients revealed an association of CC genotype with serum triglycerides levels (P=0.001).
Conclusions:Our results suggested that the IL-12B+1188A/C polymorphism may be a relevant host susceptibILity factor for gout development.
方法采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)检测377例痛风患者和576名健康对照者的IL-12B+1188A/C位点的基因多态性分布,并进行基因型-表型相关性分析。
结果IL-12B+1188位点AA和AC基因型频率与痛风易感性相关(P<0.001)。痛风组A等位基因频率高于正常对照组(P<0.001,OR=1.404,95%CI=1.165-1.691)。基因型-表型分析显示IL-12B+1188A/C和血清甘油三酯水平具有相关性(P=0.001)。
结论中国汉族男性人群中IL-12B+1188位点(A/C)基因多态性与原发性痛风易感性相关联,说明此位点在痛风发病过程中起重要作用。
Objective:To investigate whether the IL12+1188A/C polymorphism are associated with susceptiblLity to gout in a Chinese Han male population.
Methods:377gout cases and576controls were included in our study. Genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Hardy-Weinberg was used to verify the representativeness of the sample. Comparisons between the groups were performed with x2test and t-test. In addition, we performed analysis of genotype-phenotype.
Results:There was a clear link between the IL-12+1188AA and AC genotypic and A allelic frequencies between gout cases and controls (P<0.001, df=2). The A allele of IL-12B+1188appeared to be the risk allele for predisposition to gout (P<0.001, OR=1.404,95%CI=1.165-1.691). Genotype-phenotype analysis among gout patients revealed an association of CC genotype with serum triglycerides levels (P=0.001).
Conclusions:Our results suggested that the IL-12B+1188A/C polymorphism may be a relevant host susceptibILity factor for gout development.
引文
1. Bieber JD, Terkeltaub RA. Gout:On the brink of novel therapeutic options for an ancient disease. Arthritis Rheum 2004;50:2400-2414.
2. Miao Z, Li C, Chen Y, et al. Dietary and lifestyle changes associated with high prevalence of hyperuricemia and gout in the shandong coastal cities of eastern china. J Rheumatol 2008;35:1859-1864.
3. Lyu LC, Hsu CY, Yeh CY,. et al. A case-control study of the association of diet and obesity with gout in taiwan. Am J Clin Nutr 2003;78:690-701.
4. Stark K, Reinhard W, Neureuther K, et al. Association of common polymorphisms in GLUT9 gene with gout but not with coronary artery disease in a large case-control study. PLoS One 2008,3:e1948.
5. Wang B. Miao Z, Liu S, et al. Genetic analysis of ABCG2 gene C421A polymorphism with gout disease in Chinese Han male population. Hum Genet 2010,127:245-246.
6. Li C, Han L, Levin AM, et al:Multiple single nucleotide polymorphisms in the human urate transporter 1 (hURAT1) gene are associated with hyperuricaemia in Han Chinese. J Med Genet 2010,47:204-210.
7.施桂英.痛风——降尿酸治疗的新策略.中华风湿病学杂志,2007,11：129—131.
8. Martinon F, PetrILli V, Mayor A, et al. Gout-associated uric acid crystals activate the nalp3 inflammasome. Nature 2006:440:237-241.
9. Sieburth D, Jabs EW, Warrington JA, et al. Assignment of genes encoding a unique cytokine (IL12) composed of two unrelated subunits to chromosomes 3 and 5. Genomics 1992; 14:59-62.
10. Seegers D, Zwiers A, Strober W, Pena AS, Bouma G. A taqi polymorphism in the 3'utr of the IL-12 p40 gene correlates with increased IL-12 secretion. Genes Immun 2002;3:419-423.
11. van Veen T, Crusius JB, Schrijver HM, et al. Interleukin-12p40 genotype plays a role in the susceptiblLity to multiple sclerosis. Ann Neurol 2001;50:275.
12. Morahan G, Huang D, Ymer SI, et al. Linkage disequILibrium of a type 1 diabetes susceptibILity locus with a regulatory IL12b allele. Nat Genet 2001;27:218-221.
13. Mikuls TR, Farrar JT, BILker WB, et al.Gout epidemiology:Results from the uk general practice research database.1990-1999. Ann Rheum Dis 2005;64:267-272.
14. Tsai PC, Chen CJ, Lai HM. Chang SJ. Analysis of polymorphisms in the promoter region and protein levels of interleukin-6 gene among gout patients. Clin Exp Rheamatol 2008;26:841-847
15. Chang SJ, Chen CJ, Tsai FC, et al. Associations between gout tophus and polymorphisms 869t/c and -509c/t in transforming growth factor beta1 gene. Rheumatology (Oxford) 2008;47:617-621.
16. Chang SJ, Tsai PC, Chen CJ, et al. The polymorphism -863c/a in tumour necrosis factor-alpha gene contributes an independent association to gout. Rheumatology (Oxford) 2007;46:1662-1666.
17.初楠,李长贵,贾兆通,等.中国沿海地区汉族男性人群白细胞介素一1β-31C/T基因多态性与痛风的易感性研究.中华风湿病学杂志,2011,15(1)：7—11.
18. Shokrgozar MA, Sarial S, Amirzargar A, et al. IL-2, ifn-gamma, and IL-12 gene polymorphisms and susceptiblLity to multiple sclerosis. J Clin Immunol 2009;29:747-751.
19. Alayli G, Aydin F, Coban AY, et al. T helper 1 type cytokines polymorphisms:Association with susceptibILity to behcet's disease. Clin Rheumatol 2007;26:1299-1305.
20. Rodriguez-Sosa M, Satoskar AR, Calderon R, et al. Chronic helminth infection induces alternatively activated macrophages expressing high levels of ccr5 with low interleukin-12 production and th2-biasing abILity. Infect Immun 2002;70:3656-3664.
21. Landis RC, Haskard DO. Pathogenesis of crystal-induced inflammation. Curr Rheumatol Rep 2001;3:36-41.
22. YILmaz V, Yentur SP, Saruhan-Direskeneli G. IL-12 and IL-10 polymorphisms and their effects on cytokine production. Cytokine 2005;30:188-194.
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2. Miao Z, Li C, Chen Y, et al. Dietary and lifestyle changes associated with high prevalence of hyperuricemia and gout in the shandong coastal cities of eastern china. J Rheumatol 2008;35:1859-1864.
3. Lyu LC, Hsu CY, Yeh CY,. et al. A case-control study of the association of diet and obesity with gout in taiwan. Am J Clin Nutr 2003;78:690-701.
4. Stark K, Reinhard W, Neureuther K, et al. Association of common polymorphisms in GLUT9 gene with gout but not with coronary artery disease in a large case-control study. PLoS One 2008,3:e1948.
5. Wang B. Miao Z, Liu S, et al. Genetic analysis of ABCG2 gene C421A polymorphism with gout disease in Chinese Han male population. Hum Genet 2010,127:245-246.
6. Li C, Han L, Levin AM, et al:Multiple single nucleotide polymorphisms in the human urate transporter 1 (hURAT1) gene are associated with hyperuricaemia in Han Chinese. J Med Genet 2010,47:204-210.
7.施桂英.痛风——降尿酸治疗的新策略.中华风湿病学杂志,2007,11：129—131.
8. Martinon F, PetrILli V, Mayor A, et al. Gout-associated uric acid crystals activate the nalp3 inflammasome. Nature 2006:440:237-241.
9. Sieburth D, Jabs EW, Warrington JA, et al. Assignment of genes encoding a unique cytokine (IL12) composed of two unrelated subunits to chromosomes 3 and 5. Genomics 1992; 14:59-62.
10. Seegers D, Zwiers A, Strober W, Pena AS, Bouma G. A taqi polymorphism in the 3'utr of the IL-12 p40 gene correlates with increased IL-12 secretion. Genes Immun 2002;3:419-423.
11. van Veen T, Crusius JB, Schrijver HM, et al. Interleukin-12p40 genotype plays a role in the susceptiblLity to multiple sclerosis. Ann Neurol 2001;50:275.
12. Morahan G, Huang D, Ymer SI, et al. Linkage disequILibrium of a type 1 diabetes susceptibILity locus with a regulatory IL12b allele. Nat Genet 2001;27:218-221.
13. Mikuls TR, Farrar JT, BILker WB, et al.Gout epidemiology:Results from the uk general practice research database.1990-1999. Ann Rheum Dis 2005;64:267-272.
14. Tsai PC, Chen CJ, Lai HM. Chang SJ. Analysis of polymorphisms in the promoter region and protein levels of interleukin-6 gene among gout patients. Clin Exp Rheamatol 2008;26:841-847
15. Chang SJ, Chen CJ, Tsai FC, et al. Associations between gout tophus and polymorphisms 869t/c and -509c/t in transforming growth factor beta1 gene. Rheumatology (Oxford) 2008;47:617-621.
16. Chang SJ, Tsai PC, Chen CJ, et al. The polymorphism -863c/a in tumour necrosis factor-alpha gene contributes an independent association to gout. Rheumatology (Oxford) 2007;46:1662-1666.
17.初楠,李长贵,贾兆通,等.中国沿海地区汉族男性人群白细胞介素一1β-31C/T基因多态性与痛风的易感性研究.中华风湿病学杂志,2011,15(1)：7—11.
18. Shokrgozar MA, Sarial S, Amirzargar A, et al. IL-2, ifn-gamma, and IL-12 gene polymorphisms and susceptiblLity to multiple sclerosis. J Clin Immunol 2009;29:747-751.
19. Alayli G, Aydin F, Coban AY, et al. T helper 1 type cytokines polymorphisms:Association with susceptibILity to behcet's disease. Clin Rheumatol 2007;26:1299-1305.
20. Rodriguez-Sosa M, Satoskar AR, Calderon R, et al. Chronic helminth infection induces alternatively activated macrophages expressing high levels of ccr5 with low interleukin-12 production and th2-biasing abILity. Infect Immun 2002;70:3656-3664.
21. Landis RC, Haskard DO. Pathogenesis of crystal-induced inflammation. Curr Rheumatol Rep 2001;3:36-41.
22. YILmaz V, Yentur SP, Saruhan-Direskeneli G. IL-12 and IL-10 polymorphisms and their effects on cytokine production. Cytokine 2005;30:188-194.
1. Pater PI, Framson PE, Caskey CT, et al. Fine structure of the human hypoxanthine pphosphoribosyl-transferase gene.Mol Cell Biol,1986,6:393-403
2. Kim SH, Moores JC, David D, et al. The organization of the human HPRT gene. Nucleic Acids Res,1986,14:3103-3118
3. Kelley MN, Rosenbloom FM, Henderson JF, et al. A specific enzyme defect in gout associated with over production of uric acid. Proc Nat Acad Sci,1967,57:1735-1739
4.Jinnah HA, Friedmann T, Lesch-Nyhan disease and its varianta. In:Scriver CR,Beaudet AL,Sly WS,et al(eds).The metabolic and Molecular Bases of Inherited Disease.Vol.Ⅱ.8th ed.New York;McGraw-Hill,2001.2537
5. Sperling O, Eliam G, Persky-Brosh S, et al. Accelerated erythrocyte 5-phosphoribosyl-1-pyrophosyn thesis:a familial abnormality associated with excessive uric acid production and gout. Biochem Med,1972,5:310-316
6. Sperling O, Persky-Brosh S, Boer P, et al. Human erythrocyte phospho-ribosylpyrophosphate synthetase mutationally altered in regulatory properties. Biochem Med,1973,7:389-395
7. Garcia-Pavia, T ores RJ, Rivero M, et al. Phosphoribosylpyrophosphate synthetase overactivity as a cause of uric acid overproduction in a young woman. Arthritis Rheum,2003,48(7):2036-2041
8. Rossler BJ, Palella TD, Heidler S, et al. Identification of distinct PRPS1mutations in two patients with X-lincked phosphoribosylpyrophosphate synthetase superactivixy(Abstract).Clin Res,1991,39:267A
9. Ch YT:Glycogen storage disease. In:Scriver CR, Beaudet AL, Sly WS,et al(eds).The metabolic and Molecular Basis of Inherited Disease.New York:McGraw Hill.2001.1521-1551
10. Stone TW, Simmondonds HA.Purine:Basic and clinical aspects. London:Kluwer.1991
11. Enomoto A, Kimura H, Chairoungdua A, et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature,2002,417:447-452.
12. Ichida K, Hosoyamada M. Hisatome I,et al. Clinical and molecular analysis of patients with renal hyperuricemia in Japan-influence of URAT1 gene on urinary urate excretion. J Am Soc Nephrol, 004,15(1):164-173
13. Cheong HI, Kang JH,Lee JH,et al.Mutational analysis of idiopathic renal hypouricemia in Korea.Pediatr Nephrol.2005,20(7):886-890
14. Iwai N, Mino Y, Hosoyamada M,et al. A high prevalence of renal hypouricemia caused by inactive SLC22A12 in Japanese. Kidney Int,2004,66:935-944
15. Taniguchi A,Urano W, Yamanaka M, et al. A common mutation in an organic anion transporter gene, SLC22A12, is a suppressing factor for the development of gout. Arthritis Rheum,2005, 52:2576-2577
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