摘要
目的:研究广西地区壮、汉族系统性硬皮病(systemic sclerosis,SSc)与HLA-DRB1等位基因的相关性。
方法:采用聚合酶链反应-序列特异性引物(polymerase chainreaction-special sequence primers,PCR-SSP)的方法,对广西地区壮族58例、汉族53例SSc患者和壮、汉族各50例健康对照者进行HLA-DRB1等位基因分型。
结果:1.HLA-DRB1等位基因频率分布
(1).壮族SSc患者组中,共检出14种等位基因,基因频率范围为0.826%-26.724%。其中DRB1*1301、*1305、*15等位基因的频率较高(分别为7.760%、11.207%、26.724%),DRB1*04、*07、*1001频率较低(均为0.826%),DRB1*01、*1402均未检出。壮族对照组中,共检出16种等位基因,基因频率范围为1.00%-15.00%。其中DRB1*15等位基因的频率较高(为15%),DRB1*01、*0301、*04、*1301、*1402的频率较低(均为1.00%)。
(2).汉族SSc患者组中,共检出14种等位基因,基因频率范围为0.943%-28.302%。其中DRB1*1305、*15等位基因的频率较高(为16.981%、28.302%),DRB1,0301频率较低(为0.943%),DRB1*01、*07均未检出。汉族对照组中,共检出16种等位基因,基因频率范围为1.00%-12.00%。其中DRB1*15等位基因的频率较高(为12%),DRB1*01、*04、*08、*1001、*11、*1301、*1302、*1401、*1402的频率较低(均为1.00%)。
2.HLA-DRB1等位基因频率比较
(1).壮族SSc患者组与正常对照组HLA-DRB1等位基因频率,HLA-DRB1*1301、*1305、*15等位基因出现频率患者组分别为7.760%(RR=9.00、X~2=4.341、P=0.037)、11.207%(RR=3.322、X~2=4.206、P=0.04)、26.724%(RR=2.697、X~2=6.038、P=0.014),与对照组(1%、4%、15.00%)相比显著升高,组间差异有统计学意义。
(2).汉族SSc患者组与正常对照组HLA-DRB1等位基因频率,HLA-DRB1*1305、*15等位基因出现频率患者组分别为16.981%(RR=4.629、X~2=8.518、P=0.004)、28.302%(RR=4.130、X~2=11.325、P=0.001),与对照组(5%、12%)相比显著升高,组间差异有统计学意义。
(3).其他等位基因在两组间并未发现有显著性差异。
结论:HLA-DRB1*1305、*15等位基因可能是广西壮、汉族SSc患者的共同易感基因;HLA-DRB1*1301等位基因可能是广西壮族SSc患者的变异基因。未发现广西壮、汉族SSc患者的保护基因。
Objective:To explore the association of HLA-DRB1 alleles with systemic sclerosis(SSc) of Zhuang and Han nationality in Guangxi region.
Methods:Polymerase Polymerase chain reaction-sequence specific primer technique(PCR-SSP) was used to study the HLA-DRB1 alleles in 58 Zhuang and 53 Han nationality patients with SSc.50 randomly selected,unreleated healthy controls of Zhuang and Han nationality respectively in Guangxi region.
Results:1.The distribution of HLA-DRB1 alleles:
(1) 14 alleles were observed in SSc group.In Zhuang nationality,the range of allelic frequencies was from 0.826%to26.724%.Among them the DRBI*1301,*1305and*15 allele were high(7.760%,11.207%,26.724%),the DRB1*04,*07,*10 were rare(0.826%,equally),DRB1*01 and *1402 have not been examined.In controls,the range of allelic frequencies was from 1.00%to 15.00%,the DRB1*01、*0301、*04、*1301、*1402 were rare(1.00%,equally).
(2) 14 alleles were observed in SSc group.In Han nationality,the range of allelic frequencies was from 0.943%to28.302%.Among them the DRB1*1305and*15 allele were high(16.981%,28.302%),the DRB1*0301was rare,DRB1*01 and *07 have not been examined.In controls,the range of allelic frequencies was from 1.00%to 12.00%,the DRB1*01、*04、*08、*1001、*11*、1301、*1302、*1401、*1402 were rare(1.00%,equally).
2.The comparison of HLA-DRB1 allelic frequency:
(1) DRB1*1301,*1305,*15 allelic in the SSc group of Zhuang were significantly higher than that in the control group(7.760%VS1.00%,RR＝9.00,X~2＝4.341,P＝0.037;11.207%VS 4.00%,RR＝3.322,X~2＝4.206,P＝0.04; 26.724%VS15.00%,RR＝2.697,X~2＝6.038,P＝0.014)
(2) DRB1*1305,*15 allelic in the SSc group of Han were significantly higher than that in the control group(16.981%VS5.00%,RR＝4.629,X~2＝8.518,P＝0.004;28.302%VS12%,RR＝4.130,X~2＝11.325,P＝0.001).
(3)No significant difference of other allelic frequencies was observed between the two subjects.
Conclusion:HLA-DRB1*15、*1305、*1301 were closely related to the invasion of SSc in Guangxi;HLA-DRB1*1305and*15may be the susceptible genes of SSc in Guangxi Zhuang and Han nationality,HLA-DRB1*1301 may be the variation gene of SSc in Guangxi Zhuang;The protecting gene was not found in Guangxi Zhuang and Han nationality.
引文
[1]A1lcOCk R,Forrest I,Corris P,et a1.A study of the prevalence 0f systemic SClerosis in northeast England[J].Rheumatology,2004,43:596-602.
[2]Tan FK,Arnett FC.Genetic factors in the etiology of systemic SClerosis and Raynaud phenomenon[J].Curr Opin Rheumatol,2000,12:511-519.
[3]Jacobsen S,Halberg P,Ullman S.Mortality and causes of death of 344 Danish patients with systemic sclerosis(scleroderma)[J].Br J Rheumatol,1998,37(7):750-5.
[4]Lekakis J,Mavrikakis M,Papamicheal C,et a1.Short-termestrogen administratiOn improves abnormal endOthelial functionin women with systemic sclerosis and Raynaud's phenomenon[J].Am Heart J,1998,136:905-912.
[5]Choi JJ,Min DJ,ChoML,et a1.Elevated vascular endothelial growthfactor in systemic sclerosis[J]J Rheumatol,2003,30:1529-1533.
[6]Takagi K,Kawaguchi Y,Hara M,et a1.Serum nitric oxide(NO)levels in systemic sclerosis patients'correlation between NO levels and clinical features[J].C1in Exp Immunol,2003,134:538-544.
[7]Young-Min SA,Beeton C,Laughton R,et al.Sertlm TMP-1,TMP-2 and MMP-1 in patients with systemic sclerosis,primary Raynaud's phenomenon and in rlormal controls[J].Ann Rheum Dis,2001,60(9):846-851.
[8]Susol E,RandsAL,Herrick A,et a1.Association of markers for TGFbeta3,TGFbeta2 and TMP1 with systemic sclerosis[J].heumatology(Oxford),2000.39:1332-1336.
[9]Yamane K,Ihn H,KuboM,et al.Increased transcriptional actiVities of transforming growth factor beta receptors in scleroderma fibroblasts[J].Arthritis Rheum,2002,46(9):2421-2428.
[10]Duncan MR,FrazierKS,Abramson S,et al.Connective tissue growth factor mediates transforming growth factoe beta-induced col-lagen synthesis:down-regulation by CAMP[J].FASEB J,1999,13(13):17746-1786.
[11]Kubo M,Ihn H,Yamane K,et al.Up regulated expression of transforming growth factor-beta receptors in dermal fibroblasts of skin sections from patients with systemic sclerosis[J].J Rheumatol,2002,29(12):2558-2556.
[12]Murota H,Hamasaki Y,Nakashima T,et al.Disruption of tumornecrosis factor receptor p55 impairs collagen turnover in experimentallyinduced sclerodermic skin fibroblasts [J].Arthritis Rheum,2003,48:1117-1125.
[13]Neikole M,Iatsyshyn R I.Role of interleukin-1 and interleukin-2 in the pathogenesis of systemic scleroderma[J].Fiziol Zh,2002,48:56-61.
[14]Riccieri V,Rinaldi T,Spadaro A,et al.Interleukin-13 in systemic sclerosis relationship to nailfold cap illaroscopy bnormalities[J].ClinRheumatol,2003,22:102-106.
[15]Rands AL,Whyte J,Cox B,et al.MHC class Ⅱ associations wit autoantibody and T cell immune responses to the scleroderma autoantigen topoisomerase I [J].J Autoimmun,2000,15(4):451-458.
[16]Cepeda EJ,Reveille JD.Autoantibodies in systemic sclerosis and fibrosing syndromes xlinical indications and relevance[J].Curr Opin Rheumatol,2004,16 (6):723-732.
[17]Meyer O.Prognostic markers for systemic sclerosis[J].Joint Bone Spine,2006,73(5):490-4.
[18]C-I.Joung,J-B.Jun,et al.Association between the HLA-DRBI gene and clinical features of systemic sclerosis in Korea[J].Scandinavian Journal of Rheumatology,2006,35(1):39-43.
[19]Tzkeuchi F,Nakano K.Yamada H,et al.Association of HLA-DR with progressiVe systemic SClerosis in Japanese[J].J heumatol,1994,21(5):857—863.
[20]Arnett FC,Reveille JD,Goldstein R,et a1.Autoantibodies to fibrillarin in systemic SClerosis(scleroderma).An immunogenetic,serologic,and clinical analysis[J].Arthritis Rheum,1996,39(7):1151-60.
[21]L S.Loubie｀re,N.C.Lambertl,M.M.Madeleine,et al.HLA allelic variants encoding DR11 in diffuse and limited systemic SClerosis in Caucasian women[J].Rheumatology,2005,44:318-322.
[22]Ariane LH,and Jane W.Genetic epidemiology:Systemic SClerosis[J].Arthritis Res,2002,4(3):165-168.
[23]De Keyser F,Peene I,JOOS R,et al.Occurrence of SCleroderma in mollozygotic twins[J].J Rheumatol,2000,27:2267-2269.
[24]Arnett FC,Howard RF,Tan FK,et al.Increased prevalenee of systemic sclerosis in a Native Alnerican tribe in klahoma.Associatioil with an Amerindian HLA haplotype[J].ArthritisRheum,1996,39:1362-1370.