云南省彝族人群SRD5A2基因多态性与前列腺癌的相关性
|
摘要
目的探讨云南省彝族人群中睾酮5-α还原酶Ⅱ(SRD5A2)基因rs523349(V89L)、rs9282858(A49T)和TA重复序列多态性与前列腺癌的相关性。方法通过Sanger测序法对122例云南彝族前列腺患者和135例云南彝族非前列腺癌健康男性SRD5A2基因rs523349(V89L)、rs9282858(A49T)和TA重复序列多态性进行检测,并分析其与前列腺癌之间的相关性。结果云南彝族前列腺癌组和对照组中均未发现SRD5A2基因rs9282858位点的AA基因型。两组间SRD5A2基因rs523349和rs9282858位点的基因型和等位基因频率分布差异无统计学意义(P>0.05)。而两组间TA重复序列位点的基因型和等位基因频率分布差异有统计学意义(P<0.05),在前列腺癌组中含有(TA)9等位基因的基因型[(TA)0(TA)9+(TA)9(TA)9]较对照组多见(P=0.033)。与携带(TA)0等位基因者相比,携带(TA)9等位基因者患前列腺癌的风险明显增高(OR=2.181,95%CI:1.111~4.281,P=0.021)。结论云南彝族人群中SRD5A2基因TA重复序列多态性与前列腺癌发病危险相关,可作为前列腺癌的基因危险因素,来确定高危人群。
Objective To investigate the association of rs523349(V89 L),rs9282858(A49 T)and TArepeat polymorphisms in testosterone 5-alpha-reductase Ⅱ(SRD5 A2)gene with prostate cancer(PCa)in thepopulation of Yi nationality in Yunnan Province. Methods Sanger sequence detection technique was used todetect rs523349(V89 L),rs9282858(A49 T)and TA repeat polymorphisms of SRD5 A2 gene in 122 subjects withconfirmed PCa and 135 age-matched healthy controls in the Yunnan Yi population,then the association of thesepolymorphisms with prostate cancer was analyzed. Results The AA genotype of rs9282858 site in SRD5 A2 genewas not found between the Pca patients and the healthy controls in the Yunnan Yi population. The genotypic andallelic frequency distributions of rs523349 and rs9282858 were not significantly varied between the Pca patientsand the controls(P > 0.05). But the genotypic and allelic frequency distributions of TA repeat site were significantlyvaried(P < 0.05). The genotype containing(TA)9 allele was more common in the Pca patients than the healthycontrols(P = 0.033). Compared with(TA)0 allele subjects,(TA)9 allele subjects had a higher PCa risk(OR = 2.181,95%CI:1.111 ~ 4.281,P = 0.021). Conclusion The TA repeat polymorphisms of SRD5 A2 gene was associatedwith PCa risk in the Yunnan Yi population,which could be used as a risk factor to screen the high-risk individuals.
Objective To investigate the association of rs523349(V89 L),rs9282858(A49 T)and TArepeat polymorphisms in testosterone 5-alpha-reductase Ⅱ(SRD5 A2)gene with prostate cancer(PCa)in thepopulation of Yi nationality in Yunnan Province. Methods Sanger sequence detection technique was used todetect rs523349(V89 L),rs9282858(A49 T)and TA repeat polymorphisms of SRD5 A2 gene in 122 subjects withconfirmed PCa and 135 age-matched healthy controls in the Yunnan Yi population,then the association of thesepolymorphisms with prostate cancer was analyzed. Results The AA genotype of rs9282858 site in SRD5 A2 genewas not found between the Pca patients and the healthy controls in the Yunnan Yi population. The genotypic andallelic frequency distributions of rs523349 and rs9282858 were not significantly varied between the Pca patientsand the controls(P > 0.05). But the genotypic and allelic frequency distributions of TA repeat site were significantlyvaried(P < 0.05). The genotype containing(TA)9 allele was more common in the Pca patients than the healthycontrols(P = 0.033). Compared with(TA)0 allele subjects,(TA)9 allele subjects had a higher PCa risk(OR = 2.181,95%CI:1.111 ~ 4.281,P = 0.021). Conclusion The TA repeat polymorphisms of SRD5 A2 gene was associatedwith PCa risk in the Yunnan Yi population,which could be used as a risk factor to screen the high-risk individuals.
引文
[1]FITZMAURICE C,ALLEN C,BARBER R M,et al.Global,regional,and national cancer incidence,mortality,years oflife lost,years lived with disability,and disability-adjusted life-years for 32 cancer groups,1990 to 2015:a systematic analy-sis for the global burden of disease study[J].JAMA Oncol,2017,3(4):524-548.
[2]叶定伟,朱耀.中国前列腺癌的流行病学概述和启示[J].中华外科杂志,2015,53(4):249-252.
[3]CHEN R,REN S,YIU M K,et al.Prostate cancer in Asia:acollaborative report[J].Asian J Urol,2014,1(1):15-29.
[4]MARCELLI M,CUNNINGHAM G R.Hormonal signaling inprostatic hyperplasia and neoplasia[J].J Clin EndocrinolMetab,1999,84(10):3463-3468.
[5]WU Y,GODOY A,AZZOUNI F,et al.Prostate cancer cellsdiffer in testosterone accumulation,dihydrotestosterone conver-sion,and androgen receptor signaling response to steroid 5α-re-ductase inhibitors[J].Prostate,2013,73(13):1470-1482.
[6]LI X,HUANG Y,FU X,et al.Meta-analysis of three polymor-phisms in the steroid-5-alpha-reductase,alpha polypeptide 2gene(SRD5A2)and risk of prostate cancer[J].Mutagenesis,2010,26(3):371-383.
[7]REICHARDT J K V,MAKRIDAKIS N,HENDERSON B E,et al.Genetic variability of the human SRD5A2 gene:implica-tions for prostate cancer risk[J].Cancer Res,1995,55(18):3973-3975.
[8]RAJENDER S,VIJAYALAKSHMI K,POOJA S,et al.Longer(TA)n repeat but not A49T and V89L polymorphisms inSRD5A2 gene may confer prostate cancer risk in South Indianmen[J].J Androl,2009,30(6):703-710.
[9]NWOSU V,CARPTEN J,TRENT J M,et al.Heterogeneity ofgenetic alterations in prostate cancer:evidence of the complexnature of the disease[J].Hum Mol Genet,2001,10(20):2313-2318.
[10]MAKRIDAKIS N M,ROSS R K,PIKE M C,et al.Associa-tion of mis-sense substitution in SRD5A2 gene with prostatecancer in African-American and Hispanic men in Los Angeles,USA[J].Lancet,1999,354(9183):975-978.
[11]YAMADA Y,WATANABE M,MURATA M,et al.Impact ofgenetic polymorphisms of 17-hydroxylase cytochrome P-450(CYP17)and steroid 5α-reductase type II(SRD5A2)geneson prostate-cancer risk among the Japanese population[J].IntJ Cancer,2001,92(5):683-686.
[12]MAKRIDAKIS N M,DI SALLE E,REICHARDT J K V.Bio-chemical and pharmacogenetic dissection of human steroid 5α-reductase type II[J].Pharmacogenetics,2000,10(5):407-413.
[13]CUSSENOT O,AZZOUZI A R,NICOLAIEW N,et al.Low-ac-tivity V89L variant in SRD5A2 is associated with aggressiveprostate cancer risk:an explanation for the adverse effects ob-served in chemoprevention trials using 5-alpha-reductase inhibi-tors[J].Eur Urol,2007,52(4):1082-1089.
[14]GIWERCMAN Y L,ABRAHAMSSON P A,GIWERCMAN A,et al.The 5α-reductase type II A49T and V89L high-activity al-lelic variants are more common in men with prostate cancercompared with the general population[J].Eur Urol,2005,48(4):679-685.
[15]佟明,金艳阳,李刚,等.睾酮5-α还原酶Ⅱ基因V89L多态性与前列腺癌预后关系的研究[J].中华男科学杂志,2010(11):990-993.
[16]JAFFE J M,MALKOWICZ S B,WALKER A H,et al.Associ-ation of SRD5A2 genotype and pathological characteristics ofprostate tumors[J].Cancer Res,2000,60(6):1626-1630.
[17]LATIL A G,AZZOUZI R,CANCEL G S,et al.Prostate carci-noma risk and allelic variants of genes involved in androgen bio-synthesis and metabolism pathways[J].Cancer,2001,92(5):1130-1137.
[18]MONONEN N,IKONEN T,SYRJAKOSKI K,et al.A mis-sense substitution A49T in the steroid 5-alpha-reductase gene(SRD5A2)is not associated with prostate cancer in Finland[J].Br J Cancer,2001,84(10):1344-1347.
[19]SODERSTROM T,WADELIUS M,ANDERSSON S O,et al.5α-Reductase 2 polymorphisms as risk factors in prostate can-cer[J].Pharmacogenetics,2002,12(4):307-312.
[20]刘建河,李鸿伟,佟明,等.北方汉族人群易感基因多态性与前列腺癌危险关系及对发病种族差异的分析[J].中华医学杂志,2004,84(5):364-368.
[21]KACHAKOVA D,MITKOVA A,POPOV E,et al.Polymor-phisms in androgen metabolism genes AR,CYP1B1,CYP19,and SRD5A2 and prostate cancer risk and aggressiveness inBulgarian patients[J].Turk J Med Sci,2016,46(3):626-640.
[22]SALAM M T,URSIN G,SKINNER E C,et al.Associationsbetween polymorphisms in the steroid 5-αreductase type II(SRD5A2)gene and benign prostatic hyperplasia and prostatecancer[J].Urol Oncol,2005,23(4):246-253.
[23]NTAIS C,POLYCARPOU A,TSATSOULIS A.Molecular epi-demiology of prostate cancer:androgens and polymorphisms inandrogen-related genes[J].Eur J Endocrinol,2003,149(6):469-477.
[2]叶定伟,朱耀.中国前列腺癌的流行病学概述和启示[J].中华外科杂志,2015,53(4):249-252.
[3]CHEN R,REN S,YIU M K,et al.Prostate cancer in Asia:acollaborative report[J].Asian J Urol,2014,1(1):15-29.
[4]MARCELLI M,CUNNINGHAM G R.Hormonal signaling inprostatic hyperplasia and neoplasia[J].J Clin EndocrinolMetab,1999,84(10):3463-3468.
[5]WU Y,GODOY A,AZZOUNI F,et al.Prostate cancer cellsdiffer in testosterone accumulation,dihydrotestosterone conver-sion,and androgen receptor signaling response to steroid 5α-re-ductase inhibitors[J].Prostate,2013,73(13):1470-1482.
[6]LI X,HUANG Y,FU X,et al.Meta-analysis of three polymor-phisms in the steroid-5-alpha-reductase,alpha polypeptide 2gene(SRD5A2)and risk of prostate cancer[J].Mutagenesis,2010,26(3):371-383.
[7]REICHARDT J K V,MAKRIDAKIS N,HENDERSON B E,et al.Genetic variability of the human SRD5A2 gene:implica-tions for prostate cancer risk[J].Cancer Res,1995,55(18):3973-3975.
[8]RAJENDER S,VIJAYALAKSHMI K,POOJA S,et al.Longer(TA)n repeat but not A49T and V89L polymorphisms inSRD5A2 gene may confer prostate cancer risk in South Indianmen[J].J Androl,2009,30(6):703-710.
[9]NWOSU V,CARPTEN J,TRENT J M,et al.Heterogeneity ofgenetic alterations in prostate cancer:evidence of the complexnature of the disease[J].Hum Mol Genet,2001,10(20):2313-2318.
[10]MAKRIDAKIS N M,ROSS R K,PIKE M C,et al.Associa-tion of mis-sense substitution in SRD5A2 gene with prostatecancer in African-American and Hispanic men in Los Angeles,USA[J].Lancet,1999,354(9183):975-978.
[11]YAMADA Y,WATANABE M,MURATA M,et al.Impact ofgenetic polymorphisms of 17-hydroxylase cytochrome P-450(CYP17)and steroid 5α-reductase type II(SRD5A2)geneson prostate-cancer risk among the Japanese population[J].IntJ Cancer,2001,92(5):683-686.
[12]MAKRIDAKIS N M,DI SALLE E,REICHARDT J K V.Bio-chemical and pharmacogenetic dissection of human steroid 5α-reductase type II[J].Pharmacogenetics,2000,10(5):407-413.
[13]CUSSENOT O,AZZOUZI A R,NICOLAIEW N,et al.Low-ac-tivity V89L variant in SRD5A2 is associated with aggressiveprostate cancer risk:an explanation for the adverse effects ob-served in chemoprevention trials using 5-alpha-reductase inhibi-tors[J].Eur Urol,2007,52(4):1082-1089.
[14]GIWERCMAN Y L,ABRAHAMSSON P A,GIWERCMAN A,et al.The 5α-reductase type II A49T and V89L high-activity al-lelic variants are more common in men with prostate cancercompared with the general population[J].Eur Urol,2005,48(4):679-685.
[15]佟明,金艳阳,李刚,等.睾酮5-α还原酶Ⅱ基因V89L多态性与前列腺癌预后关系的研究[J].中华男科学杂志,2010(11):990-993.
[16]JAFFE J M,MALKOWICZ S B,WALKER A H,et al.Associ-ation of SRD5A2 genotype and pathological characteristics ofprostate tumors[J].Cancer Res,2000,60(6):1626-1630.
[17]LATIL A G,AZZOUZI R,CANCEL G S,et al.Prostate carci-noma risk and allelic variants of genes involved in androgen bio-synthesis and metabolism pathways[J].Cancer,2001,92(5):1130-1137.
[18]MONONEN N,IKONEN T,SYRJAKOSKI K,et al.A mis-sense substitution A49T in the steroid 5-alpha-reductase gene(SRD5A2)is not associated with prostate cancer in Finland[J].Br J Cancer,2001,84(10):1344-1347.
[19]SODERSTROM T,WADELIUS M,ANDERSSON S O,et al.5α-Reductase 2 polymorphisms as risk factors in prostate can-cer[J].Pharmacogenetics,2002,12(4):307-312.
[20]刘建河,李鸿伟,佟明,等.北方汉族人群易感基因多态性与前列腺癌危险关系及对发病种族差异的分析[J].中华医学杂志,2004,84(5):364-368.
[21]KACHAKOVA D,MITKOVA A,POPOV E,et al.Polymor-phisms in androgen metabolism genes AR,CYP1B1,CYP19,and SRD5A2 and prostate cancer risk and aggressiveness inBulgarian patients[J].Turk J Med Sci,2016,46(3):626-640.
[22]SALAM M T,URSIN G,SKINNER E C,et al.Associationsbetween polymorphisms in the steroid 5-αreductase type II(SRD5A2)gene and benign prostatic hyperplasia and prostatecancer[J].Urol Oncol,2005,23(4):246-253.
[23]NTAIS C,POLYCARPOU A,TSATSOULIS A.Molecular epi-demiology of prostate cancer:androgens and polymorphisms inandrogen-related genes[J].Eur J Endocrinol,2003,149(6):469-477.