云南汉族痤疮与雄激素相关基因研究
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摘要
目的:研究雄激素相关基因CYP17、CYP11α、雄激素受体(AR)基因多态性与云南汉族痤疮发病危险性的关系,从分子遗传学角度探讨痤疮的发病机制。方法:提取206例云南汉族痤疮患者和200例健康对照者外周血的DNA样本后,应用PCR-限制性酶切长度多态性、测序及PCR-genescan方法对CYP17、CYP11α、AR基因的多态性位点进行检测,并对患者组不同多态性位点基因型分布频率与对照组进行比较研究。
结果:CYP17基因-34T/C多态性病例对照研究显示,男性重型痤疮组CC基因型和C等位基因分布的频率分别为60.9%和33.3%,与男性对照组CC基因型频率(18.2%)、C等位基因频率(46.6%)均存在统计学差异(P<0.05),而在男性轻型痤疮组及女性痤疮组中均未发现统计学差异(P>0.05);对CYP11α tttta多态性研究显示,男性重型痤疮中215-和215+基因型频率(59%,41%),与男性对照组(40.1%,59.1%)相比有显著性差异(P<0.05),但在女性痤疮组以及男性轻型痤疮组中这两种基因型频率分布与各自对照组相比未发现差异(P>0.05);AR基因CAG多态性的研究表明,男性对照组CAG重复片段均数为22.07,男性轻型、重型痤疮组的重复片段均数为20.79、20.50,两组分别与对照组相比有明显差异(P<0.01),女性痤疮组中CAG重复片段数与对照组相比未发现差异(P>0.05)。
结论:首次发现CYP17基因T(-34)C多态性、CYP11基因tttta微卫星重复多态性与云南汉族男性重型痤疮相关;AR基因第一外显子CAG重复片段多态性与云南汉族男性痤疮相关。
Objective: To investigate the relationship between acne and polymorphisms in genes associated with androgen, CYP17, CYP11α and AR gene, in the Han nationality of Yunnan province.Methods; Restriction fragment length polymorphisms (RFLP) and genescan techniques were used to detect the polymorphic sites in the DNAs from the peripheral blood samples of 206 patients with acne 200 normal control in Han nationality of Yunnan province. The distribution frequencies of different polymorphic sites were compared between patients group and controls.Results: CYP17-34 T/C polymorphism was found and the distribution frequencies of the C/C homozygotes and C allele in the severe male acne patients (33.3% and 60.9% respectively) were obviously statistically significant difference than in those of the control samples (18.2% and 46.6%) (P<0.05), but we didn't find difference in the female patients and moderate male patients comparing with respectively controls; The frequencies of 215- and 215+ genotype were 59% and 41% in the male severe acne. Comparing with the male controls (40.1%, 59.1%), the difference was statistically significant (P<0.05), but we also didn't find difference in the female patients and moderate male patients comparing with respectively controls; The mean length of the CAG repeat was 20.79 in the group of moderate male acne and 20.50 in the group of severe male acne, comparing with control (22.07), there were significantly different in two group respectively (P<0.01) , but we didn't find similar phenomenon in female acne.Conclusion: This is first report that polymorphisms of CYP17 and CYP11α genes are associated with severe male acne, and shorter CAG repeats in the AR gene may play a role in the etiology of male acne in the Han nationality of Yunnan province.
结果:CYP17基因-34T/C多态性病例对照研究显示,男性重型痤疮组CC基因型和C等位基因分布的频率分别为60.9%和33.3%,与男性对照组CC基因型频率(18.2%)、C等位基因频率(46.6%)均存在统计学差异(P<0.05),而在男性轻型痤疮组及女性痤疮组中均未发现统计学差异(P>0.05);对CYP11α tttta多态性研究显示,男性重型痤疮中215-和215+基因型频率(59%,41%),与男性对照组(40.1%,59.1%)相比有显著性差异(P<0.05),但在女性痤疮组以及男性轻型痤疮组中这两种基因型频率分布与各自对照组相比未发现差异(P>0.05);AR基因CAG多态性的研究表明,男性对照组CAG重复片段均数为22.07,男性轻型、重型痤疮组的重复片段均数为20.79、20.50,两组分别与对照组相比有明显差异(P<0.01),女性痤疮组中CAG重复片段数与对照组相比未发现差异(P>0.05)。
结论:首次发现CYP17基因T(-34)C多态性、CYP11基因tttta微卫星重复多态性与云南汉族男性重型痤疮相关;AR基因第一外显子CAG重复片段多态性与云南汉族男性痤疮相关。
Objective: To investigate the relationship between acne and polymorphisms in genes associated with androgen, CYP17, CYP11α and AR gene, in the Han nationality of Yunnan province.Methods; Restriction fragment length polymorphisms (RFLP) and genescan techniques were used to detect the polymorphic sites in the DNAs from the peripheral blood samples of 206 patients with acne 200 normal control in Han nationality of Yunnan province. The distribution frequencies of different polymorphic sites were compared between patients group and controls.Results: CYP17-34 T/C polymorphism was found and the distribution frequencies of the C/C homozygotes and C allele in the severe male acne patients (33.3% and 60.9% respectively) were obviously statistically significant difference than in those of the control samples (18.2% and 46.6%) (P<0.05), but we didn't find difference in the female patients and moderate male patients comparing with respectively controls; The frequencies of 215- and 215+ genotype were 59% and 41% in the male severe acne. Comparing with the male controls (40.1%, 59.1%), the difference was statistically significant (P<0.05), but we also didn't find difference in the female patients and moderate male patients comparing with respectively controls; The mean length of the CAG repeat was 20.79 in the group of moderate male acne and 20.50 in the group of severe male acne, comparing with control (22.07), there were significantly different in two group respectively (P<0.01) , but we didn't find similar phenomenon in female acne.Conclusion: This is first report that polymorphisms of CYP17 and CYP11α genes are associated with severe male acne, and shorter CAG repeats in the AR gene may play a role in the etiology of male acne in the Han nationality of Yunnan province.
引文
1、Odom RB, James WD, Berger TG. Andrew's diseases of the skin. Ninth edition. 2001, 284-306.
2.、Leyden JJ, Berger RS, Dunlap FE, Ellis CN, Connolly MA, Levy SF. Comparison of the efficacy and safety of a combination topical gel formulation of benzoyl peroxide and clindamycin with benzoyl peroxide, clindamycin and vehicle gel in the treatments of acne vulgaris. Am J Clin Dermatol. 2001; 2(1): 33-9.
3、Maria I, Herane, Iwao Ando. Acne in infancy and acne genetics. Dermatology. 2003; 206: 24-28.
4、Taylor SC, Cook-Bolden F, Rahman Z. acne vulgaris in skin of color. J Am Acad Dermatol. 2002; 46: S98-106.
5、Freyre EA, Rebaza RM, Sami DA. The prevalence of facial acne in Peruvian adolescents and its relation to their ethnicity. J Adolesc Health. 1998; 22(6): 480-484.
6、Bataille V, Senieder H, Macgregor AJ et al. The influence of genetics and environmental factors in the pathogenesis of acne: atwin study of ache in women. J Soc Invest Dermatol. 2002, 119: 1317-1322.
7、Shernaz Walton, Wyatt EH, Cunliffe WJ. Genetic control of sebum excretion and acne-a twin study. Br J Dermatology. 1988, 118: 393-396.
8、Thiboutot D, Harris G, Iles V, et al. Activity of the type 1 5 alpha-reductase exhibits regional differences in isolated sebaceous glands and whole skin. J Invest Dermatol, 1995, 105(20, 209-214.
9、Rosenfield RL, Deplewski D, Kentsis A et al. mechanisms of androgen induction of sebocyte differentiation. Dermatology, 1998, 196(1): 43-46.
10、Deplewski D, Rosenfield Rl. Role of hormones in pilosebaceous unit development. Endocr rev, 2000, 21 (4): 363-392.
11、Rook A, et al. Textbook of dermatology. 6th ed. Miland: Blackwell, 1998, 1927-1940.
12、Cunliffe WJ. The sebaceous gland and acne. Dermatology, 1998, 196(1): 9-15.
13、Lunn RM, Bell DA, Mohler JL, et al. A prostate cancer risk and polymorphism in CYP 17 and SRD5A2. Carcinogenesis, 1999, 20: 1727-1731.
14、Wadelius M, Andersson AO, Johansson JE, Wadelius C, Rane E. Prostate cancer associated with CYP17 genotype. Pharmacogenetics. 1999; 9: 635-9.
15、Latil AG, Azzouzi R, Cancel GS, Guillaume EC, Cochan-Priollet B, Berthon PL, Cussenot O. Prostate carcinoma risk and allelic variants of genes involved in androgen biosynthesis and metabolism pathways. Cancer. 2001 Sep 1; 92 (5): 1130-7.
16、Giovanucci E, Stampfer M, Krithivas K et al. The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc Natl Acad Sci USA 1997; 94: 3320-3.
17、Carey AH, Waterworth D, Patel K, White D, Little J, Novelli P, Franks S, Williamson R. Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17. Hum Mol Genet. 1994; 3: 1873-6.
18、Diamanti KE, Bartzis MI, Evangelia D Z, et al. Polymorphism T→C (-34bp) of gene C YP17 promoter in Greek patients with PCOS [J]. Fertil Steril, 1999, 71(3): 431-435.
19、Dowsing AT, Yong EL, Clark M, et al. Linkage between male infertility and trinucleotide repeat expansion in the androgen receptor gene. Lancet, 1999, 354(9179): 640-643.
20、Justine A, Ellis, Margaret Stebbing, et al. Polymorphism of the androgen receptor gene is associated with male pattern baldness. J Invest Dermatol. 2001, 116(3), 452-455.
21、赵辩,临床皮肤病学,第三版,南京,江苏科技出版社,2003,936.
22、Picado-Leonard J, Miller WL. Cloning and sequence of the human gene for P450c17 (steroid 17 alpha-hydroxylase/17, 20 lyase): similarity with the gene for P450c21. DNA. 1987; 6: 439-48.
23、Kadonaga JT, Jones KA, Tijan R. promoter-specific activation of RNA polymerase Ⅱ transcription by SPI. Trends Biochem Sci 1986; 11: 20-23.
24、Jacq X, Brou C, Lutz Y, et al. Human TAFII30 is present in a distinct TFIID complex and is required for transcriptional activation by the estrogen receptor. Cell, 1994,79(1): 107-117.
25 Fritsch M,Orfanos CE,zouboulis CC.Sebocytes are the key regulators of androgen homeostasis in human skin.J Invest Dermatol,2001,116(5):793-800.
26 Morohashi K, Sogawa K, Omura T, et al. Gene structure of human cytochrome P450SCC, cholesterol desmolase. J Biochem. 1987,101, 879-887.
27 Mooser V, Francesco PM, Bopp S,et al. Sequence polymorphisms in the Apo(a) gene associated with specific levels of Lp(a) in plasma. Hum Mol Genet. 1995, 4, 173-181.
28 Gharani N, Waterworth DM,Batty S,et al. association of the steroid synthesis gene CYP11α with polycystic ovary syndrome and hyperandrogenism. Hum Mol Genet. 1997, 6: 397-402.
29 Waterworth Dm, Bennett ST, Gharani S, et al. Linkage and association of insulin
gene VNTR regulatory polymorphisms with polycystic ovary syndrome. Lancet, 1997;
349:986-90.
30 Franks S, Gharani N, Gilling-Smith C. Polycystic ovary syndrome evidence for a
primary disorder of ovarian steroidigenesis. J Steroid Biochem Mol Biol,1999, 69:
269-272.
31 Diamanti KE, Bartzis MI, Bergiele A T, et al. Microsatellite polymorphism (tttta) at - 528bp of gene CYP11α inf luences hyperandrogenemia in p atients with PCOS[J ]. Fertil Steril ,2000 ,73 (4) :735 - 741.
32 Liang T, Hoyer S, Yu R, Soltani K, Lorincz AL, Hiipakka RA, Liao S. Immunocytochemical localization of androgen receptors in human skin using monoclonal antibodies against the androgen receptor. J Invest Dermatol. 1993 May;100(5):663-6.
33 Janne OA, Palvimo JJ, Kallio P, et al. Androgen recptor and mechanism of androgen action. Ann Med . 1993,25: 83-89.
34 Chamberlain NL,Drive ED, Miesfeld RL, et al. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res, 1994,22:3181-3186.
35、Sawaya ME, Shalita AR. Androgen receptor polymorphisms (CAG repeat lengths) in androgenetic alopecia, hirsutism, and acne. J Cutan Med Surg. 1998. 3: 9-15.
36、Chamberlain NL, Drive ED, Miesfeld RL, et al. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res, 1994, 22: 3181-3186.
37、Kazemi-Esfarjani P, Trifiro M A, Pinsky L. Evidence for a repressive function of the long polyglutamine tract in the human androgen receptor: possible pathogenetic relevance for the (CAG)n -expanded neuropathies. Hum Mol Genet 1995; 4 (4): 523.
38、Brinkmann AO. Molecular basis of androgen insensitivity [J]. Mol Cell Endocrinol, 2001; 179: 105-109.
39、Wallerand H, Remu2Martin A, Chabannes E, et al. Relationship between expansion of the CAG repeat in exon 1 of the androgen receptor gene and idiopathic male infertility [J]. Fertil Steril, 2001; 76: 769-774.
40、Suter NM, Malone KE, Daling JR, et al. Androgen receptor (CAG) n and (GGC) n polymorphisms and breast cancer risk in a population based case-control study of young women [J]. Cancer Epidemiol Biomarkers Prev, 2003; 12: 127-135.
41、Haiman CA, Brown M, Hankinson SE, et al. The androgen receptor CAG repeat polymorphism and risk of breast cancer in the Nurses' Health Study [J]. Cancer Res, 2002; 62: 1045-1049.
42、Yaron M, Levy T, Chetrit A, et al. The polymorphie CAG repeat in the androgen receptor gene in Jewish Israeli women with endometrial carcinoma [J]. Cancer, 2001; 92: 1190-1194.
43、郑强荪,舒青,冯蕾,等.动脉粥样硬化遗传易感性与HUMURA多态性的相关性[J].第四军医大学学报,2001;22(17):1590-1593.
44、Park TW, Felix JC, Wright TC. X chromosome inactivation and microsatellite instability in early and advanced bilateral ovarian carcinomas [J]. Cancer Res, 1995, 55(21): 4793-4796.
45、王刚,陈光椿,王晓慧,等.中国男性雄性激素受体基因(CAG)n重复多态性 的初步研究[J].中华医学遗传学杂志,2001,18(6):456-458.
46、李斌.刁小莉.张伟,等.雄激素受体第一外显子CAG重复序列长度多态性与子宫平滑肌瘤遗传易感性有关.第四军医大学学报 2004,25(9):836-840.
2.、Leyden JJ, Berger RS, Dunlap FE, Ellis CN, Connolly MA, Levy SF. Comparison of the efficacy and safety of a combination topical gel formulation of benzoyl peroxide and clindamycin with benzoyl peroxide, clindamycin and vehicle gel in the treatments of acne vulgaris. Am J Clin Dermatol. 2001; 2(1): 33-9.
3、Maria I, Herane, Iwao Ando. Acne in infancy and acne genetics. Dermatology. 2003; 206: 24-28.
4、Taylor SC, Cook-Bolden F, Rahman Z. acne vulgaris in skin of color. J Am Acad Dermatol. 2002; 46: S98-106.
5、Freyre EA, Rebaza RM, Sami DA. The prevalence of facial acne in Peruvian adolescents and its relation to their ethnicity. J Adolesc Health. 1998; 22(6): 480-484.
6、Bataille V, Senieder H, Macgregor AJ et al. The influence of genetics and environmental factors in the pathogenesis of acne: atwin study of ache in women. J Soc Invest Dermatol. 2002, 119: 1317-1322.
7、Shernaz Walton, Wyatt EH, Cunliffe WJ. Genetic control of sebum excretion and acne-a twin study. Br J Dermatology. 1988, 118: 393-396.
8、Thiboutot D, Harris G, Iles V, et al. Activity of the type 1 5 alpha-reductase exhibits regional differences in isolated sebaceous glands and whole skin. J Invest Dermatol, 1995, 105(20, 209-214.
9、Rosenfield RL, Deplewski D, Kentsis A et al. mechanisms of androgen induction of sebocyte differentiation. Dermatology, 1998, 196(1): 43-46.
10、Deplewski D, Rosenfield Rl. Role of hormones in pilosebaceous unit development. Endocr rev, 2000, 21 (4): 363-392.
11、Rook A, et al. Textbook of dermatology. 6th ed. Miland: Blackwell, 1998, 1927-1940.
12、Cunliffe WJ. The sebaceous gland and acne. Dermatology, 1998, 196(1): 9-15.
13、Lunn RM, Bell DA, Mohler JL, et al. A prostate cancer risk and polymorphism in CYP 17 and SRD5A2. Carcinogenesis, 1999, 20: 1727-1731.
14、Wadelius M, Andersson AO, Johansson JE, Wadelius C, Rane E. Prostate cancer associated with CYP17 genotype. Pharmacogenetics. 1999; 9: 635-9.
15、Latil AG, Azzouzi R, Cancel GS, Guillaume EC, Cochan-Priollet B, Berthon PL, Cussenot O. Prostate carcinoma risk and allelic variants of genes involved in androgen biosynthesis and metabolism pathways. Cancer. 2001 Sep 1; 92 (5): 1130-7.
16、Giovanucci E, Stampfer M, Krithivas K et al. The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc Natl Acad Sci USA 1997; 94: 3320-3.
17、Carey AH, Waterworth D, Patel K, White D, Little J, Novelli P, Franks S, Williamson R. Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17. Hum Mol Genet. 1994; 3: 1873-6.
18、Diamanti KE, Bartzis MI, Evangelia D Z, et al. Polymorphism T→C (-34bp) of gene C YP17 promoter in Greek patients with PCOS [J]. Fertil Steril, 1999, 71(3): 431-435.
19、Dowsing AT, Yong EL, Clark M, et al. Linkage between male infertility and trinucleotide repeat expansion in the androgen receptor gene. Lancet, 1999, 354(9179): 640-643.
20、Justine A, Ellis, Margaret Stebbing, et al. Polymorphism of the androgen receptor gene is associated with male pattern baldness. J Invest Dermatol. 2001, 116(3), 452-455.
21、赵辩,临床皮肤病学,第三版,南京,江苏科技出版社,2003,936.
22、Picado-Leonard J, Miller WL. Cloning and sequence of the human gene for P450c17 (steroid 17 alpha-hydroxylase/17, 20 lyase): similarity with the gene for P450c21. DNA. 1987; 6: 439-48.
23、Kadonaga JT, Jones KA, Tijan R. promoter-specific activation of RNA polymerase Ⅱ transcription by SPI. Trends Biochem Sci 1986; 11: 20-23.
24、Jacq X, Brou C, Lutz Y, et al. Human TAFII30 is present in a distinct TFIID complex and is required for transcriptional activation by the estrogen receptor. Cell, 1994,79(1): 107-117.
25 Fritsch M,Orfanos CE,zouboulis CC.Sebocytes are the key regulators of androgen homeostasis in human skin.J Invest Dermatol,2001,116(5):793-800.
26 Morohashi K, Sogawa K, Omura T, et al. Gene structure of human cytochrome P450SCC, cholesterol desmolase. J Biochem. 1987,101, 879-887.
27 Mooser V, Francesco PM, Bopp S,et al. Sequence polymorphisms in the Apo(a) gene associated with specific levels of Lp(a) in plasma. Hum Mol Genet. 1995, 4, 173-181.
28 Gharani N, Waterworth DM,Batty S,et al. association of the steroid synthesis gene CYP11α with polycystic ovary syndrome and hyperandrogenism. Hum Mol Genet. 1997, 6: 397-402.
29 Waterworth Dm, Bennett ST, Gharani S, et al. Linkage and association of insulin
gene VNTR regulatory polymorphisms with polycystic ovary syndrome. Lancet, 1997;
349:986-90.
30 Franks S, Gharani N, Gilling-Smith C. Polycystic ovary syndrome evidence for a
primary disorder of ovarian steroidigenesis. J Steroid Biochem Mol Biol,1999, 69:
269-272.
31 Diamanti KE, Bartzis MI, Bergiele A T, et al. Microsatellite polymorphism (tttta) at - 528bp of gene CYP11α inf luences hyperandrogenemia in p atients with PCOS[J ]. Fertil Steril ,2000 ,73 (4) :735 - 741.
32 Liang T, Hoyer S, Yu R, Soltani K, Lorincz AL, Hiipakka RA, Liao S. Immunocytochemical localization of androgen receptors in human skin using monoclonal antibodies against the androgen receptor. J Invest Dermatol. 1993 May;100(5):663-6.
33 Janne OA, Palvimo JJ, Kallio P, et al. Androgen recptor and mechanism of androgen action. Ann Med . 1993,25: 83-89.
34 Chamberlain NL,Drive ED, Miesfeld RL, et al. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res, 1994,22:3181-3186.
35、Sawaya ME, Shalita AR. Androgen receptor polymorphisms (CAG repeat lengths) in androgenetic alopecia, hirsutism, and acne. J Cutan Med Surg. 1998. 3: 9-15.
36、Chamberlain NL, Drive ED, Miesfeld RL, et al. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res, 1994, 22: 3181-3186.
37、Kazemi-Esfarjani P, Trifiro M A, Pinsky L. Evidence for a repressive function of the long polyglutamine tract in the human androgen receptor: possible pathogenetic relevance for the (CAG)n -expanded neuropathies. Hum Mol Genet 1995; 4 (4): 523.
38、Brinkmann AO. Molecular basis of androgen insensitivity [J]. Mol Cell Endocrinol, 2001; 179: 105-109.
39、Wallerand H, Remu2Martin A, Chabannes E, et al. Relationship between expansion of the CAG repeat in exon 1 of the androgen receptor gene and idiopathic male infertility [J]. Fertil Steril, 2001; 76: 769-774.
40、Suter NM, Malone KE, Daling JR, et al. Androgen receptor (CAG) n and (GGC) n polymorphisms and breast cancer risk in a population based case-control study of young women [J]. Cancer Epidemiol Biomarkers Prev, 2003; 12: 127-135.
41、Haiman CA, Brown M, Hankinson SE, et al. The androgen receptor CAG repeat polymorphism and risk of breast cancer in the Nurses' Health Study [J]. Cancer Res, 2002; 62: 1045-1049.
42、Yaron M, Levy T, Chetrit A, et al. The polymorphie CAG repeat in the androgen receptor gene in Jewish Israeli women with endometrial carcinoma [J]. Cancer, 2001; 92: 1190-1194.
43、郑强荪,舒青,冯蕾,等.动脉粥样硬化遗传易感性与HUMURA多态性的相关性[J].第四军医大学学报,2001;22(17):1590-1593.
44、Park TW, Felix JC, Wright TC. X chromosome inactivation and microsatellite instability in early and advanced bilateral ovarian carcinomas [J]. Cancer Res, 1995, 55(21): 4793-4796.
45、王刚,陈光椿,王晓慧,等.中国男性雄性激素受体基因(CAG)n重复多态性 的初步研究[J].中华医学遗传学杂志,2001,18(6):456-458.
46、李斌.刁小莉.张伟,等.雄激素受体第一外显子CAG重复序列长度多态性与子宫平滑肌瘤遗传易感性有关.第四军医大学学报 2004,25(9):836-840.