CYP11A1基因单核苷酸多态性与多囊卵巢综合征的关系
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摘要
目的CYP11A1基因单核苷酸多态性(SNP)与多囊卵巢综合征(PCOS)的关系。方法选择2005年10月至2010年3月于南京大学医学院附属鼓楼医院妇产科就诊的289例PCOS患者为研究对象,并纳入PCOS组;选择同期于本院参加健康体检的220例健康妇女纳入对照组。采用放射免疫法(RIA)检测患者血清中黄体生成素(LH)、促卵泡生成素(FSH)、雌二醇及睾酮水平等。采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)法对两组受试者CYP11A1基因SNP rs4077582和rs11632698位点进行基因分型,分析两组受试者的等位基因型频率及等位基因频率,并对年龄、人体质量指数(BMI)及血清性激素水平在不同基因型受试者中进行比较。本研究遵循的程序符合南京大学医学院附属鼓楼医院医学伦理委员会制定的伦理学标准,本研究得到该委员会批准,分组征得受试者本人及其家属的知情同意,并与之签署临床研究知情同意书。结果 1两组受试者的年龄、BMI等基本资料和FSH、LH、LH/FSH、雌二醇和睾酮等激素水平比较,差异均有统计学意义(P<0.001)。2CYP11A1基因SNP rs4077582等位基因型(CC、CT和TT)在PCOS组患者中的分布分别为24.9%、49.8%和25.3%,而在对照组中分别为34.5%、46.4%和19.1%,二者比较,差异有统计学意义(χ~2=6.399,P=0.041)。等位基因T在PCOS组中的频率显著高于对照组(χ~2=6.263,P=0.012)。而CYP11A1基因SNP rs11632698的等位基因型分布在两组受试者中比较,差异无统计学意义(χ~2=3.416,P=0.181)。3血清学检测结果显示,PCOS组中,CYP11A1基因SNP rs4077582位点3个不同基因型PCOS患者的年龄、BMI等基本资料和各性激素水平比较,差异均无统计学意义(P>0.05)。而在对照组中,LH与LH/FSH在3个不同基因型受试者(CC、CT、TT)间比较,差异有统计学意义(F=9.362、21.046,P<0.001)。结论 CYP11A1基因SNP rs4077582位点与PCOS的易感性有关,其作用机制可能是通过调节个体的LH水平最终影响雄激素合成速率,而SNP rs11632698则与PCOS发病无关。
Objective To discuss the relationship between CYP11A1 gene single nucleotide polymorphism(SNP)rs4077582and rs11632698 sites and polycystic ovarian syndrome(PCOS).Methods From October 2005 to March 2010,a total of 289 cases with PCOS who were admitted to Nanjing Drum Tower Hospital,Affiliated Hospital of Nanjing University Medical School were included into this study as PCOS group. Meanwhile,another 220 cases who received physical examination were included as control group.The serum luteinizing hormone(LH),follicle-stimulating hormone(FSH),estradiol and testosterone were detected by radioimmunoassay(RIA).Genotypings of the two SNPs(rs4077582and rs11632698)were conducted by the polymerase chain reactionrestriction fragment length polymorphism(PCR-RFLP)method.Furthermore,age,body mass index(BMI),and different sex hormone levels among different genotypings were also analyzed.The study protocol was approved by the Ethical Review Board of Investigation in Human Being of Nanjing Drum Tower Hospital,Affiliated Hospital of Nanjing University Medical School.Informed consent was obtained from each participates.Results 1 There were no significant differences between two groups in the aspects of age,BMI,FSH,LH,LH/FSH,estradiol and testosterone(P<0.001).2The genotypic distribution(CC,CT and TT)of CYP11A1 gene SNP rs4077582 site were 24.9%,49.8%and 25.3%in PCOS group,and 34.5%,46.4% and 19.1%in control group,which with significant difference(χ~2=6.399,P=0.041).The frequency of the T allele in PCOS group was significantly higher than that in control group(χ~2=6.263,P=0.012).However,no significant difference was found in terms of SNP rs11632698(χ~2=3.416,P=0.181).3LH and LH/FSH levels were different among the three genotypes(CC,CT,TT)in control group(F=9.362,21.046;P <0.001).Conclusions CYP11A1 gene SNP rs4077582 site is associated with the susceptibility of PCOS.Moreover,the genotype of SNP rs4077582 is associated with serum LH levels,which may alter the testosterone levels and ultimately lead to PCOS.
Objective To discuss the relationship between CYP11A1 gene single nucleotide polymorphism(SNP)rs4077582and rs11632698 sites and polycystic ovarian syndrome(PCOS).Methods From October 2005 to March 2010,a total of 289 cases with PCOS who were admitted to Nanjing Drum Tower Hospital,Affiliated Hospital of Nanjing University Medical School were included into this study as PCOS group. Meanwhile,another 220 cases who received physical examination were included as control group.The serum luteinizing hormone(LH),follicle-stimulating hormone(FSH),estradiol and testosterone were detected by radioimmunoassay(RIA).Genotypings of the two SNPs(rs4077582and rs11632698)were conducted by the polymerase chain reactionrestriction fragment length polymorphism(PCR-RFLP)method.Furthermore,age,body mass index(BMI),and different sex hormone levels among different genotypings were also analyzed.The study protocol was approved by the Ethical Review Board of Investigation in Human Being of Nanjing Drum Tower Hospital,Affiliated Hospital of Nanjing University Medical School.Informed consent was obtained from each participates.Results 1 There were no significant differences between two groups in the aspects of age,BMI,FSH,LH,LH/FSH,estradiol and testosterone(P<0.001).2The genotypic distribution(CC,CT and TT)of CYP11A1 gene SNP rs4077582 site were 24.9%,49.8%and 25.3%in PCOS group,and 34.5%,46.4% and 19.1%in control group,which with significant difference(χ~2=6.399,P=0.041).The frequency of the T allele in PCOS group was significantly higher than that in control group(χ~2=6.263,P=0.012).However,no significant difference was found in terms of SNP rs11632698(χ~2=3.416,P=0.181).3LH and LH/FSH levels were different among the three genotypes(CC,CT,TT)in control group(F=9.362,21.046;P <0.001).Conclusions CYP11A1 gene SNP rs4077582 site is associated with the susceptibility of PCOS.Moreover,the genotype of SNP rs4077582 is associated with serum LH levels,which may alter the testosterone levels and ultimately lead to PCOS.
引文
1 Dumesic DA,Abbott DH,Padmanabhan V.Polycystic ovary syndrome and its developmental origins[J].Rev Endocr Metab Disord,2007,8(2):127-141.
2 Bates GW Jr,Propst AM.Polycystic ovarian syndrome management options[J].Obstet Gynecol Clin North Am,2012,39(4):495-506.
3 Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group.Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome[J].Fertil Steril,2004,81(1):19-25.
4 Gaasenbeek M,Powell BL,Sovio U,et al.Large-scale analysis of the relationship between CYP11A promoter variation,polycystic ovarian syndrome,and serum testosterone[J].J Clin Endocrinol Metab,2004,89(5):2408-2413.
5 Jones MR,Italiano L,Wilson SG,et al.Polymorphism in HSD17B6is associated with key features of polycystic ovary syndrome[J].Fertil Steril,2006,86(5):1438-1446.
6 Bulun SE,Sebastian S,Takayama K,et al.The human CYP19(aromatase P450)gene:update on physiologic roles and genomic organization of promoters[J].J Steroid Biochem Mol Biol,2003,86(3-5):219-224.
7 Slominski AT,Kim TK,Li W,et al.The role of CYP11A1in the production of vitamin D metabolites and their role in the regulation of epidermal functions[J].J Steroid Biochem Mol Biol,2014,144(Pt A):28-39.
8 Wang Y,Wu X,Cao Y,et al.A microsatellite polymorphism(tttta)n in the promoter of the CYP11agene in Chinese women with polycystic ovary syndrome[J].Fertil Steril,2006,86(1):223-226.
9 Miller WL,Auchus RJ.The molecular biology,biochemistry,and physiology of human steroidogenesis and its disorders[J].Endocr Rev,2011,32(1):81-151.
10 Sidler D,Renzulli P,Schnoz C,et al.Colon cancer cells produce immunoregulatory glucocorticoids[J].Oncogene,2011,30(21):2411-2419.
11 Slominski A,Zbytek B,Nikolakis G,et al.Steroidogenesis in the skin:implications for local immune functions[J].J Steroid Biochem Mol Biol,2013,137:107-123.
12 Taves MD,Gomez-Sanchez CE,Soma KK.Extra-adrenal glucocorticoids and mineralocorticoids:evidence for local synthesis,regulation,and function[J].Am J Physiol Endocrinol Metab,2011,301(1):E11-E24.
13 Teplyuk NM,Zhang Y,Lou Y,et al.The osteogenic transcription factor runx2controls genes involved in sterol/steroid metabolism,including CYP11A1in osteoblasts[J].Mol Endocrinol,2009,23(6):849-861.
14 Tripodi G,Citterio L,Kouznetsova T,et al.Steroid biosynthesis and renal excretion in human essential hypertension:association with blood pressure and endogenous ouabain[J].Am J Hypertens,2009,22(4):357-363.
15 Setiawan VW,Cheng I,Stram DO,et al.A systematic assessment of common genetic variation in CYP11Aand risk of breast cancer[J].Cancer Res,2006,66(24):12019-12025.
16 Liu Y,Jiang H,He LY,Abnormal expression of uncoupling protein-2correlates with CYP11A1 expression in polycystic ovary syndrome[J].Reprod Fertil Dev,2011,23(4):520-526.
17 Sekar N,Veldhuis JD.Concerted transcriptional activation of the low density lipoprotein receptor gene by insulin and luteinizing hormone in cultured porcine granulosa-luteal cells:possible convergence of protein kinase a,phosphatidylinositol3 -kinase,and mitogen-activated protein kinase signaling pathways[J].Endocrinology,2001,142(7):2921-2928.
18 高贵花,曹云霞,易龙,等.胆固醇侧链裂解酶CYP11A1基因多态性与多囊卵巢综合征发病的相关性[J].中华妇产科杂志,2010,45(3):191-196.
19 Zhang CW,Zhang XL,Xia YJ,et al.Association between polymorphisms of the CYP11A1 gene and polycystic ovary syndrome in Chinese women[J].Mol Biol Rep,2012,39(8):8379-8385.
20 Falck B.Site of production of oestrogen in the ovary of the rat[J].Nature,1959,184(Suppl 14):1082.
21 Garmey JC,Guthrie HD,Garrett WM,et al.Localization and expression of low-density lipoprotein receptor,steroidogenic acute regulatory protein,cytochrome P450side-chain cleavage and P450 17-alpha-hydroxylase/C17-20 lyase in developing swine follicles:in situ molecular hybridization and immunocytochemical studies[J].Mol Cell Endocrinol,2000,170(1-2):57-65.
22 Nelson-DeGrave VL,Wickenheisser JK,Cockrell JE,et al.Valproate potentiates androgen biosynthesis in human ovarian theca cells[J].Endocrinology,2004,145(2):799-808.
23 李荔,张江宇,王晓琴,等.多囊卵巢综合征蛋白质组学的研究现状[J/CD].中华妇幼临床医学杂志:电子版,2015,11(1):86-89.
24 高艳,张少华.阴道超声诊断多囊卵巢综合征60例分析[J].成都医学院学报,2013,8(4):462-464.
2 Bates GW Jr,Propst AM.Polycystic ovarian syndrome management options[J].Obstet Gynecol Clin North Am,2012,39(4):495-506.
3 Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group.Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome[J].Fertil Steril,2004,81(1):19-25.
4 Gaasenbeek M,Powell BL,Sovio U,et al.Large-scale analysis of the relationship between CYP11A promoter variation,polycystic ovarian syndrome,and serum testosterone[J].J Clin Endocrinol Metab,2004,89(5):2408-2413.
5 Jones MR,Italiano L,Wilson SG,et al.Polymorphism in HSD17B6is associated with key features of polycystic ovary syndrome[J].Fertil Steril,2006,86(5):1438-1446.
6 Bulun SE,Sebastian S,Takayama K,et al.The human CYP19(aromatase P450)gene:update on physiologic roles and genomic organization of promoters[J].J Steroid Biochem Mol Biol,2003,86(3-5):219-224.
7 Slominski AT,Kim TK,Li W,et al.The role of CYP11A1in the production of vitamin D metabolites and their role in the regulation of epidermal functions[J].J Steroid Biochem Mol Biol,2014,144(Pt A):28-39.
8 Wang Y,Wu X,Cao Y,et al.A microsatellite polymorphism(tttta)n in the promoter of the CYP11agene in Chinese women with polycystic ovary syndrome[J].Fertil Steril,2006,86(1):223-226.
9 Miller WL,Auchus RJ.The molecular biology,biochemistry,and physiology of human steroidogenesis and its disorders[J].Endocr Rev,2011,32(1):81-151.
10 Sidler D,Renzulli P,Schnoz C,et al.Colon cancer cells produce immunoregulatory glucocorticoids[J].Oncogene,2011,30(21):2411-2419.
11 Slominski A,Zbytek B,Nikolakis G,et al.Steroidogenesis in the skin:implications for local immune functions[J].J Steroid Biochem Mol Biol,2013,137:107-123.
12 Taves MD,Gomez-Sanchez CE,Soma KK.Extra-adrenal glucocorticoids and mineralocorticoids:evidence for local synthesis,regulation,and function[J].Am J Physiol Endocrinol Metab,2011,301(1):E11-E24.
13 Teplyuk NM,Zhang Y,Lou Y,et al.The osteogenic transcription factor runx2controls genes involved in sterol/steroid metabolism,including CYP11A1in osteoblasts[J].Mol Endocrinol,2009,23(6):849-861.
14 Tripodi G,Citterio L,Kouznetsova T,et al.Steroid biosynthesis and renal excretion in human essential hypertension:association with blood pressure and endogenous ouabain[J].Am J Hypertens,2009,22(4):357-363.
15 Setiawan VW,Cheng I,Stram DO,et al.A systematic assessment of common genetic variation in CYP11Aand risk of breast cancer[J].Cancer Res,2006,66(24):12019-12025.
16 Liu Y,Jiang H,He LY,Abnormal expression of uncoupling protein-2correlates with CYP11A1 expression in polycystic ovary syndrome[J].Reprod Fertil Dev,2011,23(4):520-526.
17 Sekar N,Veldhuis JD.Concerted transcriptional activation of the low density lipoprotein receptor gene by insulin and luteinizing hormone in cultured porcine granulosa-luteal cells:possible convergence of protein kinase a,phosphatidylinositol3 -kinase,and mitogen-activated protein kinase signaling pathways[J].Endocrinology,2001,142(7):2921-2928.
18 高贵花,曹云霞,易龙,等.胆固醇侧链裂解酶CYP11A1基因多态性与多囊卵巢综合征发病的相关性[J].中华妇产科杂志,2010,45(3):191-196.
19 Zhang CW,Zhang XL,Xia YJ,et al.Association between polymorphisms of the CYP11A1 gene and polycystic ovary syndrome in Chinese women[J].Mol Biol Rep,2012,39(8):8379-8385.
20 Falck B.Site of production of oestrogen in the ovary of the rat[J].Nature,1959,184(Suppl 14):1082.
21 Garmey JC,Guthrie HD,Garrett WM,et al.Localization and expression of low-density lipoprotein receptor,steroidogenic acute regulatory protein,cytochrome P450side-chain cleavage and P450 17-alpha-hydroxylase/C17-20 lyase in developing swine follicles:in situ molecular hybridization and immunocytochemical studies[J].Mol Cell Endocrinol,2000,170(1-2):57-65.
22 Nelson-DeGrave VL,Wickenheisser JK,Cockrell JE,et al.Valproate potentiates androgen biosynthesis in human ovarian theca cells[J].Endocrinology,2004,145(2):799-808.
23 李荔,张江宇,王晓琴,等.多囊卵巢综合征蛋白质组学的研究现状[J/CD].中华妇幼临床医学杂志:电子版,2015,11(1):86-89.
24 高艳,张少华.阴道超声诊断多囊卵巢综合征60例分析[J].成都医学院学报,2013,8(4):462-464.
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