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Clinical Study of the Impact of ACE I/D Gene Variation on the Clinical Parameters of Patients with Polycystic Ovary Syndrome
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摘要:目的 探讨血管紧张素Ⅰ转换酶（angiotensin Ⅰ-converting enzyme, ACE）的基因I/D多态性与多囊卵巢综合征（polycystic ovary syndrome, PCOS）发病的遗传风险的关系，评价该基因变异对PCOS患者临床特征、激素、代谢和氧化应激指标的影响。方法 采用回顾性病例-对照研究，选择2006−2019年在四川大学华西第二医院生殖内分泌科门诊就诊的17～44岁PCOS患者1 020例及同期就诊的对照妇女825例纳入研究，使用聚合酶链反应（PCR）和琼脂糖凝胶电泳对ACE I/D基因进行分型。选择PCOS组667例和对照组527例进行基因型与生殖激素、糖脂代谢和氧化应激相关指标分析。结果 对照组与PCOS组基因型频率分布均符合Hardy-Weinberg平衡（P均>0.05），具有群体代表性。PCOS组与对照组间基因型和等位基因频率差异无统计学意义。在调整年龄和体质量指数之后，无论是在PCOS组内还是在对照组内，各基因型间临床特征差异均无统计学意义。在PCOS组中，与II基因型亚组比较，ID基因型亚组有更低的黄体生成素（luteinizing hormone, LH）/卵泡刺激素（follicle-stimulating hormone, FSH）比值，DD基因型亚组稳态模型胰岛素抵抗指数（homeostatic model assessment of insulin resistance, HOMA-IR）与血清丙二醛（malondialdehyde, MDA）水平增高；与ID基因型亚组比较，DD基因型亚组血清性激素结合球蛋白（sex hormone-binding globulin, SHBG）水平降低，但总胆固醇（total cholesterol, TC）与低密度脂蛋白胆固醇（low-density lipoprotein cholesterol, LDL-C）水平增高。在对照组中，II基因型亚组比DD基因型亚组具有更高的血清总氧化状态（total oxidant status, TOS）水平。结论 ACE基因I/D变异不是PCOS发生的遗传危险因素。ACE基因I/D变异可能与PCOS患者胰岛素抵抗、异常脂血症、高雄激素血症和氧化应激的发生有关。Abstract:Objective To investigate the relationship between angiotensin Ⅰ-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism and the genetic risks for polycystic ovary syndrome (PCOS) and to evaluate the impact of ACE I/D genotypes on clinical, hormonal, metabolic and oxidative stress parameters in patients with PCOS.Methods This was a retrospective case-control study involving a total of 1 020 PCOS patients and 825 female controls who visited the outpatient clinic of the Department of Reproductive Endocrinology, West China Second Hospital of Sichuan University between 2006 and 2019. The ages of the subjects ranged between 17 and 44. The ACE I/D genotypes were determined by polymerase chain reaction (PCR) and gel electrophoresis. 667 PCOS patients and 527 controls were selected for an analysis of their genotypes and the hormonal, metabolic and oxidative stress parameters.Results The genotype distributions of the ACE I/D single nucleotide polymorphism was in Hardy-Weinberg equilibrium in both the PCOS group and the control group (all P>0.05), which was representative of the population. There were no statistically significant differences in genotype and allele frequencies between the PCOS and the control groups (P>0.05). After adjusting for both age and body mass index (BMI), there was no statistically significant difference in clinical characteristics among all genotypes in either the PCOS group or the control group. In the PCOS group, compared with the II genotype subgroup, the ID genotype subgroup had lower luteinizing hormone (LH)/follicle-stimulating hormone (FSH) ratio, while the DD genotype subgroup had higher homeostatic model assessment of insulin resistance (HOMA-IR) and malondialdehyde (MDA) levels. Compared with the ID genotype subgroup, the DD genotype subgroup had lower serum sex hormone binding globulin (SHBG) level, but higher total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels ( P<0.05). In the control group, II genotype subgroup had a higher level of total oxidant status (TOS) than that of the DD genotype subgroup.Conclusion
ACE I/D genetic polymorphism is not associated with risks for PCOS. The I/D variation of ACE gene may be related to insulin resistance, dyslipidaemia, hyperandrogenemia and oxidative stress in PCOS patients. -
多囊卵巢综合征（polycystic ovary syndrome, PCOS）是一种内分泌代谢紊乱性疾病，全世界育龄期女性中的患病率为6%～20%[1]。PCOS以排卵功能障碍、临床或/和生化高雄激素血症以及B超卵巢多囊样改变为特征，常伴有胰岛素抵抗、糖脂代谢紊乱、肥胖、氧化应激增加、长期低级慢性炎症，明显增加抑郁症、2型糖尿病、妊娠期并发症、远期心血管疾病发生的危险性[1-5]。PCOS的病因至今尚不明确，研究表明它可能是一种受表观遗传影响的复杂的多基因疾病，此外可能还与环境因素有关[1, 6]。
血管紧张素Ⅰ转换酶（angiotensin Ⅰ-converting enzyme, ACE）是肾素-血管紧张素系统（renin-angiotensin system, RAS）的关键酶，催化无活性的血管紧张素Ⅰ转化为高活性的血管紧张素Ⅱ（angiotensin Ⅱ, Ang Ⅱ），在调节RAS相关激素水平和多种生理、病理过程中起重要作用[7-8]。ACE基因位于染色体17q23区，由26个外显子和25个内含子构成，定位于第16内含子的一个287 bp 的Alu重复序列的插入（insertion, I）与缺失（deletion, D）多态性（rs4646994）与血清ACE浓度有关，ACE浓度：DD>ID>II基因型[9]。此外，该基因多态性与心脑血管疾病、肾脏疾病、糖尿病并发症等有关[7, 10]。
研究表明RAS和ACE的异常可能促进PCOS发生与发展，在PCOS患者发生高雄激素血症和胰岛素抵抗的过程中起重要作用[8, 11]。迄今已有多篇文章报道了ACE I/D基因多态性与PCOS的关系，但结果并不一致，由于多数研究样本量较小，统计学效率偏低，难以得出明确的结论[8, 12-14]。Ang Ⅱ具有促进氧化应激的作用[15]。PCOS患者常伴有氧化应激的增加，然而ACE I/D变异与PCOS氧化应激的关系仍不清楚。在本研究中，我们采用了一个较大的样本量，分析ACE I/D多态性与PCOS发生的相关性，探讨这个基因变异对临床特征、激素、代谢和氧化应激的影响。
1. 对象与方法
1.1 研究对象
采用回顾性病例-对照研究。选择2006−2019年在四川大学华西第二医院生殖内分泌科门诊就诊的17～44岁PCOS患者1 020例及同期就诊的17～44岁对照妇女825例纳入研究。该研究经四川大学华西第二医院伦理委员会批准（批准号2014-014～PF），所有研究对象均签署了知情同意书。
每个纳入研究的患者均符合2003年在鹿特丹修订的欧洲人类生殖与胚胎学会（European Society of Human Reproduction and Embryology, ESHRE）和美国生殖医学学会（American Society for Reproductive Medicine, ASRM）PCOS诊断标准[16]：在排除其他引起高雄激素血症的疾病后，具有下列条件中的2项，则可确诊为PCOS[17-18]：①稀发排卵和/或不排卵；②临床和/或生化高雄激素血症；③超声检查出多囊卵巢。对于小于20岁的女性而言，雄激素增多症为PCOS确诊的必备条件[19]。对照组为因输卵管梗阻或丈夫不育而不孕的妇女或健康妇女。所有对照女性临床健康，月经周期正常（22～35 d），血液中雄性激素水平正常〔总睾酮（total testosterone, TT）<0.75 ng/mL或游离雄激素指数（free androgen index, FAI）<9.5〕，体格检查无明显痤疮或多毛（F-G评分<6），B超测定卵巢形态正常。
研究对象均排除感染性疾病、自身免疫性/炎症性疾病、肿瘤、心血管疾病、甲状腺功能障碍、肝肾疾病、高泌乳素血症、子宫内膜异位症、促性腺功能低下或早发性卵巢功能不全等。
在进行基因型与生殖激素、糖脂代谢和氧化应激相关指标分析时，为了避免相关干扰因素的影响，要求被纳入的研究对象：在3个月内未服用影响糖脂代谢或激素水平的药物；为非吸烟者；处于月经周期的卵泡早、中期（孕酮水平<9.54 nmol/L）；对照组女性非糖尿病患者。在所有研究对象中，符合上述要求的PCOS患者有667例，对照妇女有527例。
1.2 方法
1.2.1 临床资料与标本收集
收集与统计PCOS组和对照组女性的临床资料，包括：年龄、收缩压（systolic blood pressure, SBP）、体质量、腰围、身高、舒张压（diastolic blood pressure, DBP）、臀围、月经情况、多毛F-G评分（Ferriman-Gallwey score, F-G score）、既往史、家族史、痤疮情况、卵巢体积[17]（单位为cm3），计算体质量指数（body mass index, BMI）和腰臀比（waist-hip ratio, WHR）。
抽取空腹12 h后的肘静脉血，于4 ℃ 1 500 r/min离心15 min，分别吸取上层血浆和血清，分装后储存于−80 ℃冰箱，用于测定激素、代谢和氧化应激指标。血细胞保存在4 ℃冰箱，用于提取基因组DNA。
1.2.2 基因型分析
ACE基因I/D多态性的PCR扩增引物参照文献[20]：ACE上游引物：5′-CTGGAGACCACTCCCATCCTTTCT-3′，下游引物：5′-GATGTGGCCATCACATTCGTCAGAT-3′，由上海生工生物有限公司合成。PCR反应体系：2 mmol/L MgC12、2.5 μL 10×PCR缓冲液、0.2 mmol/L dNTP、5%二甲基亚砜、各0.2 µmol/L上、下游引物、0.625 U TaqDNA聚合酶（Thermo）、DNA模板2.0 µL（30～80 ng），共25 μL。PCR扩增：95 ℃ 3 min，94 ℃ 1 min，58 ℃ 1 min, 72 ℃ 2 min，32个循环后，在72 ℃条件下延伸7 min。配制2.5%琼脂糖凝胶（含Genecolour荧光试剂）待其凝固后，取10 μL产物进行电泳通过扩增片段确定基因型。其中I等位基因扩增片段为490 bp，D等位基因扩增片段为190 bp。为了控制基因分型质量，随机选择30%以上的DNA样本由不同的操作人员再次进行基因分型。
1.2.3 激素、代谢与氧化应激指标分析
激素和代谢指标送往四川大学华西第二医院检验科测定。使用化学发光法测定血浆胰岛素（insulin, Ins）、TT、血清卵泡刺激素（follicle-stimulating hormone, FSH）、黄体生成素（luteinizing hormone, LH）、性激素结合球蛋白（sex hormone-binding globulin, SHBG）。采用酶法试剂盒测定血糖（glucose, Glu）、高密度脂蛋白胆固醇（high-density lipoprotein cholesterol, HDL-C）、三酰甘油（triglycerides, TG）、低密度脂蛋白胆固醇（low-density lipoprotein cholesterol, LDL-C）和总胆固醇（total cholesterol, TC）。
血清丙二醛（malondialdehyde, MDA）浓度和总抗氧化能力（total antioxidant capacity, T-AOC）分别使用相应的试剂盒（南京建成生物工程研究所）测定。血清总氧化状态（total oxidant status, TOS）采用本室建立的微孔板比色方法[5]测定。
上述所有测定的批内变异系数均小于5%，批间变异系数均小于10%。
FAI=（TT×100）/SHBG，稳态模型评估胰岛素抵抗指数（homeostatic model assessment of insulin resistance, HOMA-IR）的计算方法参考以往研究[21]。
1.2.4 统计学方法
PCOS组1 020例和对照组825例是纳入统计分析的总例数，也是进行基因分型的例数；PCOS组667例和对照组527例是进行基因型与生殖激素、糖脂代谢和氧化应激相关指标分析时，排除了部分样本后的例数。采用独立样本t检验和非参数检验（Mann-Whitney U检验），分别用来分析PCOS组与对照组女性之间的连续变量和非正态分布变量。使用卡方分析来评估基因型分布是否符合Hardy-Weinberg平衡以及两组之间的基因型和等位基因频率差异。不同基因型亚组间临床特征、激素、代谢及氧化应激指标的比较采用方差分析。校正年龄、BMI后，不同基因型亚组间相关指标的比较采用协方差分析。P<0.05为差异有统计学意义。
2. 结果
2.1 ACE I/D基因型和等位基因频率的比较
对照组与PCOS组基因型频率分布均符合Hardy-Weinberg平衡（P均>0.05），具有群体代表性。如表1所示，I等位基因频率在PCOS组和对照组中分别为0.644和0.653，D等位基因频率在PCOS组和对照组中分别为0.356和0.347。卡方分析表明ACE基因I/D基因型和等位基因频率在两组间差异无统计学意义（P>0.05）。
表 1 PCOS与对照组之间ACE基因I/D基因型和等位基因频率分布Table 1. Frequencies of ACE gene I/D genotype and allele in PCOS patients compared with the controlsIndex Frequencies (case) Controls
(n=825)PCOS patients
(n=1 020)χ2/P Genotype χ2=0.881，P=0.644 II 0.425 (351) 0.421 (429) ID 0.456 (376) 0.446 (455) DD 0.119 (98) 0.133 (136) Allele χ2=0.377，P=0.539 I 0.653 (1 078) 0.644 (1 313) D 0.347 (572) 0.356 (727) 2.2 ACE I/D多态性不同基因型亚组间临床特征的比较
如表2所示，与对照组相比，PCOS组年龄降低（P<0.05），BMI、WC、WHR、F-G score、痤疮分级评分、SBP、DBP和卵巢体积均升高（P<0.05）。在调整年龄和BMI之后，无论是在PCOS组内，还是在对照组内，不同基因型间临床特征差异均无统计学意义。
表 2 ACE I/D多态性不同基因型亚组间临床特征的比较Table 2. Comparison of clinical features of different genotypes of ACE I/D polymorphism subgroupsIndex Controls PCOS patients Total (n=825) II (n=229) ID (n=241) DD (n=57) Total (n=1 020) II (n=274) ID (n=298) DD (n=95) Age/yr. 28.22±4.10 27.53±3.98 28.05±4.13 29.44±4.32 25.08±4.20# 25.02±4.12 25.02±4.18 25.00±4.74 BMI/(kg/m2) 21.17±2.86 21.06±2.75 21.03±2.59 20.99±3.18 22.90±4.03# 22.82±4.11 23.51±4.30 23.28±4.44 WC/cm 73.79±8.13 73.29±8.34 73.47±7.60 73.68±9.12 79.19±11.05# 78.70±11.22 80.94±11.32 80.43±11.91 WHR 0.82±0.06 0.81±0.06 0.81±0.06 0.81±0.06 0.85±0.07# 0.85±0.08 0.86±0.07 0.86±0.07 F-G score 0.26±0.76 0.28±0.76 0.26±0.75 0.11±0.36 1.71±2.04# 1.72±2.02 1.71±2.09 1.70±2.08 Acne grade score 0.14±0.35 0.15±0.36 0.14±0.35 0.07±0.26 0.64±0.89# 0.69±0.91 0.59±0.89 0.70±0.94 SBP/mmHg 112.62±11.36 112.14±10.72 112.69±10.82 112.95±13.61 114.25±10.51# 113.97±10.09 115.88±11.10 113.99±10.89 DBP/mmHg 73.56±8.91 73.74±8.45 73.33±8.36 72.33±8.99 75.43±8.72# 75.48±9.51 76.47±8.47 74.34±8.91 Ovarian volume/cm3 7.40±2.75 7.18±2.46 8.15±3.12 7.13±2.07 9.91±4.05# 10.24±4.02 10.04±4.14 10.15±3.90 BMI: Body mass index; WC: Waist circumference; WHR: Waist-hip ratio; F-G score: Ferriman-Gallwey score; SBP: Systolic blood pressure; DBP: Diastolic blood pressure. 1 mmHg=0.133 kPa. # P<0.05, vs. total controls. 2.3 ACE I/D多态性不同基因型亚组间代谢指标分析
如表3所示，调整年龄和BMI之后，与对照组相比，PCOS组血浆胰岛素、HOMA-IR、TG、TC和LDL-C均上升（P<0.05），HDL-C降低（P<0.05）。在进行不同基因型间代谢指标分析时，PCOS组中，与II基因型亚组相比，DD基因型亚组具有更高的HOMA-IR水平（P<0.05）；与ID基因型亚组相比，DD基因型亚组具有更高的TC和LDL-C水平（P<0.05）。对照组中代谢指标在不同基因型间无明显差异（P>0.05）。
表 3 ACE I/D多态性不同基因型亚组间代谢水平的比较Table 3. Comparison of metabolic levels of different genotypes of ACE I/D polymorphisms subgroupsIndex Controls PCOS patients Total (n=825) II (n=229) ID (n=241) DD (n=57) Total (n=1 020) II (n=274) ID (n=298) DD (n=95) Fasting Ins/(pmol/L) 62.30±35.71 62.18±36.81 63.42±35.41 58.05±32.72 105.15±71.82# 97.35±58.32 110.28±75.88 112.05±91.48 Fasting Glu/(mmol/L) 5.23±0.47 5.23±0.47 5.26±0.45 5.18±0.59 5.36±0.86 5.32±0.62 5.34±0.85 5.48±1.35 HOMA-IR 2.21±1.29 2.23±1.30 2.24±1.31 2.09±1.12 3.78±3.06# 3.43±2.31 3.93±3.18 4.29±4.31§ TG/(mmol/L) 1.04±0.89 1.00±0.63 1.09±1.15 0.98±0.38 1.44±1.38# 1.43±1.39 1.41±1.03 1.58±2.12 TC/(mmol/L) 4.25±0.72 4.26±0.68 4.25±0.74 4.24±0.78 4.42±0.81# 4.44±0.80 4.35±0.83 4.61±0.75△ HDL-C/(mmol/L) 1.51±0.32 1.51±0.32 1.50±0.32 1.52±0.36 1.38±0.34# 1.40±0.34 1.35±0.32 1.40±0.41 LDL-C/(mmol/L) 2.36±0.63 2.38±0.62 2.35±0.64 2.34±0.67 2.56±0.76# 2.54±0.75 2.54±0.77 2.71±0.73△ Glu: Glucose; HDL-C: High-density lipoprotein cholesterol; HOMA-IR: Homeostatic model assessment of insulin resistance; Ins: Insulin; LDL-C: Low-density lipoprotein cholesterol; TC: Total cholesterol; TG: Triglycerides. Comparisons of all parameters were corrected for differences in age and BMI between the two subgroups, except for the parameters of age and BMI. △P <0.05, vs. the ID genotype subgroup in PCOS patients; §P<0.05, vs. the II genotype subgroup in PCOS patients. #P<0.05, vs. total controls. 2.4 ACE I/D多态性不同基因型亚组间激素水平和氧化应激指标分析
如表4所示，在调整年龄和BMI之后，与对照组相比，PCOS组TT、FAI、LH/FSH等激素指标，TOS、T-AOC、OSI、MDA等氧化应激指标均上升（P<0.05），SHBG水平降低（P<0.05）。
表 4 ACE I/D多态性不同基因型亚组间激素和氧化应激水平的比较Table 4. Comparison of hormone and oxidative stress levels between different genotypes of ACE I/D polymorphism subgroupsIndex Controls PCOS patients Total (n=825) II (n=229) ID (n=241) DD (n=57) Total (n=1 020) II (n=274) ID (n=298) DD (n=95) Hormonal levels TT/(nmol/L) 1.47±0.52 1.49±0.50 1.47±0.53 1.41±0.51 2.34±0.77# 2.34±0.73 2.35±0.82 2.31±0.73 SHBG/(nmol/L) 55.06±27.26 58.62±28.23 51.84±24.89 55.70±31.94 33.49±19.26# 34.97±18.63 33.28±20.37 29.82±16.98△ FAI 3.26±2.07 3.08±1.99 3.42±2.07 3.26±2.36 9.76±7.03# 8.94±6.39 10.20±7.36 10.73±7.56 LH/FSH 1.18±1.30 1.21±0.98 1.15±1.29 1.19±0.94 2.26±1.23# 2.38±1.26 2.12±1.18§ 2.34±1.25 Oxidative stress parameters TOS/(nmol H2O2 Equiv./mL) 11.48±5.38 12.01±5.35 11.26±5.69 10.20±3.83* 15.13±10.58# 15.40±11.67 14.61±8.94 15.95±11.93 T-AOC/(U/mL/min) 14.51±2.67 14.64±2.48 14.48±2.71 14.16±3.18 15.77±3.09# 15.80±3.11 15.78±3.07 15.64±3.10 OSI 0.80±0.41 0.82±0.39 0.79±0.45 0.73±0.29 0.99±0.79# 0.99±0.79 0.97±0.78 1.04±0.81 MDA/(nmol/mL) 3.70±1.09 3.79±1.08 3.66±1.12 3.51±1.02 4.37±1.32# 4.25±1.32 4.42±1.32 4.55±1.29§ FAI: Free androgen index; FSH: Follicle-stimulating hormone; LH: Luteinizing hormone; MDA: Malondialdehyde; OSI: Oxidative stress index; SHBG: Sex hormone-binding globulin; T-AOC: Total antioxidant capacity; TOS: Total oxidant status; TT: Total testosterone. Comparisons of all parameters were corrected for differences in age and BMI between the two subgroups. * P<0.05, vs. the II genotype subgroup in controls; △ P<0.05, vs. the ID genotype subgroup in PCOS patients; § P<0.05, vs. the II genotype subgroup in PCOS patients; # P<0.05, vs. total controls. 在进行不同基因型间激素指标分析时，PCOS组中，DD基因型亚组SHBG水平低于ID基因型亚组（P<0.05）；ID基因型亚组LH/FSH比值低于II基因型亚组（P<0.05）。
在进行不同基因型间氧化应激指标分析时，PCOS组中DD基因型亚组MDA水平高于II基因型亚组（P<0.05），对照组中DD基因型亚组TOS水平低于II基因型亚组（P<0.05）。
3. 讨论
ACE基因I/D多态性与PCOS关系的报道并没有得出统一的结论。在白种人与印度人群，DD基因型、ID基因型或（和）D等位基因增加PCOS发生的危险性，是PCOS的遗传危险因素[8, 12-13]。然而，几个较小样本量的研究未能证明ACE基因I/D多态性与中国人PCOS的发生有关[8, 22]。本研究以一个较大的样本量证明ACE I/D变异不是PCOS发生的遗传危险因素，该结果支持以前在中国人群中的研究。在不同种族人群中得出的不同结果，进一步说明了单一基因在PCOS中的低效性，因此，探讨已知基因在PCOS中的作用和地位，有助于对该基因多态性与PCOS的关系提供更全面的认识，对进一步寻找未知基因，阐明其分子生物学机制具有重要意义。
雄激素增多症是PCOS发病机制中的一个关键因素。ACE是调控RAS活性的关键酶，PCOS患者RAS重要成分血清总肾素明显被上调[11]，增加RAS活性可能影响下丘脑-垂体-卵巢，提高LH水平，导致卵泡发育与排卵的异常，促进PCOS高雄激素血症的发生[8, 12]。ACE抑制剂（lisinopril）治疗可降低高血压PCOS女性的高雄激素血症[11]。有报道显示在PCOS患者中，ACE基因D等位基因携带者比II基因型携带者有更高的血清LH/FSH比值和睾酮水平[23]。本研究发现在PCOS患者中，DD基因型携带者比ID基因型携带者有更低的SHBG水平，提示ACE基因I/D变异可能通过影响游离睾酮水平，促进PCOS高雄激素血症的发生。
胰岛素抵抗在PCOS发病机制中起重要作用。ACE催化产物Ang Ⅱ可以通过改变胰岛素信号通路，减少骨骼肌血流量来降低机体对胰岛素的敏感性[24]。而ACE抑制剂（captopril）能够增加高血压患者对胰岛素的敏感性[11]。对土耳其PCOS患者的研究表明ACE基因DD基因型与增加空腹胰岛素和HOMA-IR有关[25]。本研究表明，在PCOS患者中，携带DD基因型比携带II基因型有更高的HOMA-IR。已有的研究结果支持ACE基因I/D多态性可能通过改变PCOS患者对胰岛素的敏感性来参与PCOS胰岛素抵抗的发生与发展。
在本研究中，我们发现在PCOS患者中，携带DD基因型比携带II基因型有更高的MDA水平，而对照组中，携带II基因型比DD基因型增加TOS水平，倾向于增加MDA水平，提示ACE基因I/D多态性可能影响机体氧化应激状态，在PCOS氧化应激的发生中发挥一定作用。
总之，本研究结果表明ACE基因变异可能与PCOS患者胰岛素抵抗、异常脂血症、高雄激素血症和氧化应激的发生有关。然而，这些假设还需要进一步的研究来证实。此外，我们没有进行血管紧张素Ⅰ转换酶活性和ACE基因表达量的测定。在不同基因型的患者中检测这种酶活性和基因表达量的进一步研究可能为潜在的遗传关联机制提供线索。
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表 1 PCOS与对照组之间ACE基因I/D基因型和等位基因频率分布
Table 1 Frequencies of ACE gene I/D genotype and allele in PCOS patients compared with the controls
Index Frequencies (case) Controls
(n=825)PCOS patients
(n=1 020)χ2/P Genotype χ2=0.881，P=0.644 II 0.425 (351) 0.421 (429) ID 0.456 (376) 0.446 (455) DD 0.119 (98) 0.133 (136) Allele χ2=0.377，P=0.539 I 0.653 (1 078) 0.644 (1 313) D 0.347 (572) 0.356 (727) 
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表 2 ACE I/D多态性不同基因型亚组间临床特征的比较
Table 2 Comparison of clinical features of different genotypes of ACE I/D polymorphism subgroups
Index Controls PCOS patients Total (n=825) II (n=229) ID (n=241) DD (n=57) Total (n=1 020) II (n=274) ID (n=298) DD (n=95) Age/yr. 28.22±4.10 27.53±3.98 28.05±4.13 29.44±4.32 25.08±4.20# 25.02±4.12 25.02±4.18 25.00±4.74 BMI/(kg/m2) 21.17±2.86 21.06±2.75 21.03±2.59 20.99±3.18 22.90±4.03# 22.82±4.11 23.51±4.30 23.28±4.44 WC/cm 73.79±8.13 73.29±8.34 73.47±7.60 73.68±9.12 79.19±11.05# 78.70±11.22 80.94±11.32 80.43±11.91 WHR 0.82±0.06 0.81±0.06 0.81±0.06 0.81±0.06 0.85±0.07# 0.85±0.08 0.86±0.07 0.86±0.07 F-G score 0.26±0.76 0.28±0.76 0.26±0.75 0.11±0.36 1.71±2.04# 1.72±2.02 1.71±2.09 1.70±2.08 Acne grade score 0.14±0.35 0.15±0.36 0.14±0.35 0.07±0.26 0.64±0.89# 0.69±0.91 0.59±0.89 0.70±0.94 SBP/mmHg 112.62±11.36 112.14±10.72 112.69±10.82 112.95±13.61 114.25±10.51# 113.97±10.09 115.88±11.10 113.99±10.89 DBP/mmHg 73.56±8.91 73.74±8.45 73.33±8.36 72.33±8.99 75.43±8.72# 75.48±9.51 76.47±8.47 74.34±8.91 Ovarian volume/cm3 7.40±2.75 7.18±2.46 8.15±3.12 7.13±2.07 9.91±4.05# 10.24±4.02 10.04±4.14 10.15±3.90 BMI: Body mass index; WC: Waist circumference; WHR: Waist-hip ratio; F-G score: Ferriman-Gallwey score; SBP: Systolic blood pressure; DBP: Diastolic blood pressure. 1 mmHg=0.133 kPa. # P<0.05, vs. total controls.
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表 3 ACE I/D多态性不同基因型亚组间代谢水平的比较
Table 3 Comparison of metabolic levels of different genotypes of ACE I/D polymorphisms subgroups
Index Controls PCOS patients Total (n=825) II (n=229) ID (n=241) DD (n=57) Total (n=1 020) II (n=274) ID (n=298) DD (n=95) Fasting Ins/(pmol/L) 62.30±35.71 62.18±36.81 63.42±35.41 58.05±32.72 105.15±71.82# 97.35±58.32 110.28±75.88 112.05±91.48 Fasting Glu/(mmol/L) 5.23±0.47 5.23±0.47 5.26±0.45 5.18±0.59 5.36±0.86 5.32±0.62 5.34±0.85 5.48±1.35 HOMA-IR 2.21±1.29 2.23±1.30 2.24±1.31 2.09±1.12 3.78±3.06# 3.43±2.31 3.93±3.18 4.29±4.31§ TG/(mmol/L) 1.04±0.89 1.00±0.63 1.09±1.15 0.98±0.38 1.44±1.38# 1.43±1.39 1.41±1.03 1.58±2.12 TC/(mmol/L) 4.25±0.72 4.26±0.68 4.25±0.74 4.24±0.78 4.42±0.81# 4.44±0.80 4.35±0.83 4.61±0.75△ HDL-C/(mmol/L) 1.51±0.32 1.51±0.32 1.50±0.32 1.52±0.36 1.38±0.34# 1.40±0.34 1.35±0.32 1.40±0.41 LDL-C/(mmol/L) 2.36±0.63 2.38±0.62 2.35±0.64 2.34±0.67 2.56±0.76# 2.54±0.75 2.54±0.77 2.71±0.73△ Glu: Glucose; HDL-C: High-density lipoprotein cholesterol; HOMA-IR: Homeostatic model assessment of insulin resistance; Ins: Insulin; LDL-C: Low-density lipoprotein cholesterol; TC: Total cholesterol; TG: Triglycerides. Comparisons of all parameters were corrected for differences in age and BMI between the two subgroups, except for the parameters of age and BMI. △P <0.05, vs. the ID genotype subgroup in PCOS patients; §P<0.05, vs. the II genotype subgroup in PCOS patients. #P<0.05, vs. total controls.
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表 4 ACE I/D多态性不同基因型亚组间激素和氧化应激水平的比较
Table 4 Comparison of hormone and oxidative stress levels between different genotypes of ACE I/D polymorphism subgroups
Index Controls PCOS patients Total (n=825) II (n=229) ID (n=241) DD (n=57) Total (n=1 020) II (n=274) ID (n=298) DD (n=95) Hormonal levels TT/(nmol/L) 1.47±0.52 1.49±0.50 1.47±0.53 1.41±0.51 2.34±0.77# 2.34±0.73 2.35±0.82 2.31±0.73 SHBG/(nmol/L) 55.06±27.26 58.62±28.23 51.84±24.89 55.70±31.94 33.49±19.26# 34.97±18.63 33.28±20.37 29.82±16.98△ FAI 3.26±2.07 3.08±1.99 3.42±2.07 3.26±2.36 9.76±7.03# 8.94±6.39 10.20±7.36 10.73±7.56 LH/FSH 1.18±1.30 1.21±0.98 1.15±1.29 1.19±0.94 2.26±1.23# 2.38±1.26 2.12±1.18§ 2.34±1.25 Oxidative stress parameters TOS/(nmol H2O2 Equiv./mL) 11.48±5.38 12.01±5.35 11.26±5.69 10.20±3.83* 15.13±10.58# 15.40±11.67 14.61±8.94 15.95±11.93 T-AOC/(U/mL/min) 14.51±2.67 14.64±2.48 14.48±2.71 14.16±3.18 15.77±3.09# 15.80±3.11 15.78±3.07 15.64±3.10 OSI 0.80±0.41 0.82±0.39 0.79±0.45 0.73±0.29 0.99±0.79# 0.99±0.79 0.97±0.78 1.04±0.81 MDA/(nmol/mL) 3.70±1.09 3.79±1.08 3.66±1.12 3.51±1.02 4.37±1.32# 4.25±1.32 4.42±1.32 4.55±1.29§ FAI: Free androgen index; FSH: Follicle-stimulating hormone; LH: Luteinizing hormone; MDA: Malondialdehyde; OSI: Oxidative stress index; SHBG: Sex hormone-binding globulin; T-AOC: Total antioxidant capacity; TOS: Total oxidant status; TT: Total testosterone. Comparisons of all parameters were corrected for differences in age and BMI between the two subgroups. * P<0.05, vs. the II genotype subgroup in controls; △ P<0.05, vs. the ID genotype subgroup in PCOS patients; § P<0.05, vs. the II genotype subgroup in PCOS patients; # P<0.05, vs. total controls.
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