2023年 第23卷 第4期
《工程（英文）》 >> 2023年 第23卷 第4期 doi: 10.1016/j.eng.2022.08.013
多囊卵巢综合征无排卵的胰岛素信号和雄激素合成的新遗传风险和代谢特征
a The First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin 150040, China
b Department of Reproductive Medicine, Heilongjiang Provincial Hospital, Harbin Institute of Technology, Harbin 150030, China
c Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong 999077, China
d Reproduction and Development Laboratory, Li Ka Shing Institute of Health Sciences & Chinese University of Hong Kong-Sichuan University Joint Laboratory in Reproductive Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China
e Center for Reproductive Medicine, Xuzhou Central Hospital, Xuzhou 221009, China
f Department of Obstetrics and Gynecology, The Affiliated Hospital of Gui Zhou Medical University, Guiyang 550004, China
g Biomedical Sciences Institute, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
h Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Bio-X Institutes, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200030, China
i Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200001, China
j Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai 200001, China
k Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200001, China
l Department of Computer Sciences, City University of Hong Kong, Hong Kong 999077, China
m Shanghai NewCore Biotechnology Co., Ltd., Shanghai 200240, China
n Institute of Biochemistry, Charité—University Medicine Berlin, Berlin 10117, Germany
o Center for Reproductive Medicine, Shandong University, Jinan 250001, China
p Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong 999077, China
q Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden
r Department of Biostatistics, Yale School of Public Health, New Haven, CT 06520, USA
s Department of Obstetrics and Gynecology, Pennsylvania State University, Hershey, PA 17033, USA
t Department of Obstetrics and Gynaecology, Monash University, Monash Medical Centre, Clayton, VIC 3168, Australia
u Aberdeen Centre for Women’s Health Research, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK
# These authors contributed equally to this work.
下一篇 上一篇
摘要
促排卵是多囊卵巢综合征（PCOS）不孕症的一线治疗方案。卵巢对促排卵治疗的排卵应答差被认为与胰岛素抵抗和高雄激素血症相关。在一个包含1000名PCOS不孕妇女（PCOSAct）的前瞻性队列中，我们开展了一项全外显子联合靶向单核苷酸多态性（SNP）测序以及代谢组学研究。在全基因组水平找出与无排卵显著相关的常见变异和罕见突变，并通过机器学习算法构建排卵预测模型。研究发现，ZNF438基因中标记为rs2994652 (p=2.47×10–8)的常见变异和REC114基因中的一个罕见功能突变（rs182542888，p=5.79×10–6）与促排卵治疗失败显著相关。携带rs2994652 A等位基因和REC114 p.Val101Leu (rs182542888)的PCOS不孕妇女进行促排卵治疗的总排卵率更低（分别为：比值比 （OR）=1.96，95% 置信区间（CI）[1.55~2.49]；OR=11.52，95% CI [3.08~43.05]），出现排卵的间隔时间更长（平均56.7天vs.49.0天，p<0.001；78.1天vs.68.6天，p=0.014）。对于rs2994652突变者，L-苯丙氨酸水平升高并与胰岛素抵抗稳态模型（HOMA-IR）指数（r=0.22, p=0.05）和空腹血糖（r=0.33, p=0.003）呈正相关；对于rs182542888突变者，花生四烯酸代谢产物水平下降并与升高的抗苗勒管激素（r=－0.51, p=0.01）和总睾酮（r=－0.71, p=0.02）呈负相关。整合基因变异位点、代谢产物及临床特征的联合预测模型可提高对排卵的预测能力[曲线下面积（AUC）=76.7%]。ZNF438基因的一个常见变异和REC114基因的一个罕见功能突变，以及与二者相关的苯丙氨酸和花生四烯酸代谢物改变，与PCOS女性不孕症的促排卵治疗失败相关。
补充材料
图片
图1
图2
图3
图4
参考文献
[ 1 ] Azziz R, Carmina E, Chen Z, Dunaif A, Laven JS, Legro RS, et al. Polycystic ovary syndrome. Nat Rev Dis Primers 2016;2(1):16057. 链接1
[ 2 ] Balen AH, Morley LC, Misso M, Franks S, Legro RS, Wijeyaratne CN, et al. The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance. Hum Reprod Update 2016;22(6):687‒708. 链接1
[ 3 ] Jones MR, Goodarzi MO. Genetic determinants of polycystic ovary syndrome: progress and future directions. Fertil Steril 2016;106(1):25‒32. 链接1
[ 4 ] Chen ZJ, Zhao H, He L, Shi Y, Qin Y, Shi Y, et al. Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Nat Genet 2011;43(1):55‒9. 链接1
[ 5 ] Shi Y, Zhao H, Shi Y, Cao Y, Yang D, Li Z, et al. Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome. Nat Genet 2012;44(9):1020‒5. 链接1
[ 6 ] Zhang Y, Ho K, Keaton JM, Hartzel DN, Day F, Justice AE, et al. A genome-wide association study of polycystic ovary syndrome identified from electronic health records. Am J Obstet Gynecol 2020;223(4):559.e1‒21. 链接1
[ 7 ] Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, et al.; Cooperative Multicenter Reproductive Medicine Network. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007;356(6):551‒66. 链接1
[ 8 ] Legro RS, Brzyski RG, Diamond MP, Coutifaris C, Schlaff WD, Casson P, et al.; NICHD Reproductive Medicine Network. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med 2014;371(2):119‒29. 链接1
[ 9 ] Wu XK, Stener-Victorin E, Kuang HY, Ma HL, Gao JS, Xie LZ, et al.; PCOSAct Study Group. Effect of acupuncture and clomiphene in Chinese women with polycystic ovary ayndrome: a randomized clinical trial. JAMA 2017;317(24):2502‒14. 链接1
[10] Kuang H, Li Y, Wu X, Hou L, Wu T, Liu J, et al. Acupuncture and clomiphene citrate for live birth in polycystic ovary syndrome: study design of a randomized controlled trial. Evid Based Complement Alternat Med 2013;2013:527303. 链接1
[11] Loh PR, Danecek P, Palamara PF, Fuchsberger C, Reshef YA, Finucane HK, et al. Reference-based phasing using the haplotype reference consortium panel. Nat Genet 2016;48(11):1443‒8. 链接1
[12] Das S, Forer L, Schönherr S, Sidore C, Locke AE, Kwong A, et al. Next-generation genotype imputation service and methods. Nat Genet 2016;48(10):1284‒7. 链接1
[13] Auton A, Abecasis GR, Altshuler DM, Durbin RM, Abecasis GR, Bentley DR, et al. A global reference for human genetic variation. Nature 2015;526(7571):68‒74.
[14] Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 2006;38(8):904‒9. 链接1
[15] Zhan X, Hu Y, Li B, Abecasis GR, Liu DJ. RVTESTS: an efficient and comprehensive tool for rare variant association analysis using sequence data. Bioinformatics 2016;32(9):1423‒6. 链接1
[16] Zhong Z, Wan B, Qiu Y, Ni J, Tang W, Chen X, et al. Identification of a novel human zinc finger gene, ZNF438, with transcription inhibition activity. J Biochem Mol Biol 2007;40(4):517‒24. 链接1
[17] McConnell BB, Yang VW. Mammalian Krüppel-like factors in health and diseases. Physiol Rev 2010;90(4):1337‒81. 链接1
[18] Cree-Green M, Carreau AM, Rahat H, Garcia-Reyes Y, Bergman BC, Pyle L, et al. Amino acid and fatty acid metabolomic profile during fasting and hyperinsulinemia in girls with polycystic ovarian syndrome. Am J Physiol Endocrinol Metab 2019;316(5):E707‒18. 链接1
[19] Sun Z, Chang HM, Wang A, Song J, Zhang X, Guo J, et al. Identification of potential metabolic biomarkers of polycystic ovary syndrome in follicular fluid by SWATH mass spectrometry. Reprod Biol Endocrinol 2019;17(1):45. 链接1
[20] Escobar-Morreale HF. Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nat Rev Endocrinol 2018;14(5):270‒84. 链接1
[21] Claeys Bouuaert C, Pu S, Wang J, Oger C, Daccache D, Xie W, et al. DNA-driven condensation assembles the meiotic DNA break machinery. Nature 2021;592(7852):144‒9. 链接1
[22] Wang W, Dong J, Chen B, Du J, Kuang Y, Sun X, et al. Homozygous mutations in REC114 cause female infertility characterised by multiple pronuclei formation and early embryonic arrest. J Med Genet 2020;57(3):187‒94. 链接1
[23] Duffy DM. Novel contraceptive targets to inhibit ovulation: the prostaglandin E2 pathway. Hum Reprod Update 2015;21(5):652‒70. 链接1
[24] Li S, Chu Q, Ma J, Sun Y, Tao T, Huang R, et al. Discovery of novel lipid profiles in PCOS: do insulin and androgen oppositely regulate bioactive lipid production? J Clin Endocrinol Metab 2017;102(3):810‒21.
[25] Zhang N, Wang L, Luo G, Tang X, Ma L, Zheng Y, et al. Arachidonic acid regulation of intracellular signaling pathways and target gene expression in bovine ovarian granulosa cells. Anim Open Access J MDPI 2019;9(6):374. 链接1
[26] Fauser BCJM. Reproductive endocrinology: revisiting ovulation induction in PCOS. Nat Rev Endocrinol 2014;10(12):704‒5. 链接1
[27] Wu Q, Li J, Ng EHY, Liu JP, Legro RS. Do baseline AMH levels in women with polycystic ovary syndrome predict ovulation rate and time to ovulation: a secondary analysis of PCOSAct trial? BJOG 2021;128(9):1477‒86. 链接1
[28] Kuang H, Jin S, Hansen KR, Diamond MP, Coutifaris C, Casson P, et al. Identification and replication of prediction models for ovulation, pregnancy and live birth in infertile women with polycystic ovary syndrome. Hum Reprod 2015;30(9):2222‒33. 链接1
[29] Ngiam KY, Khor IW. Big data and machine learning algorithms for health-care delivery. Lancet Oncol 2019;20(5):e262‒73. 链接1
[30] Koriath CAM, Kenny J, Ryan NS, Rohrer JD, Schott JM, Houlden H, et al. Genetic testing in dementia—utility and clinical strategies. Nat Rev Neurol 2021;17(1):23‒36. 链接1
[31] Laven JSE. Follicle Stimulating Hormone Receptor (FSHR) Polymorphisms and Polycystic Ovary Syndrome (PCOS). Front Endocrinol 2019;2019(10):00023.
京公网安备 11010502051620号
