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Original Article
FTO Gene Variants Are Associated with PCOS Susceptibility and Hyperandrogenemia in Young Korean Women
Do Kyeong Song, Hyejin Lee, Jee-Young Oh, Young Sun Hong, Yeon-Ah Sung
Diabetes Metab J. 2014;38(4):302-310.   Published online August 20, 2014
DOI: https://doi.org/10.4093/dmj.2014.38.4.302
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  • 44 Download
  • 25 Web of Science
  • 24 Crossref
AbstractAbstract PDFPubReader   
Background

The fat mass and obesity-associated (FTO) gene is associated with obesity and type 2 diabetes mellitus. Obesity and insulin resistance are also common features of polycystic ovary syndrome (PCOS). Therefore, the FTO gene might be a candidate gene for PCOS susceptibility. The aim of the present study was to evaluate the effects of FTO gene variants on PCOS susceptibility and metabolic and reproductive hormonal parameters.

Methods

We recruited 432 women with PCOS (24±5 years) and 927 healthy women with regular menstrual cycles (27±5 years) and performed a case-control association study. We genotyped the single nucleotide polymorphisms rs1421085, rs17817449, and rs8050136 in the FTO gene and collected metabolic and hormonal measurements.

Results

Logistic regression revealed that the G/G genotype (rs1421085, 1.6%), the C/C genotype (rs17817449, 1.6%), and the A/A genotype (rs8050136, 1.6%) were strongly associated with an increased risk of PCOS (odds ratio, 2.551 to 2.559; all P<0.05). The strengths of these associations were attenuated after adjusting for age and BMI. The women with these genotypes were more obese and exhibited higher free androgen indices (P<0.05) and higher free testosterone levels (P=0.053 to 0.063) compared to the other genotypes. However the significant differences disappeared after adjusting for body mass index (BMI). When we analyzed the women with PCOS and the control groups separately, there were no significant differences in the metabolic and reproductive hormonal parameters according to the FTO gene variants.

Conclusion

The rs1421085, rs17817449, and rs8050136 variants of the FTO gene were associated with PCOS susceptibility and hyperandrogenemia in young Korean women. These associations may be mediated through an effect of BMI.

Citations

Citations to this article as recorded by  
  • Free-androgen Index in Women with Polycystic Ovarian Syndrome: A Meta-Analysis
    Prakash Patil, Neevan D'Souza, Sudeep D. Ghate, Lakshmi Nagendra, Harish B. Girijashankar
    Journal of Health and Allied Sciences NU.2023; 13(03): 380.     CrossRef
  • Differential Association of FTO Gene variants and Haplotypes with the Susceptibility to Polycystic Ovary Syndrome According To Obesity in Women with PCOS
    Wassim Y. Almawi, Rita Nemr, Tomiris Atazhanova, Zainab H. Malalla, Sameh Sarray, Fekria E. Mustafa, Naeema A. Mahmood
    Reproductive Sciences.2023; 30(7): 2166.     CrossRef
  • FTO: a critical role in obesity and obesity-related diseases
    Dan Yin, Yiyang Li, Xingyue Liao, Dewei Tian, Yunsi Xu, Cuilan Zhou, Jun Liu, Suyun Li, Jing Zhou, Yulin Nie, Hongqing Liao, Cuiying Peng
    British Journal of Nutrition.2023; 130(10): 1657.     CrossRef
  • Association of FTO gene variant rs9939609 with polycystic ovary syndrome from Gujarat, India
    Hiral Chaudhary, Jalpa Patel, Nayan K. Jain, Sonal Panchal, Naresh Laddha, Rushikesh Joshi
    BMC Medical Genomics.2023;[Epub]     CrossRef
  • ASSOCIATION BETWEEN FAT MASS AND OBESITY ASSOCIATED (FTO) RS17817449 GENE POLYMORPHISM WITH INSULIN RESISTANCE AND OBESITY IN THE PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE
    Mahbobeh Moayeri, Masoumeh Nezhadali, Mahnaz Mohamadi
    Studies in Medical Sciences.2023; 33(12): 868.     CrossRef
  • Association of FTO gene variants rs9939609 and rs1421085 with polycystic ovary syndrome
    Alaa A. Alnafjan, Afrah F. Alkhuriji, Hussah M. Alobaid, Zainb A. Babay, Mahmoud I. Khalil
    Egyptian Journal of Medical Human Genetics.2022;[Epub]     CrossRef
  • Association of FTO gene variant rs9939609 with hyperandrogenemia and fasting glucose levels in South Indian women with polycystic ovarian syndrome
    Zeinab Naghshband, Suttur S. Malini
    Egyptian Journal of Medical Human Genetics.2022;[Epub]     CrossRef
  • Metabolic and Molecular Mechanisms of Diet and Physical Exercise in the Management of Polycystic Ovarian Syndrome
    Giorgia Scarfò, Simona Daniele, Jonathan Fusi, Marco Gesi, Claudia Martini, Ferdinando Franzoni, Vito Cela, Paolo Giovanni Artini
    Biomedicines.2022; 10(6): 1305.     CrossRef
  • Fat mass and Obesity Associated (FTO) gene and polycystic ovary syndrome: Insight into pathogenesis and association with insulin resistance
    Sadaf Parveen, Saba Khan, Haseeb Ahsan, Priyanka Thapa Manger, Bhavana Gupta, Roshan Alam
    Human Nutrition & Metabolism.2022; 30: 200174.     CrossRef
  • Effect of green cardamom on the expression of genes implicated in obesity and diabetes among obese women with polycystic ovary syndrome: a double blind randomized controlled trial
    Sahar Cheshmeh, Negin Elahi, Maysa Ghayyem, Elaheh Mosaieby, Shima Moradi, Yahya Pasdar, Susan Tahmasebi, Mehdi Moradinazar
    Genes & Nutrition.2022;[Epub]     CrossRef
  • In depth analysis of the association of FTO SNP (rs9939609) with the expression of classical phenotype of PCOS: a Sri Lankan study
    Umayal Branavan, Sulochana Wijesundera, Vishvanath Chandrasekaran, Carukshi Arambepola, Chandrika Wijeyaratne
    BMC Medical Genetics.2020;[Epub]     CrossRef
  • Body Mass Index and Polycystic Ovary Syndrome: A 2-Sample Bidirectional Mendelian Randomization Study
    Yalin Zhao, Yuping Xu, Xiaomeng Wang, Lin Xu, Jianhua Chen, Chengwen Gao, Chuanhong Wu, Dun Pan, Qian Zhang, Juan Zhou, Ruirui Chen, Zhuo Wang, Han Zhao, Li You, Yunxia Cao, Zhiqiang Li, Yongyong Shi
    The Journal of Clinical Endocrinology & Metabolism.2020; 105(6): 1778.     CrossRef
  • Polikistik Over Sendromu ve Obezite: FTO ve MC4R Gen Polimorfizmlerinin Rolü
    Ayçıl ÖZTURAN ŞİRİN, Yasemin AKDEVELİOĞLU
    Adnan Menderes Üniversitesi Sağlık Bilimleri Fakültesi Dergisi.2020; 4(3): 275.     CrossRef
  • Vitamin D receptor and binding protein polymorphisms in women with polycystic ovary syndrome: a case control study
    Do Kyeong Song, Hyejin Lee, Young Sun Hong, Yeon-Ah Sung
    BMC Endocrine Disorders.2019;[Epub]     CrossRef
  • Phenotype and genotype of polycystic ovary syndrome in Asia: Ethnic differences
    Jin Ju Kim, Young Min Choi
    Journal of Obstetrics and Gynaecology Research.2019; 45(12): 2330.     CrossRef
  • Sex hormone binding globulin - an important biomarker for predicting PCOS risk: A systematic review and meta-analysis
    Ritu Deswal, Arun Yadav, Amita Suneja Dang
    Systems Biology in Reproductive Medicine.2018; 64(1): 12.     CrossRef
  • Association between FTO gene polymorphisms and type 2 diabetes mellitus, serum levels of apelin and androgen hormones among Iranian obese women
    Farzaneh Ghafarian-Alipour, Shayan Ziaee, Mohamad Reza Ashoori, Mir Saeid Zakeri, Mohammad Ali Boroumand, Naser Aghamohammadzadeh, Maryam Abbasi-Majdi, Fatemeh Shool, Navid Sarakhs Asbaghi, Abolghasem Mohammadi, Nosratollah Zarghami
    Gene.2018; 641: 361.     CrossRef
  • The role of FTO variants in the susceptibility of polycystic ovary syndrome and in vitro fertilization outcomes in Chinese women
    Ai Ling Liu, Hong Qing Liao, Jing Zhou, Yu Lin Nie, Cui Lan Zhou, Zhi Liang Li, Zi Fen Guo, Dong Xiu He, Yun Hua Zhu, Cui Ying Peng
    Gynecological Endocrinology.2018; 34(8): 719.     CrossRef
  • Causal relationship between obesity and serum testosterone status in men: A bi-directional mendelian randomization analysis
    Joel Eriksson, Robin Haring, Niels Grarup, Liesbeth Vandenput, Henri Wallaschofski, Erik Lorentzen, Torben Hansen, Dan Mellström, Oluf Pedersen, Matthias Nauck, Mattias Lorentzon, Lise Lotte Nystrup Husemoen, Henry Völzke, Magnus Karlsson, Sebastian E. Ba
    PLOS ONE.2017; 12(4): e0176277.     CrossRef
  • Post-transcriptional gene regulation by mRNA modifications
    Boxuan Simen Zhao, Ian A. Roundtree, Chuan He
    Nature Reviews Molecular Cell Biology.2017; 18(1): 31.     CrossRef
  • The Role of Serum MicroRNA-6767-5p as a Biomarker for the Diagnosis of Polycystic Ovary Syndrome
    Do Kyeong Song, Yeon-Ah Sung, Hyejin Lee, Wan-Xi Yang
    PLOS ONE.2016; 11(9): e0163756.     CrossRef
  • Haplotyping strategy highlights the specificity of FTO gene association with polycystic ovary syndrome in Tunisian women population
    Assila Ben Salem, Redha Attaoua, Nabil Mtiraoui, Sawssen Meddeb, Olfa Kacem, Mounir Ajina, Moncef Souissi, Patrick Poucheret, Christophe Normand, Touhami Mahjoub, Florin Grigorescu
    Gene.2015; 565(2): 166.     CrossRef
  • FTO gene variants are not associated with polycystic ovary syndrome in women from Southern Brazil
    Ramon B. Ramos, Poli Mara Spritzer
    Gene.2015; 560(1): 25.     CrossRef
  • Interaction between common variants of FTO and MC4R is associated with risk of PCOS
    Huiqin Yuan, Guoping Zhu, Fang Wang, Xiang Wang, Huihui Guo, Mo Shen
    Reproductive Biology and Endocrinology.2015;[Epub]     CrossRef
Review
Insulin Resistance in Polycystic Ovary Syndrome.
Yeon Ah Sung
Korean Diabetes J. 2008;32(1):1-6.   Published online February 1, 2008
DOI: https://doi.org/10.4093/kdj.2008.32.1.1
  • 2,305 View
  • 33 Download
  • 5 Crossref
AbstractAbstract PDF
Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in women of reproductive age and now recognized as an important metabolic and reproductive disorder. The majority of women with PCOS have insulin resistance and this is regarded to have a central etiological role in PCOS. Insulin resistance and concomitant hyperinsulinemia modifies reproductive function by driving androgen production, suppression of sex hormone-binding globulin (SHBG) and disruption of insulin signaling pathways in the central nervous system. Insulin resistance, together with defects in insulin secretion, confers markedly increased risk for type 2 diabetes mellitus and metabolic syndrome. There are post-binding defects in insulin receptor signaling, with selective resistance to insulin's metabolic actions and preserved other actions. Genetic and environmental abnormalities interact to produce peripheral insulin resistance in PCOS. The numerous in vivo and in vitro data supporting the central role of insulin resistance in the pathogenesis of PCOS have led a new therapy for PCOS with insulin-sensitizing agents.

Citations

Citations to this article as recorded by  
  • Epidemiology and Diagnostic Criteria of Polycystic Ovary Syndrome
    Hyejin Lee, Yeon-Ah Sung
    The Journal of Korean Diabetes.2015; 16(3): 189.     CrossRef
  • Evaluation of Apelin and Insulin Resistance in Patients with PCOS and Therapeutic Effect of Drospirenone-Ethinylestradiol Plus Metformin
    Xianchang Sun, Xingguo Wu, Yan Zhou, Xinyan Yu, Wenjuan Zhang
    Medical Science Monitor.2015; 21: 2547.     CrossRef
  • Hyperandrogenism in Women: Polycystic Ovary Syndrome
    Yeon-Ah Sung
    Hanyang Medical Reviews.2012; 32(4): 197.     CrossRef
  • Adiponectin in Women with Polycystic Ovary Syndrome
    Hyun-Young Shin, Duk-Chul Lee, Ji-Won Lee
    Korean Journal of Family Medicine.2011; 32(4): 243.     CrossRef
  • Polycystic Ovary Syndrome in Korean Women: Clinical Characteristics and Diagnostic Criteria
    Yeon-Ah Sung
    Endocrinology and Metabolism.2011; 26(3): 203.     CrossRef
Original Articles
Peroxisome Proliferator-activated Receptor-gamma (PPARgamma) Polymorphism in Korean Women with Polycystic Ovary Syndrome.
Jee Young Oh, Hyejin Lee, Young Sun Hong, Yeon Ah Sung, Hye Won Chung
Korean Diabetes J. 2007;31(6):480-487.   Published online November 1, 2007
DOI: https://doi.org/10.4093/jkda.2007.31.6.480
  • 1,964 View
  • 22 Download
AbstractAbstract PDF
BACKGROUND
Polycystic ovary syndrome (PCOS) is a common endocrine disease affecting 5~10% of women with reproductive age. Familial aggregation suggests the evidence supporting a genetic basis for PCOS. The mode of inheritance of PCOS is not yet clear, however, probably polygenic and might be related to insulin resistance. Polymorphism of peroxisome proliferator-activated receptor (PPAR)-gamma gene is a susceptible gene for the development of obesity and diabetes. In this study, we examined the frequency and genetic effect of PPAR-gamma polymorphism on insulin resistance or hyperandrogenemia in Korean women with PCOS. METHODS: One-hundred twenty five Korean women with PCOS were evaluated for their metabolic and reproductive hormonal status. PPAR-gamma polymorphism was analyzed. RESULTS: Genetic frequency of PPAR-gamma was not significantly different between women with PCOS (n = 125) and those with regular menstrual cycles (n = 344). PCOS with Pro12Ala polymorphism had significantly higher levels of waist circumference and subcutaneous fat area compared with those with Pro12Pro genotype. They also had tendency of higher levels of fasting glucose concentration, body mass index (BMI) and visceral fat area. After BMI adjustment, this polymorphism was related to lower fasting insulin and higher insulin sensitivity index, and higher sex hormone binding globulin and lower free testosterone levels. CONCLUSION: Pro12Ala polymorphism of PPAR-gamma gene might be associated with obesity. However, after BMI adjustment, it may have favorable effect on insulin resistance and hyperandrogenemia. Because this study has limitations to conclude the genetic causality, further study is needed to support these findings.
Usefulness of Insulin Sensitivity Indexes derived from Oral Glucose Tolerance Test in Women with Polycystic Ovary Syndrome.
Hyo Jeong Kim, Eun Kyung Byun, Jee Young Oh, Yeon Ah Sung, Hye Won Chung
Korean Diabetes J. 2006;30(4):277-284.   Published online July 1, 2006
DOI: https://doi.org/10.4093/jkda.2006.30.4.277
  • 2,136 View
  • 22 Download
  • 1 Crossref
AbstractAbstract PDF
BACKGROUND
Insulin resistance is prevalent in women with polycystic ovary syndrome (PCOS), and it makes them to have high risk for development of type 2 diabetes. Evaluation of insulin sensitivity would be important to predict their risks. Although the euglycemic-hyperinsulinemic clamp technique is the gold standard for measuring insulin sensitivity, it is too hard to practice in large epidemiologic studies. The aim of this study is to verify the validity of various insulin sensitivity indexes from oral glucose tolerance test (OGTT) in women with PCOS. METHODS: We performed euglycemic-hyperinsulinemic clamp (target glucose; 90 mg/dL, insulin ;~1 mU/kg.min) to obtain insulin-mediated glucose disposal rate (M-value) in 62 non-diabetic women with PCOS (BMI < 23 kg/m2; n = 37, BMI > or = 23 kg/m2; n = 25). Homeostasis model assessment [HOMA(IR)], quantitative insulin sensitivity check index (QUICKI), glucose to insulin ratio (G/I ratio), whole body insulin sensitivity index [ISI(COMP)], metabolic clearance rate of glucose [MCR(est)-OGTT(1,2)], and insulin sensitivity indexes [ISI(est)-OGTT(1,2)] were calculated from plasma glucose and insulin levels from standard 75-g OGTT. The correlations of various insulin sensitivity indexes from OGTT with M-value were evaluated. RESULTS: In lean women with PCOS (BMI < 23 kg/m2, n = 37), ISI(COMP) (r = 0.36, P < 0.05), MCRest-OGTT1 (r = 0.49, P < 0.01), ISI(est)-OGTT(1) (r = 0.50, P < 0.01), MCR(est)-OGTT(2) (r = 0.45, P < 0.01) and ISI(est)-OGTT(2) (r = 0.40, P < 0.05) were significantly correlated with M-value. In overweight and obese women with PCOS (BMI > or = 23 kg/m2, n = 25), HOMA(IR) (r = -0.40, P < 0.05), QUICKI (r = 0.40, P < 0.05), MCR(est)-OGTT(1) (r = 0.76, P < 0.001), ISI(est)-OGTT(1) (r = 0.63, P < 0.001), MCR(est)-OGTT(2) (r = 0.58, P < 0.01) and ISI(est)-OGTT(2) (r = 0.42, P < 0.05) showed significant correlations with M-value. CONCLUSION: MCR(est)-OGTT(1) and ISI(est)-OGTT(1) were the most reliable and easily accessible insulin sensitivity indexes obtained from OGTT for measuring of insulin sensitivity in women with PCOS regardless of obesity.

Citations

Citations to this article as recorded by  
  • Insulin resistance in a large cohort of women with polycystic ovary syndrome: a comparison between euglycaemic-hyperinsulinaemic clamp and surrogate indexes
    Flavia Tosi, Enzo Bonora, Paolo Moghetti
    Human Reproduction.2017; 32(12): 2515.     CrossRef
Insulin Resistance in Normal Weight Women with Polycystic Ovary Syndrome.
Eun Kyung Byun, Hye Jin Lee, Jee Young Oh, Young Sun Hong, Hye Won Chung, Yeon Ah Sung
Korean Diabetes J. 2004;28(4):315-323.   Published online August 1, 2004
  • 1,252 View
  • 20 Download
AbstractAbstract PDF
BACKGROUND
Insulin resistance is considered a regular component of polycystic ovary syndrome (PCOS). However, several studies have failed to confirm insulin resistance in non-obese women with PCOS. The aim of the study was to identify whether insulin resistance is present in normal weight women with PCOS and the factors associated with insulin sensitivity. METHODS: Twenty-two normal weight (body mass index, BMI < 25 kg/m2) women with PCOS, and 16 age and BMI comparable control women with regular menstrual cycles were examined during their early follicular phase. The levels of serum hormones and lipids were measured. The visceral fat area was assessed by computed tomography at umbilical level. The standard 75g oral glucose tolerance test was performed to determine the glucose tolerance status. The insulin sensitivity was measured using the euglycemic hyperinsulinemic clamp technique (target glucose 90 mg/dL, insulin~1 mu/kg/min). RESULTS: The levels of free testosterone (1.9+/-0.6 pg/mL vs. 0.8+/-0.3 pg/mL, p<0.001), androstenedione (14.5+/-3.7 nmol/L vs. 8.8+/-1.3 nmol/L, p<0.001), LH (10.7+/-4.5 IU/L vs 4.6+/-4.8 IU/L, p<0.001) and FSH (5.8+/-1.7 IU/L vs. 4.2+/-2.4 IU/L, p<0.05) of the women with PCOS were significantly higher than those of the control subjects. The fasting plasma glucose (4.92+/-0.31 mmol/L vs. 4.42+/-0.61 mmol/L, p<0.01) and post glucose load plasma insulin (233.2+/-119.5pmol/L vs. 109.0+/-46.4 pmol/L, p<001) levels of women with PCOS were significantly higher than those of the control subjects. The glucose disposal rate (M value) was significantly lower in women with PCOS compared to the controls (5.3+/-1.2 mg/kg min vs. 6.7+/-1.6 mg/kg min, p<0.05), even after adjusting for age and BMI. There was no significant correlation of the M value with the anthropometric and a metabolic indices, and a multiple regression analysis of the M value showed no significant variables. CONCLUSION: Our non-obese women with PCOS showed significant insulin resistance compared to their age and BMI comparable control subjects, and-their insulin resistance may be an intrinsic defect not associated with other features, such as hyperandrogenemia or body fat distribution patterns.
Association of High Intracellular Calcium Levels with Insulin Resistance in Women with Polycystic Ovary Syndrome.
Jee Young Oh, Hye Jin Lee, Young Sun Hong, Hye Won Chung, Yeon Ah Sung
Korean Diabetes J. 2004;28(2):101-110.   Published online April 1, 2004
  • 1,262 View
  • 24 Download
AbstractAbstract PDF
BACKGROUND
Insulin resistance is an intrinsic defect of polycystic ovary syndrome (PCOS), and elevated levels of cytosolic free calcium in insulin target cells may cause insulin resistance. To our knowledge, the relationship between intracellular calcium and insulin resistance in PCOS has not been investigated. The purpose of this study was to determine whether the levels of intracelluar calcium are changed and if they have any association with insulin resistance in women with PCOS. METHODS: The intracellular calcium levels in the platelets and the insulin sensitivity were measured by fluorescent spectrophotometry and the euglycemic hyperinsulinemic clamp technique, respectively, in 16 women with PCOS and 6 normal cycling women. A 2h, 75 g oral glucose tolerance test was performed to determine the glucose tolerance. RESULTS: The insulin sensitivity measured by the glucose disposal rate(the M-value), was significantly lower in women with PCOS(4.6+/-1.5mg/kg/min vs. 7.0+/-1.3mg/kg/min, p<0.01), but the intracellular calcium levels were significantly higher in women with PCOS compared to the controls(122.7+/-36.7 vs 59.1+/-29.3mmol/L, p<0.01). When the women with PCOS were divided into the overweight or obese(n=9, BMI ?23kg/m2) and lean(n=7, BMI<23kg/m2) groups, both groups had significantly lower M values compared to the control subjects(3.9+/-1.3, 5.5+/-1.2 vs. 7.0+/-1.3mumg/kg/min, p<0.001), and these levels between the overweight/obese and lean PCOS groups showed a significant difference(p<0.001). The overweight/ obese and lean women with PCOS had significantly higher levels of intracellular calcium compared to the control subjects(131.3+/-39.6, 111.7+/-31.8 vs. 59.1+/-29.3nmol/L, p<0.01), but these levels did not differ significantly between the overweight/obese and lean women with PCOS. The intracellular calcium levels showed a significant positive correlation with age, and a negative correlation with the M value(r=-0.55, p<0.05). The BMI-adjusted partial correlation showed marginal significance between elevated levels of intracellular calcium and insulin sensitivity (r=-0.47, p=0.07). CONCLUSION: Women with PCOS showed both insulin resistance and increased levels of intracellular calcium compared to the control subjects. Increased levels of intracellular calcium were associated with insulin resistance in women with PCOS.

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