Susceptibility Loci for Polycystic Ovary Syndrome on Chromosome 2p16.3, 2p21, and 9q33.3 in a Cohort of Caucasian Women

E. Lerchbaum; O. Trummer; A. Giuliani; H.-J. Gruber; T. R. Pieber; B. Obermayer-Pietsch

doi:10.1055/s-0031-1286279

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2011; 43(11): 743-747
DOI: 10.1055/s-0031-1286279

Original Basic

Susceptibility Loci for Polycystic Ovary Syndrome on Chromosome 2p16.3, 2p21, and 9q33.3 in a Cohort of Caucasian Women

Authors

E. Lerchbaum

¹Department of Internal Medicine, Division of Endocrinology and Metabolism, Medical University of Graz, Graz, Austria
O. Trummer

¹Department of Internal Medicine, Division of Endocrinology and Metabolism, Medical University of Graz, Graz, Austria
A. Giuliani

²Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria
H.-J. Gruber

³Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
T. R. Pieber

¹Department of Internal Medicine, Division of Endocrinology and Metabolism, Medical University of Graz, Graz, Austria
B. Obermayer-Pietsch

¹Department of Internal Medicine, Division of Endocrinology and Metabolism, Medical University of Graz, Graz, Austria

Abstract

In a recent genome-wide association study investigating Han Chinese PCOS women 3 loci that are strongly associated with PCOS were identified on chromosome 2p16.3 (rs13405728), 2p21 (rs13429458), and 9q33.3 (rs2479106). The aim of the study was to investigate the impact of rs13405728, rs13429458, and rs2479106 variants on PCOS susceptibility in a Caucasian cohort of PCOS and control women. Metabolic, endocrine, and anthropometric measurements and oral glucose tolerance tests were performed in 545 PCOS and 317 control women. The rs13405728, rs13429458, and rs2479106 polymorphisms were genotyped. There was no significant difference in genotype frequencies of rs13405728 and rs13429458 variants between PCOS and controls. There was a trend towards an association of the rs2479106 variant with PCOS susceptibility (p=0.053). PCOS women with the rs2479106 GG genotype had significantly higher WHR than PCOS women carrying the AG and AA genotype (p=0.034 and p=0.020, respectively). Moreover, QChol/HDL and LDL levels were significantly higher in PCOS women carrying the rs2479106 GG genotype when compared to those carrying the AA genotype (p=0.024 and p=0.035, respectively). PCOS women carrying the G allele of rs13405728 had significantly higher AUCgluc, glucose-30 min, and AUCins levels than those carrying the AA genotype (p=0.039, p=0.047, and p=0.044, respectively). In PCOS women, rs13405728 genotypes are associated with glucose and insulin metabolism. Moreover, rs2479106 genotypes were associated with increased WHR levels and an adverse serum lipid profile. Further, we observed a trend towards decreased PCOS susceptibility within carriers of the rs2479106 G-allele. Further studies in large Caucasian PCOS cohorts are warranted to confirm our findings.

Key words

PCOS - genetics - glucose metabolism

Full Text

References

References
1 Goodarzi MO, Dumesic DA, Chazenbalk G, Azziz R. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol 2011; 7: 219-231
2 Broekmans FJ, Knauff EA, Valkenburg O, Laven JS, Eijkemans MJ, Fauser BC. PCOS according to the Rotterdam consensus criteria: Change in prevalence among WHO-II anovulation and association with metabolic factors. BJOG. 2006. 113. 1210-1217
3 Wehr E, Möller R, Horejsi R, Giuliani A, Kopera D, Schweighofer N, Groselj-Strele A, Pieber TR, Obermayer-Pietsch B. Subcutaneous Adipose Tissue Topography and Metabolic Disturbances in Polycystic Ovary Syndrome. Wien Klin Wochenschr 2009; 121: 262-269
4 Wehr E, Pilz S, Schweighofer N, Giuliani A, Kopera D, Pieber TR, Obermayer-Pietsch B. Association of hypovitaminosis D with metabolic disturbances in polycystic ovary syndrome. Eur J Endocrinol 2009; 161: 575-582
5 Cho LW, Kilpatrick ES, Keevil BG, Jayagopal V, Coady AM, Rigby AS, Atkin SL. Insulin resistance variability in women with anovulatory and ovulatory polycystic ovary syndrome, and normal controls. Horm Metab Res 2011; 43: 141-145
6 Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2005; 352: 1223-1236
7 Qiu S, Wu C, Lin F, Chen L, Huang Z, Jiang Z. Exercise training improved insulin sensitivity and ovarian morphology in rats with polycystic ovary syndrome. Horm Metab Res. 2009 41. 880-885
8 Moran LJ, Hutchison SK, Norman RJ, Teede HJ. Lifestyle changes in women with polycystic ovary syndrome. Syst Rev . 2011 CD 007506
9 Goodarzi MO. Looking for polycystic ovary syndrome genes: rational and best strategy. Semin Reprod Med 2008; 26: 5-13
10 Wellcome Trust Case Control Consortium . Genome-wide association study of 14,000 cases of seven common diseases an 3,000 shared controls. Nature 2007; 447: 661-678
11 Chen ZJ, Zhao H, He L, Shi Y, Qin Y, Shi Y, Li Z, You L, Zhao J, Liu J, Liang X, Zhao X, Zhao J, Sun Y, Zhang B, Jiang H, Zhao D, Bian Y, Gao X, Geng L, Li Y, Zhu D, Sun X, Xu JE, Hao C, Ren CE, Zhang Y, Chen S, Zhang W, Yang A, Yan J, Li Y, Ma J, Zhao Y. Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Nat Gen 2010; 43: 45-49
12 The Rotterdam ESHRE/ASRM-Sponsored consensus workshop group . Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004; 19: 41-47
13 Legro RS, Castracane VD, Kauffman RP. Detecting insulin resistance in polycystic ovary syndrome: purposes and pitfalls. Obstet Gynecol Surv 2004; 59: 141-154
14 Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 1999; 22: 1462-1470
15 Cecil JE, Tavendale R, Watt P, Hetherington MM, Palmer CN. An obesity-associated FTO gene variant and increased energy intake in children. N Engl J Med 2008; 359: 2558-2566
16 Wehr E, Schweighofer N, Möller R, Giuliani A, Pieber TR, Obermayer-Pietsch B. Association of FTO gene with hyperandrogenemia and metabolic parameters in women with polycystic ovary syndrome. Metabolism 2010; 59: 575-580
17 Wehr E, Trummer O, Giuliani A, Gruber HJ, Pieber TR, Obermayer-Pietsch B. Vitamin D-associated polymorphisms are related to insulin resistance and vitamin D deficiency in polycystic ovary syndrome. Eur J Endocrinol 2011; 164: 741-749
18 Graupp M, Wehr E, Schweighofer M, Pieber TR, Obermayer-Pietsch B. Association of genetic variants in the two isoforms of the 5-alpha-Reductase SRD5A1 and SRD5A2 in lean patients with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol 2011; 157: 175-179
19 Chae SJ, Kim JJ, Choi YM, Hwang KR, Jee BC, Ku SY, Suh CS, Kim SH, Kim JG, Moon SY. Clinical and biochemical characteristics of polycystic ovary syndrome in Korean women. Hum Reprod 2008; 23: 1924-1931
20 Del Villar K, Miller CA. Down-regulation of DENN/MADD, a TNF receptor binding protein, correlates with neuronal cell death in Alzheimer’s disease brain and hippocampal neurons. Proc Natl Acad Sci USA 2004; 101: 4210-4215
21 Olszanecka-Glinianowicz M, Banaś M, Zahorska-Markiewicz B, Janowska J, Kocełak P, Madej P, Klimek K. Is the polycystic ovary syndrome associated with chronic inflammation per se?. Eur J Obstet Gynecol Reprod Biol 2007; 133: 197-202
22 Huang M, Wang H, Li J, Zhou Z, Du Y, Lin M, Sha J. Involvement of ALF in human spermatogenesis and male infertility. Int J Mol Med 2006; 17: 599-604
23 Latronico AC, Chai Y, Arnhold IJ, Liu X, Mendonca BB, Segaloff DL. A homozygous microdeletion in helix 7 of the luteinizing hormone receptor associated with familial testicular and ovarian resistance is due to both decreased cell surface expression and impaired effector activation by the cell surface receptor. Mol Endocrinol 1998; 12: 442-450
24 Toledo SP, Brunner HG, Kraaij R, Post M, Dahia PL, Hayashida CY, Kremer H, Themmen AP. An inactivating mutation of the luteinizing hormone receptor causes amenorrhea in a 46,XX female. J Clin Endocrinol Metab 1996; 81: 3850-3854
25 Morales AJ, Laughlin GA, Bützow T, Maheshwari H, Baumann G, Yen SS. Insulin, somatotropic, and luteinizing hormone axes in lean and obese women with polycystic ovary syndrome: common and distinct features. J Clin Endocrinol Metab 1996; 81: 2854-2864
26 Arroyo A, Laughlin GA, Morales AJ, Yen SS. Inappropriate gonadotropin secretion in polycystic ovary syndrome: influence of adiposity. J Clin Endocrinol Metab 1997; 82: 3728-3733
27 Maciel GA, Hayashida SA, da Costa LC, Marcondes JA, da Fonseca AM, Soares Jr JM, Baracat EC. Influence of LH and high-density lipoprotein cholesterol (HDL-C) on metformin response in women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol 2011; 157: 180-184