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BMC Medical Genetics
Published in: BMC Medical Genetics 1/2010

Open Access 01-12-2010 | Research article

Large effects on body mass index and insulin resistance of fat mass and obesity associated gene (FTO) variants in patients with polycystic ovary syndrome (PCOS)

Authors: Susanne Tan, André Scherag, Onno Eilard Janssen, Susanne Hahn, Harald Lahner, Tiina Dietz, Susann Scherag, Harald Grallert, Carla Ivane Ganz Vogel, Rainer Kimmig, Thomas Illig, Klaus Mann, Johannes Hebebrand, Anke Hinney

Published in: BMC Medical Genetics | Issue 1/2010

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Abstract

Background

The polycystic ovary syndrome (PCOS), a common endocrine disorder in women of child-bearing age, mainly characterised by chronic anovulation and hyperandrogenism, is often associated with insulin resistance (IR) and obesity. Its etiology and the role of IR and obesity in PCOS are not fully understood. We examined the influence of validated genetic variants conferring susceptibility to obesity and/or type 2 diabetes mellitus (T2DM) on metabolic and PCOS-specific traits in patients with PCOS.

Methods

We conducted an association study in 386 patients with PCOS (defined by the Rotterdam-criteria) using single nucleotide polymorphisms (SNPs) in or in proximity to the fat mass and obesity associated gene (FTO), insulin-induced gene-2 (INSIG2), transcription factor 7-like 2 gene (TCF7L2) and melanocortin 4 receptor gene (MC4R). To compare the effect of FTO obesity risk alleles on BMI in patients with PCOS to unselected females of the same age range we genotyped 1,971 females from the population-based KORA-S4 study (Kooperative Gesundheitsforschung im Raum Augsburg, Survey 4).

Results

The FTO risk allele was associated with IR traits and measures of increased body weight. In addition, the TCF7L2 SNP was associated with body weight traits. For the SNPs in the vicinity of INSIG2 and MC4R and for the other examined phenotypes there was no evidence for an association. In PCOS the observed per risk allele effect of FTO intron 1 SNP rs9939609 on BMI was +1.56 kg/m2, whereas it was +0.46 kg/m2 in females of the same age range from the general population as shown previously.

Conclusion

The stronger effect on body weight of the FTO SNP in PCOS might well have implications for the etiology of the disease.
Appendix
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Literature
1.
Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO: The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab. 2004, 89: 2745-2749. 10.1210/jc.2003-032046.CrossRefPubMed
2.
Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004, 81: 19-25.
3.
Kiddy DS, Hamilton-Fairley D, Bush A, Short F, Anyaoku V, Reed MJ, Franks S: Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf). 1992, 36: 105-111. 10.1111/j.1365-2265.1992.tb02909.x.CrossRef
4.
Dunaif A, Segal KR, Futterweit W, Dobrjansky A: Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989, 38: 1165-1174. 10.2337/diabetes.38.9.1165.CrossRefPubMed
5.
Talbot JA, Bicknell EJ, Rajkhowa M, Krook A, O'Rahilly S, Clayton RN: Molecular scanning of the insulin receptor gene in women with polycystic ovarian syndrome. J Clin Endocrinol Metab. 1996, 81: 1979-1983. 10.1210/jc.81.5.1979.PubMed
6.
Dunaif A, Wu X, Lee A, Diamanti-Kandarakis E: Defects in insulin receptor signaling in vivo in the polycystic ovary syndrome (PCOS). Am J Physiol Endocrinol Metab. 2001, 281: E392-399.PubMed
7.
Legro RS, Strauss JF: Molecular progress in infertility: polycystic ovary syndrome. Fertil Steril. 2002, 78: 569-576. 10.1016/S0015-0282(02)03275-2.CrossRefPubMed
8.
Stewart DR, Dombroski BA, Urbanek M, Ankener W, Ewens KG, Wood JR, Legro RS, Strauss JF, Dunaif A, Spielman RS: Fine mapping of genetic susceptibility to polycystic ovary syndrome on chromosome 19p13.2 and tests for regulatory activity. J Clin Endocrinol Metab. 2006, 91: 4112-4117. 10.1210/jc.2006-0951.CrossRefPubMed
9.
Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JR, Elliott KS, Lango H, Rayner NW, et al: A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007, 316: 889-894. 10.1126/science.1141634.CrossRefPubMedPubMedCentral
10.
Hinney A, Nguyen TT, Scherag A, Friedel S, Bronner G, Muller TD, Grallert H, Illig T, Wichmann HE, Rief W, et al: Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants. PLoS ONE. 2007, 2: e1361-10.1371/journal.pone.0001361.CrossRefPubMedPubMedCentral
11.
Pascoe L, Tura A, Patel SK, Ibrahim IM, Ferrannini E, Zeggini E, Weedon MN, Mari A, Hattersley AT, McCarthy MI, et al: Common variants of the novel type 2 diabetes genes CDKAL1 and HHEX/IDE are associated with decreased pancreatic beta-cell function. Diabetes. 2007, 56: 3101-3104. 10.2337/db07-0634.CrossRefPubMed
12.
Barber TM, Bennett AJ, Groves CJ, Sovio U, Ruokonen A, Martikainen H, Pouta A, Hartikainen AL, Elliott P, Lindgren CM, et al: Association of variants in the fat mass and obesity associated (FTO) gene with polycystic ovary syndrome. Diabetologia. 2008, 51: 1153-1158. 10.1007/s00125-008-1028-6.CrossRefPubMed
13.
Attaoua R, Ait El Mkadem S, Radian S, Fica S, Hanzu F, Albu A, Gheorghiu M, Coculescu M, Grigorescu F: FTO gene associates to metabolic syndrome in women with polycystic ovary syndrome. Biochem Biophys Res Commun. 2008, 373: 230-234. 10.1016/j.bbrc.2008.06.039.CrossRefPubMed
14.
Herbert A, Gerry NP, McQueen MB, Heid IM, Pfeufer A, Illig T, Wichmann HE, Meitinger T, Hunter D, Hu FB, et al: A common genetic variant is associated with adult and childhood obesity. Science. 2006, 312: 279-283. 10.1126/science.1124779.CrossRefPubMed
15.
Kumar J, Sunkishala RR, Karthikeyan G, Sengupta S: The common genetic variant upstream of INSIG2 gene is not associated with obesity in Indian population. Clin Genet. 2007, 71: 415-418. 10.1111/j.1399-0004.2007.00795.x.CrossRefPubMed
16.
Loos RJ, Barroso I, O'Rahilly S, Wareham NJ: Comment on "A common genetic variant is associated with adult and childhood obesity". Science. 2007, 315: 187-10.1126/science.1130012.CrossRefPubMedPubMedCentral
17.
Dina C, Meyre D, Samson C, Tichet J, Marre M, Jouret B, Charles MA, Balkau B, Froguel P: Comment on "A common genetic variant is associated with adult and childhood obesity". Science. 2007, 315: 187-10.1126/science.1129402.CrossRefPubMed
18.
Rosskopf D, Bornhorst A, Rimmbach C, Schwahn C, Kayser A, Kruger A, Tessmann G, Geissler I, Kroemer HK, Volzke H: Comment on "A common genetic variant is associated with adult and childhood obesity". Science. 2007, 315: 187-10.1126/science.1130571.CrossRefPubMed
19.
Lyon HN, Emilsson V, Hinney A, Heid IM, Lasky-Su J, Zhu X, Thorleifsson G, Gunnarsdottir S, Walters GB, Thorsteinsdottir U, et al: The association of a SNP upstream of INSIG2 with body mass index is reproduced in several but not all cohorts. PLoS Genet. 2007, 3: e61-10.1371/journal.pgen.0030061.CrossRefPubMedPubMedCentral
20.
Reinehr T, Hinney A, Nguyen TT, Hebebrand J: Evidence of an influence of a polymorphism near the INSIG2 on weight loss during a lifestyle intervention in obese children and adolescents. Diabetes. 2008, 57: 623-626. 10.2337/db07-0408.CrossRefPubMed
21.
Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, et al: Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet. 2006, 38: 320-323. 10.1038/ng1732.CrossRefPubMed
22.
Meigs JB, Manning AK, Fox CS, Florez JC, Liu C, Cupples LA, Dupuis J: Genome-wide association with diabetes-related traits in the Framingham Heart Study. BMC Med Genet. 2007, 8 (Suppl 1): S16-10.1186/1471-2350-8-S1-S16.CrossRefPubMedPubMedCentral
23.
Lyssenko V, Lupi R, Marchetti P, Del Guerra S, Orho-Melander M, Almgren P, Sjogren M, Ling C, Eriksson KF, Lethagen AL, et al: Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Invest. 2007, 117: 2155-2163. 10.1172/JCI30706.CrossRefPubMedPubMedCentral
24.
Palmer ND, Lehtinen AB, Langefeld CD, Campbell JK, Haffner SM, Norris JM, Bergman RN, Goodarzi MO, Rotter JI, Bowden DW: Association of TCF7L2 gene polymorphisms with reduced acute insulin response in Hispanic Americans. J Clin Endocrinol Metab. 2008, 93: 304-309. 10.1210/jc.2007-1225.CrossRefPubMed
25.
Yi F, Brubaker PL, Jin T: TCF-4 mediates cell type-specific regulation of proglucagon gene expression by beta-catenin and glycogen synthase kinase-3beta. J Biol Chem. 2005, 280: 1457-1464. 10.1074/jbc.M411487200.CrossRefPubMed
26.
Deacon CF: Therapeutic strategies based on glucagon-like peptide 1. Diabetes. 2004, 53: 2181-2189. 10.2337/diabetes.53.9.2181.CrossRefPubMed
27.
Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D, Boutin P, Vincent D, Belisle A, Hadjadj S, et al: A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature. 2007, 445: 881-885. 10.1038/nature05616.CrossRefPubMed
28.
Helgason A, Palsson S, Thorleifsson G, Grant SF, Emilsson V, Gunnarsdottir S, Adeyemo A, Chen Y, Chen G, Reynisdottir I, et al: Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution. Nat Genet. 2007, 39: 218-225. 10.1038/ng1960.CrossRefPubMed
29.
Saxena R, Gianniny L, Burtt NP, Lyssenko V, Giuducci C, Sjogren M, Florez JC, Almgren P, Isomaa B, Orho-Melander M, et al: Common single nucleotide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals. Diabetes. 2006, 55: 2890-2895. 10.2337/db06-0381.CrossRefPubMed
30.
Cauchi S, Meyre D, Dina C, Choquet H, Samson C, Gallina S, Balkau B, Charpentier G, Pattou F, Stetsyuk V, et al: Transcription factor TCF7L2 genetic study in the French population: expression in human beta-cells and adipose tissue and strong association with type 2 diabetes. Diabetes. 2006, 55: 2903-2908. 10.2337/db06-0474.CrossRefPubMed
31.
Barber TM, Bennett AJ, Groves CJ, Sovio U, Ruokonen A, Martikainen H, Pouta A, Hartikainen AL, Elliott P, Wass JA, et al: Disparate genetic influences on polycystic ovary syndrome (PCOS) and type 2 diabetes revealed by a lack of association between common variants within the TCF7L2 gene and PCOS. Diabetologia. 2007, 50: 2318-2322. 10.1007/s00125-007-0804-z.CrossRefPubMed
32.
Geller F, Reichwald K, Dempfle A, Illig T, Vollmert C, Herpertz S, Siffert W, Platzer M, Hess C, Gudermann T, et al: Melanocortin-4 receptor gene variant I103 is negatively associated with obesity. Am J Hum Genet. 2004, 74: 572-581. 10.1086/382490.CrossRefPubMedPubMedCentral
33.
Heid IM, Vollmert C, Hinney A, Doring A, Geller F, Lowel H, Wichmann HE, Illig T, Hebebrand J, Kronenberg F: Association of the 103I MC4R allele with decreased body mass in 7937 participants of two population based surveys. J Med Genet. 2005, 42: e21-10.1136/jmg.2004.027011.CrossRefPubMedPubMedCentral
34.
Young EH, Wareham NJ, Farooqi S, Hinney A, Hebebrand J, Scherag A, O'Rahilly S, Barroso I, Sandhu MS: The V103I polymorphism of the MC4R gene and obesity: population based studies and meta-analysis of 29 563 individuals. Int J Obes (Lond). 2007, 31: 1437-1441. 10.1038/sj.ijo.0803609.CrossRef
35.
Loos RJ, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I, Inouye M, Freathy RM, Attwood AP, Beckmann JS, et al: Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet. 2008, 40: 768-775. 10.1038/ng.140.CrossRefPubMedPubMedCentral
36.
Chambers JC, Elliott P, Zabaneh D, Zhang W, Li Y, Froguel P, Balding D, Scott J, Kooner JS: Common genetic variation near MC4R is associated with waist circumference and insulin resistance. Nat Genet. 2008, 40: 716-718. 10.1038/ng.156.CrossRefPubMed
37.
Tan S, Hahn S, Benson S, Dietz T, Lahner H, Moeller LC, Schmidt M, Elsenbruch S, Kimmig R, Mann K, Janssen OE: Metformin improves polycystic ovary syndrome symptoms irrespective of pre-treatment insulin resistance. Eur J Endocrinol. 2007, 157: 669-676. 10.1530/EJE-07-0294.CrossRefPubMed
38.
Vermeulen A, Verdonck L, Kaufman JM: A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999, 84: 3666-3672. 10.1210/jc.84.10.3666.CrossRefPubMed
39.
Hermans MP, Levy JC, Morris RJ, Turner RC: Comparison of tests of beta-cell function across a range of glucose tolerance from normal to diabetes. Diabetes. 1999, 48: 1779-1786. 10.2337/diabetes.48.9.1779.CrossRefPubMed
40.
Holle R, Happich M, Lowel H, Wichmann HE: KORA--a research platform for population based health research. Gesundheitswesen. 2005, 67 (Suppl 1): S19-25. 10.1055/s-2005-858235.CrossRefPubMed
41.
Vollmert C, Windl O, Xiang W, Rosenberger A, Zerr I, Wichmann HE, Bickeboller H, Illig T, Kretzschmar HA: Significant association of a M129V independent polymorphism in the 5' UTR of the PRNP gene with sporadic Creutzfeldt-Jakob disease in a large German case-control study. J Med Genet. 2006, 43: e53-10.1136/jmg.2006.040931.CrossRefPubMedPubMedCentral
42.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC: PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007, 81: 559-575. 10.1086/519795.CrossRefPubMedPubMedCentral
43.
Cauchi S, Nead KT, Choquet H, Horber F, Potoczna N, Balkau B, Marre M, Charpentier G, Froguel P, Meyre D: The genetic susceptibility to type 2 diabetes may be modulated by obesity status: implications for association studies. BMC Med Genet. 2008, 9: 45-10.1186/1471-2350-9-45.CrossRefPubMedPubMedCentral
44.
Stolerman ES, Manning AK, McAteer JB, Fox CS, Dupuis J, Meigs JB, Florez JC: TCF7L2 variants are associated with increased proinsulin/insulin ratios but not obesity traits in the Framingham Heart Study. Diabetologia. 2009, 52: 614-620. 10.1007/s00125-009-1266-2.CrossRefPubMedPubMedCentral
45.
Rizzo M, Berneis K, Hersberger M, Pepe I, Di Fede G, Rini GB, Spinas GA, Carmina E: Milder forms of atherogenic dyslipidemia in ovulatory versus anovulatory polycystic ovary syndrome phenotype. Hum Reprod. 2009, 24: 2286-2292. 10.1093/humrep/dep121.CrossRefPubMed
46.
Kauffman RP, Baker TE, Baker VM, DiMarino P, Castracane VD: Endocrine and metabolic differences among phenotypic expressions of polycystic ovary syndrome according to the 2003 Rotterdam consensus criteria. Am J Obstet Gynecol. 2008, 198: 670-10.1016/j.ajog.2008.01.037.CrossRefPubMed
47.
Barber TM, Wass JA, McCarthy MI, Franks S: Metabolic characteristics of women with polycystic ovaries and oligo-amenorrhoea but normal androgen levels: implications for the management of polycystic ovary syndrome. Clin Endocrinol (Oxf). 2007, 66: 513-517.
48.
Dewailly D, Catteau-Jonard S, Reyss AC, Leroy M, Pigny P: Oligoanovulation with polycystic ovaries but not overt hyperandrogenism. J Clin Endocrinol Metab. 2006, 91: 3922-3927. 10.1210/jc.2006-1054.CrossRefPubMed
49.
Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J, Najjar S, Nagaraja R, Orru M, Usala G, et al: Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet. 2007, 3: e115-10.1371/journal.pgen.0030115.CrossRefPubMedPubMedCentral
50.
Kowalska I, Malecki MT, Straczkowski M, Skupien J, Karczewska-Kupczewska M, Nikolajuk A, Szopa M, Adamska A, Wawrusiewicz-Kurylonek N, Wolczynski S, et al: The FTO gene modifies weight, fat mass and insulin sensitivity in women with polycystic ovary syndrome, where its role may be larger than in other phenotypes. Diabetes Metab. 2009, 35 (4): 328-31. 10.1016/j.diabet.2009.03.004.CrossRefPubMed
51.
Horikoshi M, Hara K, Ito C, Shojima N, Nagai R, Ueki K, Froguel P, Kadowaki T: Variations in the HHEX gene are associated with increased risk of type 2 diabetes in the Japanese population. Diabetologia. 2007, 50: 2461-2466. 10.1007/s00125-007-0827-5.CrossRefPubMed
52.
Wahlen K, Sjolin E, Hoffstedt J: The common rs9939609 gene variant of the fat mass- and obesity-associated gene FTO is related to fat cell lipolysis. J Lipid Res. 2008, 49: 607-611. 10.1194/jlr.M700448-JLR200.CrossRefPubMed
53.
Marzi C, Huth C, Kolz M, Grallert H, Meisinger C, Wichmann HE, Rathmann W, Herder C, Illig T: Variants of the transcription factor 7-like 2 gene (TCF7L2) are strongly associated with type 2 diabetes but not with the metabolic syndrome in the MONICA/KORA surveys. Horm Metab Res. 2007, 39: 46-52. 10.1055/s-2007-957345.CrossRefPubMed
54.
Melzer D, Murray A, Hurst AJ, Weedon MN, Bandinelli S, Corsi AM, Ferrucci L, Paolisso G, Guralnik JM, Frayling TM: Effects of the diabetes linked TCF7L2 polymorphism in a representative older population. BMC Med. 2006, 4: 34-10.1186/1741-7015-4-34.CrossRefPubMedPubMedCentral
55.
Chandak GR, Janipalli CS, Bhaskar S, Kulkarni SR, Mohankrishna P, Hattersley AT, Frayling TM, Yajnik CS: Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population. Diabetologia. 2007, 50: 63-67. 10.1007/s00125-006-0502-2.CrossRefPubMed
56.
Loos RJ, Franks PW, Francis RW, Barroso I, Gribble FM, Savage DB, Ong KK, O'Rahilly S, Wareham NJ: TCF7L2 polymorphisms modulate proinsulin levels and beta-cell function in a British Europid population. Diabetes. 2007, 56: 1943-1947. 10.2337/db07-0055.CrossRefPubMedPubMedCentral
57.
Florez JC, Jablonski KA, Bayley N, Pollin TI, de Bakker PI, Shuldiner AR, Knowler WC, Nathan DM, Altshuler D: TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med. 2006, 355: 241-250. 10.1056/NEJMoa062418.CrossRefPubMedPubMedCentral
58.
Pascoe L, Frayling TM, Weedon MN, Mari A, Tura A, Ferrannini E, Walker M: Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles. Diabetologia. 2008, 51: 1989-1992. 10.1007/s00125-008-1124-7.CrossRefPubMed
Metadata
Title
Large effects on body mass index and insulin resistance of fat mass and obesity associated gene (FTO) variants in patients with polycystic ovary syndrome (PCOS)
Authors
Susanne Tan
André Scherag
Onno Eilard Janssen
Susanne Hahn
Harald Lahner
Tiina Dietz
Susann Scherag
Harald Grallert
Carla Ivane Ganz Vogel
Rainer Kimmig
Thomas Illig
Klaus Mann
Johannes Hebebrand
Anke Hinney
Publication date
01-12-2010
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue 1/2010
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/1471-2350-11-12

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