Australian Journal of Basic and Applied Sciences

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1 AENSI Jounals Austalian Jounal of Basic and Applied Sciences ISSN: Jounal home page: A Study on Fat Mass and Obesity Associated (FTO) Gene s Vaiant in Egyptian Women with Polycystic Ovaian Syndome ¹Hussein G. Osman, ²Abdel Aziz A. El-Refaeey, ¹Ahmed M.A. El-Sokkay, 3 Mohamed M.A. El-Sokkay, ¹Rasha A. El-Saeed 1 Biochemisty Division, Depatment of Chemisty, Faculty of Science 2 Depatment of Obstetics and Gynecology, Faculty of Medicine 3 Depatment of Micobiology, Faculty of Phamacy, Mansoua Univesity, Mansoua-Egypt A R T I C L E I N F O A B S T R A C T Aticle histoy: Received 25 June 2014 Received in evised fom 8 July 2014 Accepted 25 July 2014 Available online 20 August 2014 Keywods: FTO vaiants- obesity - polycystic ovaian syndome - single nucleotide polymophism Vaiations in the fat mass and obesity associated (FTO) gene have ecently been associated with obesity among diffeent ethnic populations. Given that the phenotype of polycystic ovay syndome (PCOS) ovelaps with obesity, it has been hypothesized that the common s vaiant of FTO gene may be elated to PCOS susceptibility. We pefomed a case contol study on 50 women with PCOS, and 45 healthy women as the contol goup. The association between s vaiant of FTO gene and PCOS susceptibility in Egyptian women was examined. The A allele was significantly moe fequent among PCOS patients than in the contol goup (60% vs. 45.5%; A allele vs. T allele, OR = 2.37, P = 0.005). The A allele caie genotype (AA and AT) fequencies wee also significantly geate in PCOS patients than in the contols (82% vs. 64.4%; AT and AA vs. TT genotype, OR = 2.51, P = 0.049). In conclusions, the s vaiant in the FTO gene is associated with PCOS susceptibility in the Egyptian population, pobably because of its effect on body mass index (BMI) AENSI Publishe All ights eseved. To Cite This Aticle: Hussein G. Osman, Abdel Aziz A. El-Refaeey, Ahmed M.A. El-Sokkay, 3Mohamed M.A. El-Sokkay, ¹Rasha A. El- Saeed, A study on fat mass and obesity associated (FTO) gene s vaiant in Egyptian women with polycystic ovaian syndome. Aust. J. Basic & Appl. Sci., 8(13): , 2014 INTRODUCTION Polycystic ovaian syndome (PCOS) is the most common endocine abnomality in epoductive-age women, its pevalence is estimated to be 5 10% in diffeent ethnic populations and as much as 22% of women in geneal population have polycystic ovaies on ultasound. It is a heteogeneous disode, chaacteized by menstual distubances, clinical and biochemical manifestations of hypeandogenism and polycystic ovaies (Gesak and Fek, 2007 and Allahbadia and Mechant, 2011). The etiologies of PCOS have not been fully elucidated, it oiginates in multiple genetic and envionmental factos and its futhe development involves inteaction of divese ogans o tissues (Wang and Zhu, 2012). Obesity plays a key ole in the development of PCOS and affects about % of women with PCOS depending on ethnicity. Both PCOS and obesity ae consideed highly heitable complex diseases (Weh et al., 2010). Discovey of fat mass and obesity associated (FTO) gene was the fist majo success in the field of obesity genetics (Fayling et al., 2007 and Scutei et al., 2007). The human FTO gene is located on chomosome 16 and expessed in a wide ange of tissues, including the adipose tissue and specific aeas of the bain and muscles, suggesting its potential ole in body weight egulation (Weh et al., 2010). The FTO gene is highly polymophic, and seveal polymophisms of the gene have been descibed. The vaiant FTO s , located within the fist FTO inton has two alleles, A and T, the fome has been linked to an inceased isk fo both obesity and type 2 diabetes mellitus (De Luis et al., 2013). Seveal studies wee set out to establish whethe FTO vaiants also impact on the individual isk of PCOS, howeve contovesial esults wee obtained. Babe et al. (2008) and Yan et al. (2009) epoted an association between the FTO single nucleotide polymophism (SNP) s and PCOS. On the othe hand, studies of Tan et al. (2010), Weh et al. (2010) and Ewens et al. (2011) showed no association between SNPs in FTO and PCOS phenotype. Howeve, it is still unclea how this vaiation of FTO gene influences adiposity and body weight (Weh et al, 2010). Moeove, data egading these associations with PCOS in Egyptian population have not been studied befoe. Coesponding Autho: Ahmed M.A. El-Sokkay, Biochemisty Division, Depatment of Chemisty, Faculty of Science, aelsokkay@mans.edu.eg

2 99 Ahmed M.A. El-Sokkay et al, 2014 In the cuent study, the genotypes of the s polymophism of FTO in Egyptian PCOS patients and thei association with PCOS susceptibility have been investigated. Also, the influence of these genetic vaiants on some biochemical paametes has been examined. Subjects and methods: This study was done between August 2011 and Apil 2013, and included two goups of women. The fist goup was the PCOS goup which included 50 women with PCOS, ecuited fom the outpatient clinic of Obstetics and Gynecology depatment, Mansoua univesity hospitals, Egypt. Diagnosis of PCOS was made accoding to the 2003 Rottedam ESHRE/ASRM PCOS Consensus Wokshop Goup s diagnostic citeia. This poposes a diagnosis of PCOS when a patient meets two of the following thee citeia: (i) oligomenohea o amenohea fo at least 6 months; (ii) clinical and/o biochemical signs of hypeandogenism; (iii) polycystic ovaies on ultasound (Rottedam ESHRE/ASRM PCOS Consensus Wokshop Goup, 2004). Oligomenohea was defined as a eduction in the fequency of menses with intevals between 40 days and 6 months and hypeandogenism was defined as seum testosteone > 0.6 ng/ml, finally, polycystic ovaies wee defined as the pesence of 12 o moe follicles in each ovay measuing 2-9 mm in diamete and/o inceased ovaian volume (10 mm) (Gu et al., 2010). The citeia fo inclusion wee that: patients wee in thei epoductive age and none of them wee on hypoglycemic agents (including metfomin) o homonal theapy (including oal contaceptives) o undegone ovulation induction fo at least 3 months befoe enteing the study. Exclusion citeia included othe causes of hypeandogenism, as (andogen-seceting tumos, nonclassical adenal hypeplasia, and cushing's syndome), hypepolactinemia, diabetes, hypetension, thyoid disease, and enal diseases. The second goup was the contol goup, which included 45-age and BMI matched healthy women with egula menstual cycles, no clinical appeaance of hisutism, acne, alopecia, endocinopathies, o othe chonic illness and none of the contol goup had PCO pictue on ultasound. They wee ecuited in the follicula phase of menstual cycles and BMI of each patient defined as weight (kg)/height (m 2 ) was calculated. Witten infomed consent was obtained fom each paticipant, and the study potocol was appoved by Mansoua ethical committee. Collection of blood samples: Fasting whole blood samples (5ml) wee collected by vein punctue. The blood was divided into two pats, 3 ml wee placed into plain tubes and allowed to clot fo minutes, centifuged and the sepaated seum was stoed at -80 ºC fo futhe measuement of the biochemical paametes. The othe 2 ml of the whole blood wee taken in EDTA coated tubes fo extaction of DNA and pefoming genotyping woking. Biochemical Paametes: Seum concentations of total testosteone wee measued by a micoplate chemiluminescence immunoassay (Monbind Inc., Lake Foest, USA). Seum levels of total, tiglyceides, and high density lipopotein (HDL) wee measued by a commecially available kit (Spineact Co., Spain). Low density lipopotein (LDL) and vey low density lipopotein (VLDL) levels wee calculated using the fomulae of Tunali and Yanadag (2006). Genotype analysis: Genomic DNA was isolated fom blood samples using a DNA puification kit (Fementas, Gemany). The FTO SNP s was genotyped using ARMS-PCR. Pimes wee deived fom genomic enty AC ; s Fout: 5'-TGG CTC TTG AAT GAA ATA GGA TTC AGA A-3'; Rout: 5'-AGC CTC TCT ACC ATC TTA TGT CCA AAC A-3', Fin: 5'-TAG GTT CCT TGC GAC TGC TGT GAA TAT A-3', Rin: 5'-GAG TAA CAG AGA CTA TCC AAG TGC ATC TCA-3' (poduct size oute pimes: 321 bp, T-allele: 178 bp, A-allele: 201 bp) (Mülle et al, 2008). PCR was caied out in a 25 μl mixtue containing: 2.5 μl 1x PCR buffe, 0.75 μl MgCl 2, 1 μl DNTP mixtue, 0.35 μl of each pime, 0.5 μl Taq DNA polymease, μl ddh 2 O, and 5 μl genomic DNA. PCR poducts wee esolved by electophoesis in agaose gel and evealed by ethidium bomide. Fo validity of genotypes, alleles wee ated independently by at least two expeienced individuals. Statistical analyses: Statistical analyses wee caied out via Statistical Package fo Social Science (SPSS) vesion 17 pogam on windows XP. Qualitative data wee epesented in the fom of numbe and fequency, while quantitative data wee epesented in the fom of mean ± standad deviation (mean ± SD). Kolmogov-sminov test was used to test nomality of quantitative data. Peason-poduct coelation was used to test fo linea elationship between diffeent vaiables. χ2 and Fishe exact tests wee used to examine qualitative data. Wheeas, ANOVA and Kuskal Wallis tests wee used fo nomally and non-nomally

3 100 Ahmed M.A. El-Sokkay et al, 2014 distibuted quantitative data. Genetic association was pefomed by logistic egession. Results wee expessed as nominal P, odds atio (OR) and 95% confidence inteval (CI). Results wee consideed significant if P value is Results: In table 1, women with PCOS had significantly highe levels of total testosteone (P < 0.001). Also, significantly highe levels of total, tiglyceides, LDL and VLDL wee obseved in PCOS goup compaed to contols (P 0.001). No significant diffeence was obseved in levels of HDL between the studied goups (P = 0.259). Table 2 shows that a statistically significant negative coelation was obseved between age of PCOS goup and levels of HDL (P = 0.019). Also, thee was a statistically significant positive coelation between levels of total and levels of tiglyceides, LDL, and VLDL (P = 0.028, P < 0.001, P = 0.028, espectively). Moeove, a statistically significant positive coelation was obseved between levels of tiglyceides and levels of VLDL (P < 0.001). The obseved genotype distibutions wee consistent with hady Weinbeg equilibium, both in patients and contols (P = 0.56, P = 0.11, espectively, data not shown). In Table 3, the A allele was significantly moe fequent in PCOS patients than in the contols [60% vs. 45.6%; A allele vs. T allele, OR = 2.37, 95% CI = , P = 0.005], howeve, the stength of this association was attenuated afte adjustment of BMI (OR = 1.05, 95% CI = , P = 0.98). The AA genotype was pesent in 38% (n = 19) of PCOS women, the fequency of the AT genotype was 44% (n = 22) in PCOS women, and 18% (n = 9) of PCOS women wee TT. The fequency of genotypes in the contol goup was: AA; 26.7% (n = 12); AT; 37.8% (n = 17); and TT; 35.6% (n = 16). The A allele caie genotype (AA+AT genotypes) fequencies wee also significantly geate in PCOS patients compaed to the contols [82% vs.64.4%; AT and AA vs. TT genotype, OR = 2.51, 95% CI = , P = 0.049). Also, the stength of this association was attenuated afte adjustment of BMI (OR = 1.1, 95% CI = , P = 0.92). Fo futhe analysis, patients with PCOS wee divided into two subgoups accoding to FTO genotypes (Table 4). PCOS women caying the A allele had significantly highe levels of total and LDL than non-caies (P = 0.015, P = 0.027, espectively). No significant association was obseved between diffeent FTO genotypes and HDL, VLDL, tiglyceides, o total testosteone levels. Discussion: In the pesent study, PCOS women had significantly highe levels of total testosteone compaed to contols. This may be attibuted to inceased synthesis of testosteone pecusos due to a dysegulation of cytochome P450, (P450c17α), the ate-limiting enzyme in andogen biosynthesis in the theca cells of the ovay in PCOS. Hypeandogenemia was detected in aound 60% to 80% of PCOS cases and esults in the common symptoms of andogen excess in PCOS women, as hisutism, acne and alopecia (Allahbadia and Mechant, 2011). Also, in the cuent study, PCOS women had significantly highe levels of total, tiglyceides, LDL and VLDL compaed to contols (table 1). The etiology of this dyslipidemia in women with PCOS may be elated to othe factos that can influence lipid metabolism as (excess andogen, insulin esistance, vaiable amounts of estogen exposue, and some envionmental factos (Wild, 2012). Although most studies suggest an association between dyslipidemia and PCOS, esults ae conflicting. Most studies suggest that PCOS patients ae hypelipidemic (Oio et al., 2004 and Wild, 2012). On the othe hand, Bicketon et al. (2005) found no significant diffeences in lipids o lipopotein concentations between PCOS patients and weight matched contols. These conflicting esults may be elated to diffeent ethnicity with diffeent dietay habits. Table 2 shows that thee was a statistically significant negative coelation between age of PCOS goup and levels of HDL, this finding agees with that shown by Schaefe et al. (1994). Also, Wakabayashi (2012) suggested that HDL levels tend to be lowe by inceasing age. Futhemoe, thee was a statistically significant positive coelation between levels of total and levels of tiglyceides, LDL, and VLDL, these esults ae consistent with the esults of El-Hazmi et al. (1999). Moeove, a statistically significant positive coelation was obseved between levels of tiglyceides and levels of VLDL, this finding is consistent with the esults of Sommaiva et al. (1988), which suggested that as seum tiglyceide levels incease, VLDL levels ise and become eniched in tiglyceides. In the pesent wok, we studied the fequency distibutions of the diffeent genotypes of s polymophism of FTO gene in PCOS patients and contols. The A allele was significantly moe fequent in PCOS patients than in the contols (60% vs. 45.6%; A allele vs. T allele, P = 0.005).

4 101 Ahmed M.A. El-Sokkay et al, 2014 The A allele caie genotypes (AA and AT genotypes) fequency was also slightly significantly geate in PCOS patients compaed to the contols (82% vs. 64.4%; AT and AA vs. TT genotype, P = 0.049). These esults wee in ageement with that epoted by othe investigatos (Al-Atta et al., 2008; Villalobos-Compaan et al., 2008; Hassanein et al., 2010; Li et al., 2012 and Wojciechowski et al., 2012). Up to the best of ou knowledge, this is the fist epot of the association between FTO s vaiant with PCOS status in Egyptian women. The mechanism by which the s vaiant affects body size and pedicts the isk of PCOS is not pobably known. It may be elated to one o moe of the following factos: (1) multiple human studies suggest a link between vaious FTO isk alleles and inceased enegy intake, patients with at least one FTO isk allele epoted a geate intake of food, impaied satiety esponsiveness and moe fequent loss of eating contol than did those homozygous fo the non-isk allele (Lade et al., 2011). Also, AA homozygotic white women wee on aveage 3 kg heavie, with an inceased BMI of about 0.8 kg/m2, than those without the isk allele (Wojciechowski et al., 2012). (2) It has been shown that FTO gene encodes a 2-oxoglutaate dependent nucleic acid demethylase involved in divese pocesses, including DNA epai, fatty acid metabolism, and posttanslational modifications. It was suggested that it might egulate the expession of genes involved in metabolism and that dysegulation of this pocess might lead to obesity (Weh et al, 2010). (3) A diect effect of FTO vaiants on the development of PCOS, independent of the effects on fat mass may be pesent as epoted by ( Babe et al., 2008). (4) Recently, it has been suggested that the ole of FTO in the egulation of food intake is also linked to its function in the sensing of amino acids. FTO is most highly expessed in the hypothalamus, whee the sensing of amino acid levels has been demonstated to affect pathways contolling food intake. It was suggested that the isk alleles esult in subtle vaiations in the expession of FTO in key appetite contol centes within the bain, which ae likely to influence the way in which we sense and theefoe espond to amino acid levels (Gulati and Yeo, 2013). In the cuent study, no association was obseved between FTO s vaiant and BMI. These esults ae consistent with the esults of Yan et al. (2009) and Kowalska et al. (2012), who found no significant diffeences in BMI between diffeent FTO s vaiants in PCOS subjects. On the othe hand, othe studies showed that FTO isk allele was associated with a significant incease in BMI among PCOS women (Tan et al., 2010; Weh et al., 2010 and Ewens et al. 2011). This discepancy between esults could be due to inadequate powe; evidence shows that the case contol association is fa weake when esticted to the nonobese PCOS patients. To the extent that adjustment fo BMI diminishes the PCOS association, ou data suggests that the effect of FTO on PCOS susceptibility is mediated though its effect on fat mass and the isk of obesity, in a fashion analogous to the elationship between FTO vaiation and pedisposition to type 2 diabetes mellitus (Fayling et al., 2007). These findings ae consistent with the study of Yan et al. (2009) in China and Babe et al. (2008) in UK. On the othe hand, ou esults ae not in line with the esults of Tan et al. (2010), Weh et al. (2010) and Ewens et al. (2011). These conflicting esults might be attibuted to diffeences in ethnicity, envionmental, citeia in selecting cases and contols and effects of the SNPs in the genes. Also, in the pesent wok, the association of FTO s with clinical and biochemical paametes in PCOS women was examined. PCOS women caying at least one copy of A allele had significantly highe levels of total and LDL than non caies (Table 3). The exact pathophysiology of these findings was not pobably unknown, some studies suggest that the incease in consumed kilojoules of enegy in isk allele caies was due to an inceased pefeence fo enegy-dense foods, specifically those with a highe fat content, athe than a geneal incease in the amount of food consumed (Cecil et al., 2008 and Timpson et al., 2008). Othe investigatos, including, Weh et al. (2010); Kowalska et al. (2009) and Kowalska et al. (2012) found no significant association between FTO s diffeent genotypes and any of the lipid pofile paametes. In conclusion, ou esults demonstate that the common s vaiant in the FTO gene is associated with PCOS. Table 1: Clinical and some biochemical vaiables of PCOS patients and contols. PCOS Patients (50 cases) Age (Yeas) BMI (Kg/m 2 ) Total testosteone (ng/ml) Total (mg/dl) Tiglyceides (mg/dl) HDL- (mg/dl) LDL- (mg/dl) VLDL- (mg/dl) ± ± ± ± ± ± ± ± * Values ae expessed as mean ± SD; Statistical significance, P Contols (45 cases) ± ± ± ± ± ± ± ± 9.96 P value

5 102 Ahmed M.A. El-Sokkay et al, 2014 Table 2: Peason's coelation between age, BMI, and biochemical paametes among PCOS patients. Age BMI Total Tiglyceides HDL R R Total P = Tiglyceides P = HDL P = LDL P < VLDL P = P < Total Testosteone LDL Cholesteol P < VLDL R P = P < Table 3: Allele fequencies and genotypes of the FTO polymophism among women with PCOS and healthy contol women. PCOS (n=50) Contols (n=45) P value P a value OR (95% CI) Allele fequency A T Geneal genotypes AA AT TT Dominant genotype AT+AA TT Recessive genotype AT+TT AA 60 (60%) 40 (40%) 19 (38%) 22 (44%) 9 (18%) 41(82%) 9 (18%) 31 (62%) 19 (38%) 41 (45.6%) 49 (54.4%) 12 (26.7%) 17 (37.8%) 16 (35.5%) 29 (64.4%) 16 (35.6%) 33(73.3%) 12 (26.7%) Notes: - values ae given as numbes (pecent). OR = odds atio; CI = confidence inteval. - P a value: BMI adjusted P value ( ) 1.00 (Refeence) 2.82 ( ) 2.30 ( ) 1.00 (Refeence) 2.51 ( ) 1.00 (Refeence) 1.00 (Refeence) 1.69 ( ) Table 4: Clinical and biochemical vaiables of PCOS patients accoding to FTO genotypes. Caies of AT o AA Genotype (n = 41) Age (Yeas) ± 4.95 BMI (Kg/m2) 29.3 ± 6.31 Total testosteone (ng/ml) 0.78 ± 0.34 Total (mg/dl) ± Tiglyceides (mg/dl) ± HDL (mg/dl) ± LDL (mg/dl) ± VLDL (mg/dl) ± Caies of TT Genotype (n = 9) ± ± ± ± ± ± ± ± P-value Fig. 1: Detection of s gene polymophism by ARMS-PCR. PCR poducts of nine diffeent individuals with thee possible genotypes (AT, AA, o TT).

6 103 Ahmed M.A. El-Sokkay et al, 2014 REFERENCES The Rottedam ESHRE/ASRM-Sponsoed consensus wokshop goup, Revised 2003 consensus on diagnostic citeia and long-tem health isks elated to polycystic ovay syndome (PCOS). Hum Repod, 19(1): Al-Atta, S.A., R.L. Pollex, M.R. Ban, T.K. Young, P. Bjeegaad, S.S. Anand, S. Yusuf, B. Zinman, S.B. Hais, A.J. Hanley, Association between the fto s polymophism and the metabolic syndome in a non-caucasian multi-ethnic sample. Cadiovasc Diabetol, 7(5). Allahbadia, G.N. and R. Mechant, Polycystic ovay syndome and impact on health. Middle East Fetility Society Jounal, 16(1): Babe, T.M., A.J. Bennett, C.J. Goves, U. Sovio, A. Ruokonen, H. Matikainen, A. Pouta, A. L. Hatikainen, P. Elliott, C.M. Lindgen, Association of vaiants in the fat mass and obesity associated (FTO) gene with polycystic ovay syndome. Diabetologia, 51(7): Bicketon, A.S., N. Clak, D. Meeking, K.M. Shaw, M. Cook, P. Lumb, C. Tune and M.H. Cummings, Cadiovascula isk in women with polycystic ovaian syndome (PCOS). J Clin Pathol, 58(2): Cecil, J.E., R. Tavendale, P. Watt, M.M. Hetheington and C.N. Palme, An obesity-associated FTO gene vaiant and inceased enegy intake in childen. N Engl J Med, 359(24): De Luis, D.A., R. Alle, R. Conde, O. Izaola, B. De La Fuente and M.G. Sagado, Relation of the s gene vaiant in fto with metabolic syndome in obese female patients. Jounal of Diabetes and its Complications, 27(4): El-Hazmi, M.A., A.R. Al-Swailem, A.S. Wasy, A.A. Al-Meshai, R. Sulaimani, A.M. Al-Swailem and G.M. Magbool, Lipids and elated paametes in saudi type ii diabetes mellitus patients. Ann Saudi Med, 19(4): Ewens, K.G., M.R. Jones, W. Ankene, D.R. Stewat, M. Ubanek, A. Dunaif, R.S. Lego, A. Chua, R. Azziz, R.S. Spielman, Type 2 diabetes susceptibility single-nucleotide polymophisms ae not associated with polycystic ovay syndome. Fetility and Steility, 95(8): Fayling, T.M., N.J. Timpson, M.N. Weedon, E. Zeggini, R.M. Feathy, C.M. Lindgen, J.R. Pey, K.S. Elliott, H. Lango, N.W. Rayne, A common vaiant in the fto gene is associated with body mass index and pedisposes to childhood and adult obesity. Science, 316(5826): Gesak, K. and P. Fek, Genetics of polycystic ovay syndome. Gynaecol Peinatol, 16(2): Gu, B.H., J.M. Pak and K.H. Baek, Genetic vaiations of follicle stimulating homone ecepto ae associated with polycystic ovay syndome. Int J Mol Med, 26(1): Gulati, P. and G.S. Yeo, The biology of FTO: Fom nucleic acid demethylase to amino acid senso. Diabetologia, 56(10): Hassanein, M.T., H.N. Lyon, T.T. Nguyen, E.L. Akylbekova, K. Wates, G. Lette, B. Tayo, T. Foeste, D.F. Sapong, D.O. Stam, Fine mapping of the association with obesity at the fto locus in afican-deived populations. Hum Mol Genet, 19(14): Kowalska, I., A. Adamska, M.T. Malecki, M. Kaczewska-Kupczewska, A. Nikolajuk, M. Szopa, M. Goska and M. Staczkowski, Impact of the fto gene vaiation on fat oxidation and its potential influence on body weight in women with polycystic ovay syndome. Clin Endocinol (Oxf), 77(1): Kowalska, I., M.T.Malecki, M. Staczkowski, J. Skupien, M. Kaczewska-Kupczewska, A. Nikolajuk, M. Szopa, A. Adamska, N. Wawusiewicz-Kuylonek, S. Wolczynski, The fto gene modifies weight, fat mass and insulin sensitivity in women with polycystic ovay syndome, whee its ole may be lage than in othe phenotypes. Diabetes Metab, 35(4): Lade, R., M.K.M. Cheung, Y.C.L. Tung, G.S.H. Yeo and A.P. Coll, Whee to go with FTO? Tends in Endocinology andmetabolism, 22(2): Li, H., T.O. Kilpelainen, C. Liu, J. Zhu, Y. Liu, C. Hu, Z. Yang, W. Zhang, W. Bao, S. Cha, Association of genetic vaiation in fto with isk of obesity and type 2 diabetes with data fom 96,551 east and south asians. Diabetologia, 55(4): Mulle, T.D., A. Hinney, A. Scheag, T.T. Nguyen, F. Scheine, H. Schafe, J. Hebeband, C.L. Roth and T. Reineh, 'fat mass and obesity associated' gene (FTO): No significant association of vaiant s with weight loss in a lifestyle intevention and lipid metabolism makes in geman obese childen and adolescents. BMC Med Genet, 9(85). Oio, F., J., S. Palomba, L. Spinelli, T. Cascella, L. Tauchmanova, F. Zullo, G. Lombadi and A. Colao, The cadiovascula isk of young women with polycystic ovay syndome: An obsevational, analytical, pospective case-contol study. J Clin Endocinol Metab, 89(8): Schaefe, E.J., S. Lamon-Fava, S.D. Cohn, M.M. Schaefe, J.M. Odovas, W.P. Castelli and P.W. Wilson, Effects of age, gende, and menopausal status on plasma low density lipopotein and apolipopotein b levels in the famingham offsping study. J Lipid Res, 35(5):

7 104 Ahmed M.A. El-Sokkay et al, 2014 Scutei, A., S. Sanna, W.M. Chen, M. Uda, G. Albai, J. Stait, S. Najja, R. Nagaaja, M. Ou, G. Usala, Genome-wide association scan shows genetic vaiants in the fto gene ae associated with obesity-elated taits. PLoS Genet, 3(7), e115. Sommaiva, D., A. Banchi, M. Tiito, D. Bonfiglioli, C. Pini, L. Scandiani, C. Ottomano and A. Fasoli, Relationship of seum tiglyceide concentation to lipopotein composition and concentation in nomolipidemic and hypelipidemic subjects. Ric Clin Lab, 18(4): Tan, S., A. Scheag, O.E. Janssen, S. Hahn, H. Lahne, T. Dietz, S. Scheag, H. Gallet, C.I. Vogel, R. Kimmig, Lage effects on body mass index and insulin esistance of fat mass and obesity associated gene (FTO) vaiants in patients with polycystic ovay syndome (PCOS). BMC Med Genet, 11(12). Timpson, N.J., P.M. Emmett, T.M. Fayling, I. Roges, A.T. Hattesley, M. I. Mccathy and G. Davey Smith, The fat mass- and obesity-associated locus and dietay intake in childen. Am J Clin Nut, 88(4): Tunali, S. and R. Yanadag, Effect of vanadyl sulfate on the status of lipid paametes and on stomach and spleen tissues of steptozotocin-induced diabetic ats. Phamacological Reseach, 53(3): Villalobos-Compaan, M., M. Teesa Floes-Doantes, M. Teesa Villaeal-Molina, M. Rodiguez-Cuz, A.C. Gacia-Ulloa, L. Robles, A. Huetas-Vazquez, N. Saucedo-Villaeal, M. Lopez-Alacon, F. Sanchez- Munoz, The FTO gene is associated with adulthood obesity in the mexican population. Obesity (Silve Sping), 16(10): Wang, Y.X. and W.J. Zhu, Evaluation of adiponectin, esistin, il-6, tnf-α in obese and non-obese women with polycystic ovay syndome. Jounal of Repoduction and Contaception, 23(4): Weh, E., N. Schweighofe, R. Molle, A. Giuliani, T.R. Piebe and B. Obemaye-Pietsch, Association of fto gene with hypeandogenemia and metabolic paametes in women with polycystic ovay syndome. Metabolism, 59(4): Wojciechowski, P., A. Lipowska, P. Rys, K.G. Ewens, S. Fanks, S. Tan, E. Lechbaum, J. Vcelak, R. Attaoua, M. Staczkowski, Impact of fto genotypes on bmi and weight in polycystic ovay syndome: A systematic eview and meta-analysis. Diabetologia, 55(10): Yan, Q., J. Hong, W. Gu, Y. Zhang, Q. Liu, Y. Su, X. Li, B. Cui and G. Ning, Association of the common s vaiant of fto gene with polycystic ovay syndome in chinese women. Endocine, 36(3):