Article:Association between fat mass and obesity associated (FTO) gene rs9939609 A/T polymorphism and polycystic ovary syndrome: a systematic review and meta-analysis. (5563909)
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Title: BMC Medical Genetics
Association between fat mass and obesity associated (FTO) gene rs9939609 A/T polymorphism and polycystic ovary syndrome: a systematic review and meta-analysis
- Ai Ling Liu
- Hui Jun Xie
- Hong Yan Xie
- Jun Liu
- Jie Yin
- Jin Song Hu
- Cui Ying Peng
Publication date (epub): 8/2017
Publication date (pmc-release): 8/2017
Publication date (collection): /2017
Up to now, numerous case-control studies have reported the associations between fat mass and obesity associated (FTO) gene rs9939609 A/T polymorphism and polycystic ovary syndrome (PCOS), however, without a consistent result. Hence we performed current systematic review and meta-analysis to clarify the controversial results.
Case-control studies reporting the relationship of rs9939609 A/T polymorphism and PCOS published before April 2015 were searched in Pubmed database without language restriction. Data was analyzed by Review Manager 5.2.
A total of five studies involving 5010 PCOS patients and 5300 controls were included for further meta-analysis. The results of meta-analysis showed that the FTO gene rs9939609 A/T polymorphism was significantly different between PCOS group and control group in different gene models (For AA + AT vs. TT: OR = 1.41, 95% CI = 1.28–1.55, P < 0.00001. For AA vs. AT + TT: OR = 1.54, 95% CI = 1.25–1.89, P < 0.0001. For AA vs. TT: OR = 1.74, 95% CI = 1.38–2.18, P < 0.00001. For A vs. T: OR = 1.36, 95% CI = 1.25–1.47, P < 0.00001, respectively) suggesting that A allele was a risk factor for PCOS susceptibility. Furthermore, subgroup analysis in Asian and Caucasian ethnicities also found significant association between rs9939609 A/T polymorphism and PCOS (In Asian subgroup: OR = 1.43, 95% CI = 1.29–1.59, P < 0.0001. In Caucasian subgroup: OR = 1.33, 95% CI = 1.08–1.64, P = 0.008)
This meta-analysis suggests that rs9939609 A/T polymorphism of FTO gene is associated with PCOS risk, and that A allele is a risk factor for PCOS susceptibility simultaneously.
Polycystic ovary syndrome (PCOS), a common endocrine metabolic disorder in women of childbearing age, is characterized by polycystic ovary (PCO), oligomenorrhea or amenorrhea, clinical or biochemical hyperandrogenism, and insulin resistance. In addition to leading to infertility, PCOS is closely associated with diabetes mellitus type 2, cardiovascular diseases and endometrial carcinoma [–]. It was firstly reported in 1935 by Stein et al. , but its etiology still remains ambiguous. Existing data suggests that genetics is an important factor in the occurrence and development of PCOS [, ]. In recent years, a total of more than 100 candidate genes have been set out to explore the associations between single nucleotide polymorphism (SNP) and PCOS , such as fat mass and obesity associated (FTO) gene.
The human FTO gene is located on the chromosome 16q12.2 with a wide expression range of almost all tissues [, ]. The protein coded by FTO gene belongs to 2-oxoglutarate-dependent nucleic acid demethylase, involving energy metabolism . In 2007, a genome-wide association study reported that FTO is associated with body mass index (BMI) and obesity . Obesity is a common characteristic in PCOS patients. It is reported that more than 50% PCOS cases are overweight/obese . So it is reasonable to assume that FTO gene might play a role in the pathogenesis of PCOS via BMI and/or obesity. Therefore, based on this assumption, many studies have been conducted to research the associations between FTO gene and the risk of PCOS.
Recently, a common single nucleotide polymorphism (SNP) (rs9939609) in the first intron of FTO gene with T to A change is widely investigated in PCOS. However, the results from different studies are controversial. Some studies observed the positive association of FTO with PCOS [–], while others studies found the opposite relationship [–]. A recent meta-analysis by Cai et al. showed that FTO rs9939609 polymorphism was associated with PCOS risk in East Asians but not in overall population . Imperfectly, this meta-analysis considered only one genetic model and not all included studies were involved in FTO rs9939609 polymorphism. Therefore, we carried out current systemic review and meta-analysis to clarify the associations between the SNP rs9939609 and susceptibility to PCOS.
A comprehensive literature research was conducted in Pubmed to identify the studies aimed at exploring the association between FTO rs9939609 polymorphism and PCOS risk. The following keywords were used: “fat mass and obesity associated gene or FTO”, “rs9939609”, “polycystic ovary syndrome or PCOS”. All researched articles were updated on 30 March 2015 without any language limitation. When one eligible article was screened, we would check the references list of this paper manually to identify additional relevant publications.
Selection of studies
Any study included in current meta-analysis must satisfy the following criteria: (a) Case-control studies aimed at investigating the association between FTO rs9939609 polymorphism and PCOS risk. (b) The number of genotypes and allele frequency in cases and controls were respectively available to calculate odds ratio (OR) with 95% confidence interval (CI). (c) Genotypes in control group meet the Hardy − Weinberg equilibrium (HWE) (d) PCOS patients accorded with one diagnose criteria of the following three: 1990 NIH, 2003 Rotterdam, and 2006 AE-PCOS Society [–].
Data extraction and analysis
Two investigators (Liu and Xie) independently extracted data from the qualified articles. The following information were extracted: the name of first author, publication time, ethnicity, country, sample size, diagnose criteria in PCOS and controls, genotype distribution in both case and control groups, and P value of HWE in control group. If any disagreement was generated, another author would take part in to resolve it and make a final decision.
The pooled odd ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of association between FTO rs9939609 polymorphism and PCOS. The associations were calculated under the following four genetic models: dominant model (AA + AT vs. TT), recessive model (AA vs. AT + TT), additive model (AA vs. TT) and allele model (A vs. T). Subgroup analysis classified by ethnicity was conducted to explore whether ethnicity has a special effect on this association.
Heterogeneity among studies was examined by Q-test and I2 statistic. When P < 0.05 for Q statistic or I2 > 50%, random effects model was used, otherwise fixed model was applied. To assess the stability of single study in overall effect, sensitivity analysis was performed by excluding each study once a time. Publication bias was estimated via funnel plot. All data analyses were performed by Review Manager 5.2. P < 0.05 was considered statistically significant.
Characteristics of included studies
The flow diagram of study selection was presented in Fig. 1. Based on the inclusion criteria, a total of five studies exploring the association between FTO rs9939609 and PCOS were eligible for current meta-analysis, involving 5010 PCOS patients and 5300 controls [–]. All of the eligible studies provided the genotypes or allele information. One study was excluded because whether the genotypes distribution in PCOS was consistent with HWE was not mentioned, leading to the number of genotypes in PCOS group uncountable. The study by Li et al.  was a two-stage design (a GWAS and a replication study) with two populations. Because the two populations was the same ethnicity background (Han of Chinese), we considered them as one study. Among the five studies, two studies were conducted in Caucasian population and three studies were in Asian population. The diagnosis of PCOS in all studies was based on Rotterdam criteria. All the selected studies were consistent with HWE in controls. The main characteristics of the included studies are presented in Table 1.Fig. 1
The flow chart of study selectionTable 1
Characteristics of included studies in this meta-analysis
|Barber et al.||2008||UK/Caucasian||Rotterdam criteria||Unknown||463||1336||99||231||133||212||644||480||0.870|
|Yan et al.||2009||China/Asian||Rotterdam criteria||Females proven fertile with normal menstrual cycle and ovarian morphology, and no family history of abnormal menses or hirsutism||215||227||5||55||155||1||43||183||0.361|
|Li et al.||2013||China/Asian||Rotterdam criteria||Regular menstrual cycle (26–35) and normal ovarian morphology||3599||3082||67||867||2665||29||563||2490||0.650|
|Kim et al.||2014||Korea/Asian||Rotterdam criteria||Women without special health problem||552||559||7||118||427||8||106||445||0.559|
|Ramos et al.||2015||Brazil/Caucasian||Rotterdam criteria||Non-hirsute,regular ovulatory cycles, no hormone drug taking at least 3 months before the study||181||96||39||83||59||17||47||32||0.971|
HWE Hardy-Weinberg equilibrium
The results of association between FTO polymorphism and PCOS risk were presented in Fig. 2. We found that the FTO rs9939609 A/T polymorphism was associated with PCOS risk under four genetic models (For AA + AT vs. TT: OR = 1.41, 95%CI = 1.28–1.55, P < 0.00001. For AA vs. AT + TT: OR = 1.54, 95% CI = 1.25–1.89, P < 0.0001. For AA vs. TT: OR = 1.74, 95% CI = 1.38–2.18, P < 0.00001. For A vs. T: OR = 1.36, 95% CI = 1.25–1.47, P < 0.00001, respectively), suggesting A allele was a risk factor for PCOS risk.Fig. 2
The association between FTO rs9939609 A/T polymorphism and risk of PCOS. (a) AA + AT vs. TT in overall analysis, (b) AA vs. AT + TT in overall analysis, (c) AA vs. TT in overall analysis, (d) A vs. T in overall analysis. For each study, the solid squares represent the ORs from the individual studies, horizontal lines represent corresponding 95% CIs. The pooled ORs and 95% CIs are shown by the shaded diamonds
In subgroup analysis stratified by ethnicity, significant association between FTO 9939609 A/T and PCOS risk was observed in Caucasian and Asian populations under dominant model (OR = 1.33, 95% CI = 1.08–1.64, P = 0.008; OR = 1.43, 95%CI = 1.29–1.59, P < 0.00001, respectively). The relative results were displayed in Fig. 3.Fig. 3
The association between FTO rs9939609 A/T polymorphism and risk of PCOS in subgroup model. The analysis was stratified by race. AA + AT vs. TT in subgroup (Caucasian and Asian) analysis of HWE > 0.05. The solid squares represent the ORs from the individual studies, horizontal lines represent corresponding 95% CIs. The pooled ORs and 95% CIs are presented as diamonds
Sensitivity analysis and publication bias
To confirm the stability of above results, a sensitivity analysis was performed by removing studies sequentially. The results showed that the corresponding pooled ORs and P value under different genetic models were not changed significantly. Publication bias of the recruited studies was evaluated using funnel plot, the shapes of the funnel plots did not show significant asymmetry (Fig. 4).Fig. 4
Funnel plot of publication bias in selection of studies on the FTO rs9939609 A/T polymorphism. Publication bias was assessed under dominant model (AA + AT vs. TT). SE represents standard error; OR represents odds ratio
As one of the most common endocrine disorder, the etiology of PCOS remains incompletely unknown. However, family studies have showed that genetic basis is responsible for PCOS and that no single gene can explain this syndrome entirely [–]. It is reported that 40–80% of PCOS women are overweight or obese [–]. Therefore, based on the high prevalence of obesity in PCOS and the heritable of obesity , genes associated with obesity might play a role in pathogenesis of PCOS such as FTO gene. Recent years, many studies have been conducted to identify the relationships between FTO rs9939609 and PCOS susceptibility. However, the results were inconsistent, making these associations more indistinct. The current meta-analysis was aimed at clarifying the association of FTO rs9939609 and PCOS.
In our meta-analysis, we found that FTO rs9939609 polymorphism was associated with PCOS under different genetic models. This finding is consistent with the study by Li et al. They performed a two stage study involving 3599 PCOS and 3082 control subjects in Chinese population . They found that rs9939609 polymorphism of FTO is associated with PCOS in Chinese women, no matter the PCOS women are obese or non-obese. This indicated that FTO might interact with PCOS directly. However, because of insufficient data, this potential interaction way can not be re-analyzed in our meta-analysis. Contrary to our result, a case-control study by Kim et al. observed that FTO polymorphisms of rs9939609 are not major determinants of PCOS. But for women with PCOS, the variant allele of FTO rs9939609 was associated with increased BMI, suggesting FTO polymorphism contributes to PCOS risk through affecting BMI indirectly . Therefore, the associations among PCOS, BMI/obese and FTO polymorphism still remain indistinct. FTO might indirectly play a role in PCOS risk via BMI/obese. Also, FTO might contribute to PCOS by directly interacting or via the combined direct and indirect ways. More studies are needed to demonstrate it.
In subgroup analysis, the significant association between FTO polymorphism and PCOS was found not only in Caucasian but also in Asian, suggesting ethnicity was not the potential source of heterogeneity. Partly in line with our result, a case-control study by Cai et al. observed that FTO rs9939609 polymorphism (or its proxy) was associated with PCOS only in East Asians, but not in Caucasians . In Caucasians subgroup of study by Cai et al., one of the two included studies was about FTO rs9939609 and another was about FTO rs8050136. So, we inferred this point might the source of different conclusion compared with our subgroup result.
Several limitations of this meta-analysis should be acknowledged. First, the number of studies included in our meta-analysis was relatively small, thus leading to smaller studies in subgroup analysis and weaken statistical power. Second, potential sources of heterogeneity in this meta-analysis should include other factors such as BMI, waist-to-hip ratio (WHR), obese. However, because of limited data, we could not explore these factors in current meta-analysis. Finally, it is well known that the etiology of PCOS involving in gene-gene, and gene-environment interactions. However these interactions could not be investigated in our meta-analysis due to insufficient information.
In conclusion, this meta-analysis provided evidence that the FTO rs9939609 polymorphism was significantly associated with risk of PCOS risk not only in Asians but also in Caucasians. Further large studies are needed to clarify the associations among the FTO rs9939609 polymorphism, BMI/obese and PCOS risk in the future.
This meta-analysis indicates that rs9939609 A/T polymorphism of FTO gene is associated with PCOS susceptibility, and that A allele is a risk factor for PCOS simultaneously.
Dr. Kai Li provided greatly technical help and writing assistance.
This research was supported by National Natural Science Foundation of China (NSFC, No. 31371277) and the Natural Science Foundation of Hunan Province (2016JJ6126).
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
- P HardimanOC PillayW AtiomoPolycystic ovary syndrome and endometrial carcinomaLancet200336193711810181210.1016/S0140-6736(03)13409-512781553
- R HomburgThe management of infertility associated with polycystic ovary syndromeReprod Biol Endocrinol2003110910.1186/1477-7827-1-10914617367
- E Diamanti-KandarakisC PiperiJ SpinaG ArgyrakopoulouL PapanastasiouA BergielePolycystic ovary syndrome: the influence of environmental and genetic factorsHormones (Athens)200651173410.14310/horm.2002.1116516728382
- IF SteinML LeventhalAmenorrhea associated with bilateral poly-cystic ovariesAm J Obstet Gynecol19352918119110.1016/S0002-9378(15)30642-6
- JH SegarsAH DeCherneyIs there a genetic basis for polycystic ovary syndrome?J Clin Endocrinol Metab20109552058206010.1210/jc.2010-051820444933
- JM VinkS SadrzadehCB LambalkDI BoomsmaHeritability of polycystic ovary syndrome in a Dutch twin-family studyJ Clin Endocrinol Metab20069162100210410.1210/jc.2005-149416219714
- H DemirciM YilmazMA ErgunE YurtcuN BukanG AyvazFrequency of adiponectin gene polymorphisms in polycystic ovary syndrome and the association with serum adiponectin, androgen levels, insulin resistance and clinical parametersGynecol Endocrinol201026534835510.3109/0951359090336705120388053
- JA HubacekV StanekM GebauerováA PilipcincováD DlouháR PoledneA FTO variant and risk of acute coronary syndromeClin Chim Acta201041115–161069107210.1016/j.cca.2010.03.03720362563
- TM FraylingNJ TimpsonMN WeedonE ZegginiRM FreathyCM LindgrenA common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesityScience2007316582688989410.1126/science.114163417434869
- CJ WillerEK SpeliotesRJF LoosS LiCM LindgrenIM HeidSix new loci associated with body mass index highlight a neuronal influence on body weight regulationNat Genet2009411253410.1038/ng.28719079261
- Y ShiM GuoJ YanW SunX ZhangL GengAnalysis of clinical characteristics in large-scale Chinese women with polycystic ovary syndromeNeuro Endocrinol Lett200728680781018063948
- Q YanJ HongW GuY ZhangQ LiuY SuAssociation of the common rs9939609 variant of FTO gene with polycystic ovary syndrome in Chinese womenEndocrine200936337738210.1007/s12020-009-9257-019859840
- TM BarberAJ BennettCJ GrovesU SovioA RuokonenH MartikainenAssociation of variants in the fat mass and obesity associated (FTO) gene with polycystic ovary syndromeDiabetologia20085171153115810.1007/s00125-008-1028-618478198
- T LiK WuL YouX XingP WangL CuiCommon variant rs9939609 in gene FTO confers risk to polycystic ovary syndromePLoS One201387e6625010.1371/journal.pone.006625023840863
- RB RamosPM SpritzerFTO gene variants are not associated with polycystic ovary syndrome in women from southern BrazilGene20155601252910.1016/j.gene.2015.01.01225592819
- JJ KimYM ChoiMA HongJM KimSS HwangGH LeeGene dose effect between a fat mass and obesity-associated polymorphism and body mass index was observed in Korean women with polycystic ovary syndrome but not in control womenFertil Steril201410241143114810.1016/j.fertnstert.2014.07.00425086788
- R SaxenaCK WeltPolycystic ovary syndrome is not associated with genetic variants that mark risk for type 2 diabetesActa Diabetol201350345145710.1007/s00592-012-0383-422389004
- KG EwensMR JonesW AnkenerDR StewartM UrbanekA DunaifFTO and MC4R gene variants are associated with obesity in polycystic ovary syndromePLoS One201161e1639010.1371/journal.pone.001639021283731
- X CaiC LiuS MouAssociation between fat mass- and obesity- associated (FTO) gene polymorphism and polycystic ovary syndrome: a meta-analysisPLoS One20149110.1371/journal.pone.008697224466303
- JK ZawadzkiA DunaifA DunaifJR GivensHaseltineGR MerriamDiagnostic criteria for polycystic ovary syndrome: towards a rational approachPolycystic Ovary Syndrome1992BostonBlackwell Scientific Publications377384
- Rotterdam. ESHRE/ASRM-Sponsored PCOS Consensus Workshop GroupRevised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndromeFertil Steril2004811192510.1016/j.fertnstert.2003.10.004
- R AzzizE CarminaD DewaillyE Diamanti-KandarakisHF Escobar-MorrealeW FutterweitPositions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an androgen excess society guidelineJ Clin Endocrinol Metab200691114237424510.1210/jc.2006-017816940456
- S FranksN GharaniM McCarthyCandidate genes in polycystic ovary syndromeHum Reprod Update20017440541010.1093/humupd/7.4.40511476353
- HF Escobar-MorrealeM Luque-RamirezJL San MillánThe molecular-genetic basis of functional hyperandrogenism and the polycystic ovary syndromeEndocr Rev200526225128210.1210/er.2004-000415561799
- M UrbanekA WoodroffeKG EwensE Diamanti-KandarakisRS LegroJF StraussCandidate gene region for polycystic ovary syndrome on chromosome 19p13.2J Clin Endocrinol Metab200590126623662910.1210/jc.2005-062216091490
- RS LegroAR KunselmanWC DodsonA DunaifPrevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected womenJ Clin Endocrinol Metab19998411651699920077
- TM BarberMI McCarthyJA WassS FranksObesity and polycystic ovary syndromeClin Endocrinol200665213714510.1111/j.1365-2265.2006.02587.x
- E WehrN SchweighoferR MöllerA GiulianiTR PieberB Obermayer-PietschAssociation of FTO gene with hyperandrogenemia and metabolic parameters in women with polycystic ovary syndromeMetabolism201059457558010.1016/j.metabol.2009.08.02319913856
- TM BarberSJ GoldingC AlveyJA WassF KarpeS FranksGlobal adiposity rather than abnormal regional fat distribution characterizes women with polycystic ovary syndromeJ Clin Endocrinol Metab2008933999100410.1210/jc.2007-211718089693
- AJ WalleyAI BlakemoreP FroguelGenetics of obesity and the prediction of risk for healthHum Mol Genet200615R124R13010.1093/hmg/ddl21516987875