Abstract
Genetic factors play an important role in women’s fertility and embryonic development and may also contribute to the efficacy of assisted reproduction techniques. The aim of this study was to investigate the effect of His447His and Pro12Ala peroxisome proliferator-activated receptor γ (PPARγ) gene polymorphisms on oocytes and fertilization in women undergoing IVF. Follicular fluid and blood samples were obtained from 98 IVF patients referred to Tabriz Alzahra Hospital. Samples were analysed for fatty acid content by gas–liquid chromatography and for polymorphisms of the PPARγ gene using polymerase chain reaction-restriction fragment length polymorphism-based methods. Multiple regression analyses were used to test the independence of associations between the number of mature and fertilized oocytes as outcome variables and the polymorphisms of PPARγ gene. For both polymorphisms, fertilization ratio was significantly (P < 0.05) higher in carriers of the rare alleles than homozygous wild-type genotypes. The associations of His447His (P = 0.003) and Pro12Ala (P = 0.015) polymorphisms remained statistically significant in the multiple regression analyses. This study suggests that the two common gene polymorphisms of PPARγ may improve fertilization in vitro and, thus possibly, female fertility.
Keywords
Introduction
Peroxisome proliferator-activated receptors (PPAR) are nuclear receptors that regulate lipid and glucose metabolism and cellular differentiation. The subtype γ of the PPAR family (PPARγ) plays important roles in glyceroneogenesis, lipid uptake, lipid synthesis, lipid storage and lipolysis (
Chinetti-Gbaguidi et al., 2005
). PPARγ activators improve insulin sensitivity and lower blood glucose concentrations in patients with type 2 diabetes (Chinetti-Gbaguidi et al., 2005
). Low PPARγ activity has been shown to be associated with lower circulating androgen concentrations (Perret et al., 2002
). Antoine et al., 2007
found that PPARγ is an important modifier gene in the general population, but not in polycystic ovary syndrome (PCOS) patients. It has been shown that mice deleted for PPARγ specifically in granulosa cells released a reduced number of oocytes, suggesting that PPARγ is involved in regulating ovulation (Kim et al., 2008
). On the other hand, Cui et al., 2002
observed that although rodent PPARγ knockout models appeared to ovulate normally, they tended to exhibit reduced progesterone secretion as well as impaired implantation. So the relationship between PPARγ and infertility is controversial (- Cui Y.
- Miyoshi K.
- Claudio E.
- Siebenlist U.K.
- Gonzalez F.J.
- Flaws J.
- Wagner K.U.
- Hennighausen L.
Loss of the peroxisome proliferation-activated receptor gamma (PPARgamma) does not affect mammary development and propensity for tumor formation but leads to reduced fertility.
J. Biol. Chem. 2002; 277: 17830-17835
Minge et al., 2008
).Two common influential single nucleotide polymorphisms (SNP) that have been detected in the PPARγ gene include His447His polymorphism (rs3856806, also known as C161T) in exon 6 and Pro12Ala polymorphism (rs1801282) in exon 2. Despite intense study, it is still unclear whether, how and under which circumstances these PPARγ common gene variations affect female fertility. The less common T allele of the silent His447His polymorphism has been associated with low PPARγ activity, decreased ovarian androgen biosynthesis and higher risk of PCOS (
Gu and Baek, 2009
). On the contrary, a study reported that while the His447His polymorphism did not influence risk of PCOS or its component phenotypes in women with PCOS, it significantly reduced insulin resistance in the control group (Antoine et al., 2007
). Pro12Ala is a very common SNP arising from C → G transition that leads to a missense mutation with the substitution of proline for alanine at codon 12 (Yen et al., 1997
). The Pro12Ala variant of the PPARγ gene is associated with decreased PPARγ activity (- Yen C.J.
- Beamer B.A.
- Negri C.
- Silver K.
- Brown K.A.
- Yarnall D.P.
- Burns D.K.
- Roth J.
- Shuldiner A.R.
Molecular scanning of the human peroxisome proliferator activated receptor gamma (hPPAR gamma) gene in diabetic Caucasians: identification of a Pro12Ala PPAR gamma 2 missense mutation.
Biochem. Biophys. Res. Commun. 1997; 241: 270-274
Deeb et al., 1998
). Previous studies on the PPARγ Pro12Ala polymorphism have shown either no association with the risk of PCOS or diabetes (Orio et al., 2003
, Ringel et al., 1999
, Xita et al., 2009
) or a higher insulin sensitivity and elevated risk of PCOS for the carriers of mutated alleles (Altshuler et al., 2000
, - Altshuler D.
- Hirschhorn J.N.
- Klannemark M.
- Lindgren C.M.
- Vohl M.C.
- Nemesh J.
- Lane C.R.
- Schaffner S.F.
- Bolk S.
- Brewer C.
- Tuomi T.
- Gaudet D.
- Hudson T.J.
- Daly M.
- Groop L.
- Lander E.S.
The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes.
Nat. Genet. 2000; 26: 76-80
Gu and Baek, 2009
, Hara et al., 2000
).Recent findings showed that the activity of ovarian PPARγ directs follicular selection and maturation (
Minge et al., 2006
). The Pro12Ala and His447His polymorphisms are the most frequently found genetic variants of PPARγ and have also been identified as gender-specific genetic modulators of metabolic homeostasis (Chen et al., 2011
). Therefore, these genetic variations could be of potential relevance to reproductive medicine. To test this hypothesis, the influence of PPARγ His447His and Pro12Ala polymorphisms on fertility status were investigated in IVF patients.- Chen C.H.
- Lu M.L.
- Kuo P.H.
- Chen P.Y.
- Chiu C.C.
- Kao C.F.
- Huang M.C.
Gender differences in the effects of peroxisome proliferator-activated receptor gamma2 gene polymorphisms on metabolic adversity in patients with schizophrenia or schizoaffective disorder.
Prog. Neuropsychopharmacol. Biol Psychiatry. 2011; 35: 239-245
Materials and methods
Subjects
A total of 98 patients were recruited from a patient population scheduled for IVF at Alzahra Hospital in Tabriz between 1 February 2007 and 1 February 2009. The study was approved by the ethics committee of Tabriz University of Medical Sciences, and all patients gave written informed consent. The mean age of subjects was 32 years, who had unexplained infertility after a standard infertility evaluation, including a semen analysis, hormonal testing, assessment of the uterus and Fallopian tubes by means of hysterosalpingography and postcoital testing. All women had regular menstrual cycles and midluteal progesterone was in the ovulatory range. Inclusion criteria were a healthy husband with a normal spermogram and no smoking habit. Uterus abnormalities, endometriosis, poor ovarian response (<4 ovarian dominant follicles or mature oocytes at retrieval), positive history of endocrine disease and inflammatory disorders such as PCOS, thyroid and adrenal disorders and immune system defects were considered as exclusion criteria in this study. All samples were collected on day 14 of the menstrual cycle.
Ovarian stimulation was achieved with a gonadotrophin-releasing hormone agonist (decapeptyl; Debio Pharm, Geneva, Switzerland)/FSH-long down-regulation protocol. Ovarian stimulation was started with recombinant human FSH (rFSH, Gonal-F; Serono, Switzerland) on day 3 of menstrual cycle. The daily rFSH dose ranged between 150 and 300 IU, depending on body mass index, age of the women and the anticipated ovarian response. Dose adjustment was performed according to follicular development and serum oestradiol concentrations. Intramuscular human chorionic gonadatrophin (HCG, 1000 IU; Choriomon, Meizler, Brazil) was administered when sonography revealed three preovulatory follicles with an average diameter of 18–20 mm.
Oocyte retrieval was performed 36 h after HCG administration by vaginal ultrasound-guided puncture of the ovarian follicles. The collected oocytes were incubated at 37°C with 5% CO2 for 4 h and were then used for IVF. To eliminate cellular components, follicular fluid samples were centrifuged at 500g for 5 min and were frozen at −70°C until analysis.
Oocytes with sporadic cumulus oophorus and zona pellucida and also a clear ooplasm were selected for insemination (
Trounson and Gardner, 1999
). The swim-up technique was used to prepare spermatozoa for IVF. Retrieved oocytes were inseminated with 250,000 spermatozoa per oocyte in the IVF technique (Brinsden and Hall, 1999
). A maximum of three embryos were transferred at 4–8-cell stages after 48 h, using ultrasound guidance. Pregnancy was assessed by the β-HCG test, 14 days after embryo transfer. The fertilization rate was defined as the proportion of oocytes with two pronuclei.Follicular fluid fatty acid methyl esters were prepared by transmethylation and analysed for fatty acid composition as previously described (
Noori et al., 2009
). Genetic analyses were performed on genomic DNA isolated from circulating leukocytes. DNA fragments were amplified by polymerase chain reaction, using the same conditions and oligonucleotide primers as previously described (Orio et al., 2003
). Genotyping for the PPARγ His447His and Pro12Ala polymorphisms was performed by PmlI and HgaI digestion, respectively (Supplementary Figure 1, available online only).Statistical analysis
Values are presented as mean ± SD. Statistically significant differences in mean values between genotypes were assessed by t-tests. Analysis of variance test was used for comparing the group means and ratios. The relationship between two sets of variables was assessed by the Pearson’s linear correlation coefficient method. To evaluate the relative independence of the observed relationships, a multiple regression analysis with calculation of the standardized partial regression coefficient (β) was performed. A P-value <0.05 was considered statistically significant. All analyses were carried out using Statistical Package for Social Sciences for Windows version 11.0 (SPSS, Chicago, IL, USA).
Results
The clinical details and fatty acid content of follicular fluid of the study subjects and the husbands’ spermogram results are presented in Table 1. The average numbers of mature and of fertilized oocytes were 9.2 and 5.0, respectively. The pregnancy rate in the studied population was 32.3%. Correlation analysis showed significant inverse correlations between the age of women and the number of mature oocytes retrieved (r = −0.37, P = 0.001) and oocytes fertilized (r = −0.25, P = 0.015).
Table 1Characteristics of the study sample.
| Characteristic | Study sample (n = 98) |
|---|---|
| Age (years) | 31.4 ± 5.0 (20–40) |
| Body mass index (kg/m2) | 23.86 ± 1.4 (20–28) |
| Oocytes | |
| Mature (n) | 9.2 ± 5.2 (1–20) |
| Fertilized (n) | 4.98 ± 3.2 (1–14) |
| Follicular fluid fatty acid composition (%) | |
| SFA | 40.71 ± 4.5 (19–50) |
| MUFA | 15.22 ± 2.7 (7–23) |
| PUFA-ω6 | 40.59 ± 4.7 (31–63) |
| PUFA-ω3 | 3.2 ± 4.5 (0.85–44) |
| SFA/PUFA | 16.2 ± 2.7 (8–24) |
| PUFA-ω6/PUFA-ω3 | 17.9 ± 8.5 (1–41) |
| Pregnancy | 32.3 |
| Spermatozoa | |
| Count (106/ml) | 61.1 ± 15.8 (25–90) |
| Motility (%) | 78.4 ± 9.1 (60–100) |
| Normal morphology (%) | 44.6 ± 9.7 (25–71) |
| Viability (%) | 84.5 ± 7.4 (67–97) |
Values are mean ± SD (range) or %.
Laboratory pregnancy assessed by β-HCG test, 14 days after embryo transfer.
MUFA = monounsaturated fatty acids; PUFA = polyunsaturated fatty acids; SFA = saturated fatty acids.
No mutant homozygous for His447His or Pro12Ala polymorphism was found in the studied population. Genotypic and allele distribution for both polymorphisms were in the Hardy–Weinberg equilibrium. There were no significant differences between the three genotype groups for anthropometric indexes (data not shown). The results of correlation analyses showed no relationship between pregnancy rate and any of the SNPs tested. The associations of genotypes with the in-vitro fertility parameters are presented in Table 2. No significant association between these polymorphisms and the number of mature and fertilized oocytes was observed. The fertilization ratio, however, was significantly increased in both carriers of PPARγ His447His T allele (P = 0.021) and PPARγ Pro12Ala G allele (P = 0.036). After adjustment for age, body mass index, sperm count and sperm motility, differences became more significant (P = 0.006 and P = 0.019, respectively; Table 2). This elevation remained significant even after adjustment for the fatty acid content of follicular fluid (P = 0.003 and P = 0.015, respectively). Haplotype analysis also showed that women carrying the combined T allele of His447His and G allele of Pro12Ala had a higher fertilization ratio (P = 0.003) compared with those carrying wild-type genotypes for both genes (Table 2).
Table 2Association of PPARγ gene polymorphisms with fertilization parameters.
| Genotype | n | Mature oocytes | Fertilized oocytes | Fertilization ratio |
|---|---|---|---|---|
| His447His | ||||
| CC | 80 | 9.71 ± 5.03 | 5.11 ± 3.24 | 0.53 ± 0.19 |
| CT | 18 | 7.27 ± 5.61 | 4.39 ± 3.16 | 0.69 ± 0.27 |
| P | – | NS | NS | 0.021 |
| P | – | NS | NS | 0.006 |
| P | – | NS | NS | 0.003 |
| Pro12Ala | ||||
| CC | 76 | 9.59 ± 5.22 | 5.04 ± 3.26 | 0.54 ± 0.19 |
| CG | 22 | 8.14 ± 5.01 | 4.77 ± 3.18 | 0.64 ± 0.24 |
| P | – | NS | NS | 0.036 |
| P | – | NS | NS | 0.019 |
| P | – | NS | NS | 0.015 |
| Combined genotype | ||||
| All other genotype combinations | 80 | 9.71 ± 5.03 | 5.11 ± 3.24 | 0.53 ± 0.19 |
| His447His CT and Pro12Ala CG | 18 | 7.27 ± 5.60 | 4.38 ± 3.16 | 0.69 ± 0.27 |
| P | – | NS | NS | 0.021 |
| P | – | NS | NS | 0.007 |
| P | – | NS | NS | 0.003 |
Values are mean ± SD. P-values were calculated using the t-test. The observed power for tests were at least 0.83 (computed using alpha = 0.05).
NS = not statistically significant.
a Adjusted for age, body mass index, sperm count and sperm motility.
b Adjusted for age, body mass index, sperm count, sperm motility and saturated, monounsaturated and polyunsaturated fatty acids.
In multiple regression analyses, the independence of observed relationships between PPARγ polymorphisms and fertility ratio was analysed, as indicated in Table 3. Only T allele of PPARγ His447His polymorphism (β = 0.28, P = 0.01) was an independent factor associated with a raised fertilization ratio. PPARγ His447His polymorphism remained significantly associated with fertilization ratio after additional adjustment for follicular fatty acid composition (β = 0.27, P = 0.01). Notably, after adjustment for fatty acid content of follicular fluid, an independent association (β = 0.15, P = 0.04) was also found between PPARγ Pro12Ala genotype and fertilization ratio.
Table 3Multiple regression analysis of the contribution of the PPARγ gene polymorphisms to the fertilization ratio.
| Adjusted | Adjusted | |||
|---|---|---|---|---|
| β | P-value | β | P-value | |
| His447His | 0.28 | 0.01 | 0.27 | 0.01 |
| Pro12Ala | 0.10 | NS | 0.15 | 0.04 |
β = standardized partial regression coefficient; NS = not statistically significant.
a Multiple regression adjusted: age, body mass index, sperm count and sperm motility.
b In addition to variables in the multiple regression adjusted model, follicular fluid fatty acid content is also included.
Discussion
IVF has been generally recognized as the world’s leading treatment in the field of reproductive medicine, with many benefits such as effectiveness in various infertility conditions and no long-term problems for children conceived (
Gass et al., 2009
, Gibbs, 2010
, Stampfer and Colditz, 1991
, Weiss et al., 1980
). Study of potential genetic polymorphisms related to IVF rate can provide a better understanding of the role of genetics in the aetiology, diagnosis and management of female infertility. The present study has examined, as far as is known for the first time, whether PPARγ His447His and Pro12Ala polymorphisms in women undergoing IVF could affect their fertility.The effect of age on the number of retrieved oocytes agrees with previous studies, which affirms that age diminishes female fertility (
Baird et al., 2005
). However, in the present study the population had a lower age compared with similar studies (Thyzel et al., 2005
), which probably minimizes the effect of age on the reproductive system. In contrast with the present study, higher ratios of fertilized oocytes to the number of mature oocytes and pregnancy rates have been previously reported. For example, Matsubayashi et al., 2006
showed that the ratio of fertilized oocytes to mature oocytes was 70% and Von et al., 2010
reported a 45% rate of positive pregnancy. These might be attributed to the presence of higher burdens of environmental risk factors among people of reproductive age in the local population.PPARγ activation plays a key role in the processes such as modulating fatty acid uptake and energy expenditure in the liver (
Auwerx et al., 2003
). Besides its role in energy metabolism, PPARγ has also been shown to be involved in regulating ovarian follicle development, ovulation and oocyte maturation by either inducing or inhibiting steroidogenesis, angiogenesis, tissue remodelling, apoptosis and lipid metabolism (Froment et al., 2006
, Komar, 2005
, Kwintkiewicz et al., 2010
). These processes are necessary for follicle development and female fertility; it seems so obvious that they can be influenced by PPARγ genetic variations, which may alter expression and/or function of this nuclear receptor.The present findings showed that compared with the no-polymorphism group, patients heterozygous for both the 447His and 12Ala alleles had a higher fertilization ratio. Haplotype analyses also reproduced these associations. Since their identification, the two common polymorphisms His447His and Pro12Ala at the PPARγ loci have reportedly been clinically associated with the risk of PCOS and diabetes in women (
Jeninga et al., 2009
), indicating that they may influence PPARγ activity. Being located in exon 2 of the gene, the Pro12Ala variant substitutes a basic amino acid residue with a neutral one, but whether this variation itself has a direct effect on the function of PPARγ gene is not yet clear. Alternatively, the independent association of the PPARγ Pro12Ala polymorphism with oocyte fertilization ratio after adjustment for confounding factors may be due to a linkage disequilibrium with other mutations or variations in the PPARγ gene or in other genes that can affect oocyte function during IVF.The most significant association found in this study is for PPARγ His447His polymorphism. The His447His polymorphism, associated with fertilization ratio, is a synonymous coding SNP on exon 7. Although the C → G polymorphism at codon 447 does not result in an amino acid change in the PPARγ protein, it is located in a known functional domain of the PPARγ gene that directly affects protein structure or expression level (). As a ligand-sensitive transcription factor, PPARγ could be involved in regulation of the expression of genes essential at a specific stage during ovulation and thus influence the fertilizability of oocytes and their subsequent development to blastocysts.
The Gly482Ser variant in PPARGC1A, as a coactivator of PPARs, has been found to be associated with insulin resistance and PCOS. These associations were stronger when combined with mutations in the PPAR genes, such as PPARδ −87T/C polymorphism (
San-Millan and Escobar-Morreale, 2010
). On the other hand, some new evidence has been presented suggesting that PPAR plays a key role in several aspects of embryo development. Huang et al., 2007
have described PPARδ as a potential target to stimulate embryo hatching and implantation. The PPARγ gene locus has also been linked to preterm birth (Meirhaeghe et al., 2007
) and dizygotic twinning (Duffy et al., 2001
). Collectively, the observed effect of PPARγ polymorphisms on fertility can be explained by the effect of each polymorphism on the ability of oocytes to be fertilized and develop into embryos. Although there was a significant association between Pro12Ala and fertilization ratio, this association was not independent of the His447His. However, a statistically independent association was still detected, after adjustment for follicular fatty acid composition, suggesting an interaction effect among the fertilizability of oocytes, fatty acid status and PPARγ polymorphisms. One explanation for the observed difference between His447His and Pro12Ala may relate to a difference in PPARγ function. It seems that the fertility-changing effect of Pro12Ala is dependent on metabolic status. It has been shown that the effect of Pro12Ala polymorphism on type 2 diabetes mellitus and insulin sensitivity depends on fatty acid status of the host (Soriguer et al., 2006
). In epidemiological studies, certain dietary fatty acids have been associated with the development of infertility (- Soriguer F.
- Morcillo S.
- Cardona F.
- Rojo-Martinez G.
- de la Cruz A.M.
- Ruiz de Adana M.L.
- Olveira G.
- Tinahones F.
- Esteva I.
Pro12Ala polymorphism of the PPARG2 gene is associated with type 2 diabetes mellitus and peripheral insulin sensitivity in a population with a high intake of oleic acid.
J. Nutr. 2006; 136: 2325-2330
Chavarro et al., 2007
). Therefore, it is possible that fatty acid status may interfere with the relationship between the Pro12Ala and infertility risk. This hypothesis may be useful for further study on the effects of these polymorphisms.This study focused only on cases with unexplained infertility and with no interfering health conditions in which the variables of interest (two common polymorphisms of PPARγ and follicular fatty acid composition) were simultaneously included. However, despite the use of a population-based sample, generalization of the findings is somewhat constrained because of the relatively modest number of patients included. It remains to be established whether the fertilizability of oocytes is also influenced by paternal genotype. This hypothesis is motivated by the fact that human spermatozoa expressed PPARγ for physiological functions (
Aquila et al., 2006
).In conclusion, this study presents novel evidence of significant beneficial effects of PPARγ His447His and Pro12Ala polymorphisms on fertilization ratio in an in-vitro system. Although there was an interaction effect among studied polymorphisms and fatty acid status on fertilization ratio, these correlations appear to be independent of confounding factors. The identified associations as potential genetic markers provide a basis for future study aiming to improve IVF efficiency and highlight this gene as a candidate of choice for molecular genetic study of infertile women.
Acknowledgements
This study was partially supported by grants from the Drug Applied Research Centre (Grant No. 14/88), Tabriz University of Medical Sciences.
Appendix A. Supplementary data
Supplementary Figure 1Representative PCR products for PPARγ after restriction fraction length polymorphism (3% agarose). (A) PPARγ His447His with restriction with PmlI: lane 1 = molecular weight markers (50 bp ladder, range 50–500 bp); lanes 2–4 = CC homozygotes (142 bp and 39 bp); lane 5 = CT heterozygote (181 bp, 142 bp and 39 bp). (B) PPARγ Pro12Ala with restriction with HgaI: lane 1 = CC homozygote (295 bp); lane 2 = heterozygote CG (178 bp and 117 bp); lane 3 = molecular weight markers (50 bp ladder, range 50–500 bp). Gels were 3% agarose and stained with ethidium bromide.
- Supplementary data 1
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Article info
Publication history
Published online: May 19, 2011
Accepted:
May 10,
2011
Received in revised form:
May 5,
2011
Received:
November 18,
2010
Declaration: The authors report no financial or commercial conflicts of interest.Footnotes
Mohammad Noori is Associate Professor of Medical Biochemistry in the Faculty of Medicine at Tabriz University having occupied the position since 1987. He completed his MSc and PhD studies in medical biochemistry at the University of Tehran. In 1998, he was awarded a fellowship position to study in assisted reproductive sciences supported by a research Fellowship in Germany. His main research interest is molecular metabolism, with a focus on reproductive sciences.
Identification
Copyright
© 2011 Reproductive Healthcare Ltd. Published by Elsevier Inc. All rights reserved.
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