1 Julius Center for Health Sciences and Primary Care, 2 Department of Medical Genetics and 3 Department of Reproductive Medicine, University Medical Center Utrecht, The Netherlands
4 To whom correspondence should be addressed at: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, HPnr Str. 6.131, P.O.Box 85060, 3508 BA Utrecht, The Netherlands. Email: y.t.vanderschouw{at}umcutrecht.nl
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Abstract |
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Key words:
age at menopause/association study/cytochrome P450c17/estrogen receptor a/polymorphism
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Introduction |
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A number of genetic polymorphisms causing variation in estrogen levels have been reported. Examples are variants in the estrogen receptor gene (ER
) and a gene variant involved in estrogen biosynthesis (cytochrome P450c17
; CYP17). Since estrogen levels can modulate the release of pituitary gonadotrophins by negative and positive feedback, these gene variants can modulate the timing of menopause. Various reports of gene polymorphisms and menopausal age have been published.
Van Weel et al. (1999) reported that variations in the ER
were associated with onset of natural menopause and with the risk of surgical menopause in a Dutch population. Women carrying the PP genotype of the PvuII restriction fragment length polymorphism (RFLP) were found to have a 1.1 year earlier onset of menopause compared to women with the pp genotype. An allele dose effect corresponding to a 0.5 year earlier onset of menopause per copy of the P allele was demonstrated. This finding could not be replicated in a Japanese population (Gorai et al., 2003
).
ER is located on the long arm of chromosome 6 and several polymorphic sites in the gene are known. The PvuII polymorphism is located in intron 1,
0.4 kb upstream of exon 2. A second polymorphism, XbaI, is located
50 bp apart from the PvuII restriction site and a high degree of linkage disequilibrium between XbaI and PvuII has been reported (Heimdal et al., 1995
; Kobayashi et al., 1996
). A third polymorphic site of the ER
gene is located in the B-domain. The B-variant polymorphism is caused by a G/C transversion in exon1 [B-wild type (B)/B-variant type (B')] (Green et al., 1986
; Taylor et al., 1992
). It has been reported that estrogen receptors with B-variant type have decreased binding affinity to estrogen (Garcia et al., 1988
), although the mechanisms involved are not clearly understood.
It has been proposed that polymorphisms in the genes involved in estrogen biosynthesis (CYP17) (Dunning et al., 1998; Helzlsouer et al., 1998
; Weston et al., 1998
; Bergman-Jungestrom et al., 1999
; Feigelson et al., 1999
; Haiman et al., 1999b
; Kristensen et al., 1999
; Spurdle et al., 2000
; Mitrunen et al., 2000a
; Miyoshi et al., 2000
; Ambrosone et al., 2003
; Gudmundsdottir et al., 2003
; Wu et al., 2003
), hydroxylation (cytochrome P4501a) (Huang et al., 1999
; Basham et al., 2001
; da Fonte et al., 2002
; Laden et al., 2002
; Miyoshi et al., 2002
, 2003
; Li et al., 2004
), and inactivation of the reactive metabolites (catechol-O-methyltransferase) (Yaich et al., 1992b
; Millikan et al., 1998
; Thompson et al., 1998
; Bergman-Jungestrom and Wingren, 2001
; Goodman et al., 2001
; Hamajima et al., 2001
; Mitrunen et al., 2001
, 2002
; Yim et al., 2001
; Kocabas et al., 2002
; Miyoshi and Noguchi, 2003
; Wedren et al., 2003
; Cheng et al., 2004
) may be associated with an elevated risk of breast cancer (Lavigne et al., 1997
; Haiman et al., 1999a
; Huang et al., 1999
), although the findings until now have been conflicting. So far, associations of these polymorphisms with age at menopause are scarce (Gorai et al., 2003
).
The MspAI polymorphism of the CYP17 gene, located on chromosome 10, gives rise to the genotypes A1A1, A1A2 and A2A2. Two studies found that both pre-menopausal and post-menopausal women with the variant A2 allele had higher levels of circulating estrogens than those with A1 alleles (Feigelson et al., 1998; Haiman et al., 1999a
).
In the present study, we evaluate whether polymorphisms in the ER gene (PvuII, XbaI and B-variant) or in the cytochrome P450c17
gene (MspAI) are associated with age at natural menopause in a Dutch cohort.
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Materials and methods |
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Laboratory analysis
DNA isolation
DNA was isolated from 100 ml urine samples as was described earlier (van der Hel et al., 2002). In brief, after centrifugation, DNA was isolated from the urine pellet. Pellets containing cells and nuclei were resuspended in a cell lysis buffer, followed by protein precipitation. DNA was precipitated by alcohol and finally resuspended in 80 µl TE (10 mmol/l Tris, 1 mmol/l EDTA, pH 7.6).
ER
To screen for the two polymorphisms in the ER, we used PCRrestriction fragment length polymorphism (PCRRFLP) protocols (Bergink et al., 2003
; van Meurs et al., 2003
). The first polymorphism is a T
C transition at 397 bp before exon 2, which results in a restriction site for PvuII (Yaich et al., 1992a
). The second is a G
A substitution at 351 bp before exon 2, resulting in a XbaI restriction site (Zuppan et al., 1989
). A PCR fragment of 345 bp containing the two base pair changes was generated using the following primers: forward: 5'-GATATCCAGGGTTATGTGGCA-3'; and reverse: 5'-AGGTGTTGCCTATTATATTAACCTTGA-3'. PCR reactions were carried out in a final volume of 20 ml containing 1 x PerkinElmer Buffer (Applied Biosystems, USA), 2.5 mmol/l of each nucleotide (dATP, dCTP, dGTP and dTTP), 2.5 mmol/l MgCl2, 0.45 mmol/l of each primer, 1.0 IU AmpliTaq Gold polymerase (Applied Biosystems) and 2 ml of DNA. The amplification was for 35 cycles with denaturation at 94°C for 1 min, annealing at 57°C for 1 min, and extension at 72°C for 1 min. An initial denaturing step of 5 min at 95°C and a final extension step for 10 min at 72°C was used. According to the manufacturer's instructions, 5 ml of PCR product was digested with PvuII and an equal amount was digested with XbaI (New England Biolabs, USA), both at 37°C overnight and separated by agarose gel electrophoresis and stained with ethidium bromide to identify details of fragments.
A third polymorphism (a GC substitution) is located in the B-region of the ER
at codon 87 (Taylor et al., 1992
). Genotypes of the B-variant were determined with an allele-specific oligonucleotide (ASO) hybridization method (Andersen et al., 1994
; Berkowitz et al., 1994
; Roest et al., 1999
) (Accession number: NM_000125). A PCR fragment of 143 bp was amplified with the following conditions: denaturing for 4 min at 94°C, 33 cycles of 40 s denaturing at 94°C, 40 s annealing at 53°C and 1 min extending at 72°C and a final extending step of 10 min at 72°C. PCR reactions were carried out in a final volume of 25 ml containing 1 x PerkinElmer Buffer (Applied Biosystems), 0.5 mmol/l of each nucleotide (dATP, dCTP, dGTP and dTTP), 1.25 mmol/l MgCl2, 0.6 mmol/l of the forward primer (5'-TGTACCTGGACAGCAGCAAG-3'), 1.0 mmol/l of the reverse primer (5'-CGGAGACACGCTGTTGAGT-3') (Isogen Life Science, The Netherlands), 1.0 IU AmpliTaq Gold polymerase (Applied Biosystems) and 2 ml of DNA. The ASO used to detect the common B allele and B' allele respectively are 5'-TCTGAGGCTGCGGCGTTCGG-3' and 5'-TCTGAGGCTGCCGCGTTCGG-3'. The PCR products were spotted on a membrane and hybridized with the oligonucleotides. The allele-specific washing temperature was 58°C for ASO B and 66.4°C for ASO B'. Wash buffer/salt concentrations: 2xSSC 0.1% SDS. The combination of probes used could correctly separate individuals carrying the B' allele from BB homozygotes, but BB' heterozygotes could not be distinguished from B'B' homozygotes with certainty.
CYP17
The CYP17 gene contains a single nucleotide polymorphism, TC, in the 5' untranslated region at 34 bp from the initiation of translation. The base pair change creates a recognition site for the MspA1 restriction enzyme. Two alleles have been arbitrarily assigned: A1 (T) and A2 (C) (Carey et al., 1994
). Genotypes of CYP17 were assessed by PCRRFLP (Feigelson et al., 1998
) (Accession number: M31146). A PCR fragment of 459 bp containing the base pair change was generated using the following primer set: forward: 5'-CATTCGCACTCTGGAGTC-3'; and reverse: 5'-AGGCTCTTGGGGTACTTG-3'. PCR reactions were carried out in a final volume of 20 ml of 1 x PerkinElmer Buffer (Applied Biosystems), 2.4 mmol/l of each nucleotide (dATP, dCTP, dGTP and dTTP), 2.4 mmol/l MgCl2, 0.5 mmol/l of both primers, 1.0 IU AmpliTaq Gold polymerase (Applied Biosystems) and 2 ml of DNA. Thirty-five amplification cycles were carried out with denaturation at 95°C for 1 min, annealing at 57°C for 1 min, and extension at 72°C for 1 min. An initial denaturing step of 5 min at 95°C and a final extension step for 10 min at 72°C was used. Seven millilitres of PCR product was then digested with MspAI (New England Biolabs, USA) at 37°C overnight and separated by agarose gel electrophoresis and stained with ethidium bromide to identify details of fragments.
Genotyping
Two individuals assessed the genotypes independently from each other. In case of sample failure or if there was disagreement between the observers without reaching a consensus, the PCR and RFLP/ASO were repeated and a final genotype was assessed. After repeated efforts, genotyping did not succeed in 74 samples (19.2%) for PvuII, in 76 samples (19.7%) for XbaI, in 31 samples (8.1%) for B-variant and in 44 samples for CYP17 (11.4%), probably because of low amounts of DNA (van der Hel et al., 2002).
Statistical analysis
Deviations from HardyWeinberg equilibrium were assessed using a goodness-of-fit 2-test with one degree of freedom. The two RFLP of ER
were analysed separately as well as in a combined score.
The following potential confounders were considered: smoking (ever/never), oral contraceptive (ever/never) use, socio-economic status (low/high), parity (nulliparous/parous), body mass index (BMI, kg/m2), age at menarche (years).
Although for the PvuII polymorphism an allele dose effect was demonstrated on age at menopause in an earlier study (Weel et al., 1999), we tested between the homozygous wild type and homozygous mutant genotypes. This avoids making assumptions about the underlying genetic model. An exception was made for the B-variant where the BB' genotype and B'B' genotype were collapsed into one category. Two-sided t-tests were performed to assess the association between the polymorphisms and age at menopause. All analyses were performed using SPSS (version 11.0).
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Results |
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Combination of the two RFLP of ER genotypes in all subjects resulted in identification of eight genotypes: PPXX (n=51, 16.6%), PPXx (n=34, 11.1%), PPxx (n=3, 1.0%), PpXX (n=2, 0.7%), PpXx (n=103, 33.6%), Ppxx (n=33, 10.7%), ppXx (n=1, 0.3%) and ppxx (n=80, 26.1%). The genotype ppXX was not detected in this study population. No significant differences in age at menopause were found for the combined genotypes.
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Discussion |
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Several limitations need to be considered when interpreting the results. It should be noted that genotype assessment did not succeed in 19.2% of the PvuII genotypes, in 19.7% of the XbaI genotypes, in 8.1% of the B-variant genotypes and in 11.4% of the MspAI genotypes. This is mainly because it is difficult to obtain sufficient DNA from urine samples (van der Hel et al., 2002), which are the only biological samples we have collected for this cohort of women recruited in 1974. It is, however, unlikely that this was non-random and affected the findings of this study for the following reasons. First, there were no differences in characteristics between subjects for whom genotyping succeeded and subjects for whom genotyping failed for two or more polymorphisms. Secondly, genotypes were assessed by researchers blinded for the outcome, age at menopause. Furthermore, the PvuII (Gennari et al., 1998
; Weel et al., 1999
), B-variant (Schmutzler et al., 1991
; Lehrer et al., 1993
) and CYP17 (Haiman et al., 1999a
; Mitrunen et al., 2000b
) genotype distributions in our study are comparable to those found in other populations, which strongly argues against selective failure of certain genotypes.
Age at menopause was self-reported and determined retrospectively, which has been shown to be susceptible to bias (den Tonhelaar, 1997; Hahn et al., 1997
). Nevertheless, it seems unlikely that misclassification due to recall bias is different across genotypes.
The strength of this study is that the study population was a random sample from a population-based cohort, therefore excluding sources of selection bias.
Candidate gene studies can be seen as a useful step in exploring potential causal pathways between genetic determinants and complex traits, such as age at menopause. We reported an association of the factor V Leiden mutation with earlier age at menopause (Van Asselt et al., 2003), an effect possibly enhanced by smoking.
Weel et al. were the first to establish an association between an ER gene polymorphism and age at menopause. Apart from the current study, the association was also absent in a Japanese population (Gorai et al., 2003
). Previously, we reported that fertility problems, reduced parity, nulliparity and early menopause may all be related phenotypes of menopausal age as being an expression of accelerated ovarian ageing (Kok et al., 2003
). Finding an association between ER
gene polymorphism and related phenotypes as reduced parity and nulliparity, could be considered as supportive evidence for the association between the ER
gene polymorphism and menopausal age. However, the data presented by Weel et al. showed no association between the PvuII polymorphism and nulliparity or reduced parity. Discrepant findings do not necessarily indicate that the candidate gene approach is unreliable or that associations found are spurious, but does indicate caution in both design and interpretation of such studies (Colhoun et al., 2003
).
Gene variants might be associated with different relative risks in different populations and then the non-replication might result from real biological differences. This could well be expected comparing the studies of Weel et al. (1999) and Gorai et al. (2003)
, studying Caucasian and Asian populations respectively. However, this does not explain the difference between the population studied by Weel et al. and the present study.
Complex traits are aetiologically heterogeneous as they are the result of multiple genetic and environmental components. Non-replication might be due to the small magnitude of relative risks that are likely to be detected in candidate gene studies of complex traits. Furthermore, confounding, bias and misclassification are more likely to obscure small to moderate relative risks than larger relative risks (Tabor et al., 2002).
The choice of the polymorphisms could also be an explanation of non-replication. If polymorphisms are not likely to affect the function of the protein encoded for, finding an association is based on the polymorphism being in linkage disequilibrium with a causal variant. If this linkage disequilibrium does not exist or varies between different study populations, different studies might have different results for polymorphisms of the same gene. For CYP17, it was suggested that the increase in serum estradiol and progesterone levels accompanying carriage of the CYP17 A2 allele resulted from higher activity of the enzyme through up-regulation of transcriptional activation. However, this could not be found in experimental studies (Nedelcheva et al., 1999; Lin et al., 2001
), indicating that the polymorphism may be in linkage disequilibrium with another functional polymorphism or that hormone levels are affected through another mechanism.
Other potential candidate genes for menopausal age may be found among those associated with premature ovarian failure (POF). The FSH axis is of importance in ovarian function and some gene variants involved in abnormal FSH responses have indeed been shown to be associated with POF. Examples are the FSH-receptor gene (Aittomaki et al., 1995; Touraine et al., 1999
) and genes coding for inhibin (Shelling et al., 2000
; Dixit et al., 2004
). However, an earlier study showed no linkage of the FSH-receptor gene with menopausal age (Kok et al., 2004
). Other pathways should be explored for potential candidate genes.
In conclusion, no association of ER and CYP17 polymorphisms with age at natural menopause was found in a population-based sample of Dutch women.
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Acknowledgements |
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Submitted on March 25, 2004; resubmitted on April 27, 2004; accepted on October 15, 2004.