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Obstetrics & Gynecology 2002;99:1085-1092
© 2002 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

The Methylenetetrahydrofolate Reductase 677 C->T Polymorphism and Preeclampsia in Two Populations

D. Prasmusinto, MD, S. Skrablin, MD, C. Hofstaetter, R. Fimmers, MD and K. van der Ven, MD, PhD

From the Department of Obstetrics and Gynecology and Department of Medical Statistics, University of Bonn, Bonn, Germany; and Department of Obstetrics and Gynecology, University of Zagreb, Zagreb, Croatia.

Address reprint requests to: K. van der Ven, MD, PhD, University of Bonn, Department of Obstetrics and Gynecology, Section of Endocrinology and Reproductive Medicine, Sigmund Freudstrasse 25, Bonn, 53127, Germany; E-mail: reprogenetik{at}uni-bonn.de.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: The C677T polymorphism of the 5,10 methylenetetrahydrofolate reductase (MTHFR) gene is associated with decreased MTHFR activity and elevated plasma homocysteine levels with the result of an increased risk for vascular disease. Because thrombosis of the maternal spiral arteries can be one of the causative events in the disease, it has been suggested that the C677T polymorphism may also play a role in the pathogenesis of preeclampsia. Our case-control study investigated the prevalence of the 677T allele in two ethnically different populations and the potential association of the 677T allele with preeclampsia. Special attention was paid to the potential contribution of the fetal genotype to disease risk.

METHODS: Blood samples were collected from 81 mothers and 61 newborns after preeclampsia and 99 mothers and 61 newborns with normal pregnancies. Genomic DNA was amplified by polymerase chain reaction with locus-specific primers, and presence of the polymorphism was determined by enzymatic digestion with HinfI and visualization on polyacrylamide gels.

RESULTS: Genotypes carrying the MTHFR 677T allele were significantly more frequent in German-Croatians than in Indonesians in both patients and controls (P = .0033 in controls). In contrast, the prevalence of genotypes with the 677T allele was not increased among patients with preeclampsia compared with controls in both ethnic groups (P > .5 in all groups). In Germans, the frequency of 677T homozygotes among controls even exceeded that observed in preeclamptic patients (677T/T genotype frequency 0.20 in controls and 0.07 in patients). We did not find an increased prevalence of paternally inherited 677T alleles in preeclamptic fetuses relative to controls or other signs of maternal-fetal transmission distortion.

CONCLUSION: In our study, the MTHFR C677T polymorphism was not associated with an increased risk for preeclampsia on the level of the maternal or fetal genotype. However, significant differences of the frequency of genotypes carrying the 677T allele between Middle-Europeans and Indonesians were identified.

Preeclampsia, defined as pregnancy-induced proteinuric hypertension with onset of clinical symptoms beyond 20 weeks’ gestation, is a serious pregnancy complication and a leading cause of maternal mortality and fetal perinatal morbidity.1,2 Although preferentially occurring during first pregnancy, the disease is estimated to affect between 5% and 10% of all pregnancies worldwide.3 Despite significant improvements in prenatal obstetric care in western industrialized countries, the frequency of preeclampsia has remained relatively constant and no predictive tests or guidelines for disease prevention could yet be established. Clinically defined only by hypertension, proteinuria, and facultative edema, the disease may also be associated with abnormalities of the central nervous system, the liver, the kidneys, and intra-vascular disseminated coagulation.4–6

Despite decades of intensive research, the pathogenesis of preeclampsia remains incompletely understood. A multitude of possible etiologies have been proposed, including placental, immunologic, and genetic causes. However, there is consensus that the placenta is central to the disease, and many studies suggest that impaired placental bed remodeling is the basic defect, which precedes all other pathologic changes in preeclampsia.7–9 Consequently, several investigators have sought to establish an association between vascular abnormalities and preeclampsia.

Because maternal inherited thrombophilias confer an increased risk for preeclamptic toxemia, they have also been proposed to be causal factors in the pathobiology of the disease.10–13 The human methylenetetrahydrofolate reductase (MTHFR) gene, which is located on chromosome 1p36, belongs to the proposed candidate loci for preeclampsia.14 The MTHFR gene is critical in the metabolism of homocysteine because the reaction catalyzed by MTHFR is a rate-limiting step in the folate cycle and can be affected by an individual’s folate status.15,16 A common missense mutation at nucleotide 677 (C->T), which substitutes a valine for an alanine residue, has been associated with increased circulating levels of homocysteine caused by decreased enzyme activity in 677T homozygotes and heterozygotes.16 Hyperhomocystinemia can induce vascular injury, increase platelet consumption, and can result in thrombosis caused by increased oxidative stress. Clinically, hyper-homocystinemia caused by the 677T mutation has been implicated in premature cardiovascular disease,17 venous thrombosis,18 and more recently in adverse pregnancy outcome, especially preeclampsia.14,19,20 However, the majority of follow-up studies failed to reconfirm a significant disease association with preeclampsia.15,21–26

Because the frequency of the 677T allele underlies significant population-specific differences,27 we proposed that variations in the relative contribution of disease alleles in different populations might explain the discrepant results of previous studies on MTHFR and preeclampsia. We thus decided to study the frequency of the 677T allele and its disease association in preeclamptic mothers and controls in two different ethnic populations, namely German/Croatians and Indonesians. Secondly, we hypothesized that in the case of preeclampsia, a disease, which is proposed to be caused by impaired vascular placental bed remodeling, fetally expressed genes might also be relevant for disease manifestation and phenotype. We thus proposed that the MTHFR C677T mutation should occur more frequently among infants of preeclamptic mothers compared with controls if relevant for the disease.


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Blood samples were collected from 81 women and 61 newborns with preeclampsia, as well as 99 women and 61 newborns with uncomplicated pregnancies from Indonesia and Germany or Croatia. Participants from Indonesia were recruited at the time of admission for labor and delivery at the Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia, the largest hospital in Indonesia. Participants from Germany were recruited at the Womens’ Hospital of the University of Bonn during prenatal visits at the outpatient clinic or during delivery. Croatian samples were collected at the time of admission for labor at the University Women’s Hospital in Zagreb, Croatia. A sample of 20 mL of anticoagulated blood was collected from the mothers and 3–6 mL of fetal cord blood from every newborn.

The study protocol was approved by the local ethics committee of the University of Bonn, and the mothers had to give informed consent for participation in the study. Definition of preeclampsia was based on recommendations of the Consensus Report of the American Working Group on High Blood Pressure in Pregnancy9 and of the Working Group of the German Society of Obstetrics and Gynecology.28 Diagnostic criteria were as follows:

  1. Increase of systolic blood pressure of 30 mm Hg or higher and/or increase of diastolic blood pressure of 15 mm Hg or higher from average values before 20 weeks’ gestation. In case of unknown prior values, two readings of 140/90 mm Hg or higher on two different occasions more than 4 hours apart.
  2. Proteinuria defined as protein excretion of 0.3 g or more in a 24-hour specimen or repeated dipsticks of 30 mg/dL (which correlates to 1+ dipsticks in commercial kits) in two random urine specimens collected more than 4 hours apart.
  3. Onset of first symptoms beyond 20 weeks’ gestation from last menstrual period and regression of symptoms after 6 weeks postpartum.
  4. Absence of preexistent hypertension, proteinuria, and edema, as well as diabetes, chronic kidney, hepatic, or vascular disease.

Patients with hemolysis, elevated liver enzymes, low platelets syndrome were not included in the study. Controls were randomly selected from normally delivering women at the participating hospitals on the basis of fulfilling the following recruitment criteria: absence of anomalies of blood pressure, proteinuria, and edema, and absence of the predisposing diseases listed above. More than 80% of women with preeclampsia and 78% of controls agreed to participate in the study.

The DNA samples were extracted from whole blood with a modified salting out procedure29 or with a commercially available kit according to the manufacturer’s recommendations (Qia AMP blood kit [QIAGEN GmbH, Hilden, Germany]). The DNA samples were analyzed for the C677T missense mutation by polymerase chain reaction with locus-specific primers and subsequent analysis of a restriction fragment length polymorphism created by the mutation as described elsewhere.30 The 677 C->T substitution creates a HinfI recognition sequence, which digests the initial polymerase chain reaction product of 198 base-pair (bp) into 175 and 23 bp fragments. Presence of the mutation was determined by enzymatic digestion of the initial polymerase chain reaction product with HinfI at 37C for 24 hours. The resulting DNA fragments were separated on 6% polyacrylamide gels. Samples were run at 50 W for 1:45 hours and then visualized with a standard silver staining protocol. The 23 bp fragment was run off and did not appear on the gels. Consequently, individuals who lack the mutation showed one 198 bp fragment, individuals heterozygous for the mutation showed both a 198 and a 175 bp fragment, and individuals homozygous for the C677T mutation showed one 175 bp band.


   RESULTS
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Clinical characteristics for the German/Croatian and Indonesian patient groups are shown in Table 1Go. Whereas there was no difference in age between patients and controls in both groups, preeclamptic mothers had significantly earlier delivery dates (P = .048 in Indonesians and P = .000 in German/Croatians) and significantly lower birth weights of the infants (P = .043 in Indonesians and P = .000 in German/Croatians, Student t test) than controls. There was one patient with eclampsia in each of the Indonesian and German sample.


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  		Table 1. Clinical Characteristics of Indonesian and German/Croatian Patients
 
In this case-control study, MTHFR allele frequencies were analyzed by Fisher exact test or Student t test as indicated in the tables. To estimate the power of our data to detect differences in genotype frequencies between patients and controls, we performed simulations. Results of the power analysis are given in Table 2Go. Assuming sample sizes and genotype frequencies for controls as observed in the combined German/Croatian sample, we estimated a power of at least 80% to detect an increase of the risk for the carriers of the "at-risk" genotypes (Table 2Go). This means that in our study, we had a power of 80% to detect a 2.7-fold increase of the risk associated with the genotype C-C (recessive model for C), a seven-fold increase of the risk for the genotype C-C and C-T (dominant model for C), a 3.7-fold increase of the risk for the genotype T-T (recessive T), or a 3.2-fold increase of the risk for the genotypes T-T and C-T (dominant T).


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  		Table 2. Power Analysis—Increase of Risk, Detectable With a Power of at Least 80%
 
No differences in MTHFR allele or genotype frequencies could be detected between nulliparous and multiparous women with and without preeclampsia (P > .4) within their ethnic groups so that the two samples were combined for further analysis. We then compared the frequencies of the MTHFR 677 genotypes in control mothers in the different ethnic groups (Table 3Go). Whereas the German and Croatian samples did not differ in their genotype distributions, Indonesian control samples showed a significantly lower frequency of genotypes carrying the 677T allele than the Middle-European controls (P = .003 for overall comparison). The same was true for MTHFR genotype frequencies in mothers with preeclampsia (P = .003) (Table 3Go). In general, genotypes carrying the 677T allele were more frequent among Middle-Europeans compared with Indonesian patients. In the Indonesian sample, the homozygous 677C wild type was the dominant genotype in both controls (81.5%) and patients (83.0%), and the T/T genotype occurred only in one preeclampsia patient. In contrast, the T/C and T/T genotypes were more common in Germans and Croatians. Because German and Croatian patients did not show differences in genotype frequencies in both the patient and control groups, samples were combined for further analysis of maternal-fetal transmission rates of potential disease alleles.


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  		Table 3. Prevalence of the 677 C -> T Methylenetetrahydrofolate Reductase Genotypes in Maternal Samples
 
Homozygosity for the 677T allele has been proposed to be associated with an increased risk for preeclampsia caused by increased homocysteine levels.14,19,31 Direct comparison of controls and preeclamptics in the different ethnic groups did not show differences in maternal allele and genotype frequencies (Table 3Go). Pairwise comparisons of the frequency of 677T homozygotes in controls and patients with toxemia of pregnancy did not reveal differences in any of the ethnic groups. One Indonesian woman with preeclampsia was homozygous for 677T, but no 677T homozygotes were found among normal controls. In the German/Croatian sample, the frequency of 677T homozygotes among controls exceeded that observed in preeclamptic patients (20.6% in controls versus 6.7% in preeclampsia among Germans and 13.2% versus 7.6% in Croatians) (Table 3Go). In summary, we did not find evidence for an association of the maternal 677T/T genotype with an increased risk for preeclampsia in any of the ethnic groups that were studied.

Because preeclampsia is a pregnancy-associated disease, disease susceptibility might also be influenced by fetally expressed genes in the placenta. However, pairwise comparisons of the newborns from preeclamptic and normal pregnancies showed no differences in the frequency of the 677T allele and the resulting genotypes for both ethnic groups (P > .8, Table 4Go).


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  		Table 4. Prevalence of 677 C -> T Methylenetetrahydrofolate Reductase Genotypes in Fetal Samples
 
An alternative possibility in the pathophysiology of preeclampsia would be that paternally inherited disease alleles expressed in the placenta contribute to disease manifestation. We thus compared the frequency of paternally inherited 677T alleles in fetuses with preeclampsia and controls. The parental origin of the fetal 677T allele was deduced from the maternal and fetal genotype. The genotype was classified as undetermined whenever the maternal or paternal origin of the 677T allele could not be unambiguously deduced. In both Indonesians and Croatians, the number of paternally inherited 677T alleles among newborns from preeclamptic mothers did not exceed the number of paternally inherited 677T alleles in control fetuses (Figures 1Go and 2Go). In neither sample did the percentage of maternal-fetal pairs carrying one or more disease alleles in the patient group exceed that in controls. Although study samples are small, we conclude that there is no immediate evidence for an influence of the fetal MTHFR genotype on disease development in preeclampsia.



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  		Figure 1. Paternal-fetal transmission of the 677T allele in controls (n = 24, maternal-fetal pairs) and preeclampsia (n = 40, maternal-fetal pairs) in Indonesians.

Prasmusinto. MTHFR 677 Alleles in Preeclampsia. Obstet Gynecol 2002.

 


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  		Figure 2. Paternal-fetal transmission of the 677T allele in controls (n = 37, maternal-fetal pairs) and preeclampsia (n = 21, maternal-fetal pairs) in Croatians.

Prasmusinto. MTHFR 677 Alleles in Preeclampsia. Obstet Gynecol 2002.

 

   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
With the primary causes of eclampsia/preeclampsia remaining unknown, functional gene studies have concentrated on loci known to be of relevance for maternal conditions, which predispose for the disease. Inherited thrombophilias (eg, activated protein C resistance or hyper-homocystinemia) have been proposed to be associated with an increased risk of preeclampsia and other pregnancy complications32 based on the pathologic changes in the placental vascular bed, which are typical for the disease.7,8

A MTHFR deficiency is the most common inborn error of folate metabolism, and a common polymorphism of the human MTHFR gene, C677T, is associated with reduced specific MTHFR activity and elevated plasma homocysteine levels. Sohda et al14 and Kupferminc et al19 were among the first to propose the MTHFR 677T allele as a genetic risk factor in preeclampsia. The majority of follow-up studies failed to reconfirm the association of the 677T allele with toxemia of pregnancy.15,21–26,33

Although models of multifactorial inheritance with maternal-fetal genetic interactions have increasingly been proposed in the etiology of preeclampsia, previous studies on MTHFR have concentrated exclusively on the maternal genetic status. In the underlying study, we investigated the fetal and the maternal MTHFR genotype in maternal-fetal pairs with preeclampsia and normal pregnancies from two different ethnic populations with the aim to uncover a potential fetal contribution to disease manifestation.

In accordance with the majority of previous studies,15,21–26,34 we could not identify an increased frequency of 677T homozygotes or heterozygotes among mothers with preeclampsia. Within the limitations of small sample sizes, our study questions an association of the maternal 677T allele with the disease in Middle-European and Indonesian patient samples. Because pathologic changes in the placental bed are seen as initiating events in preeclampsia, it seems plausible that coexpression of maternal and fetal disease alleles in the placenta would potentially enhance those processes. However, in this study, we did not find an increase of genotypes carrying the 677T allele in fetuses from preeclamptic mothers or any evidence for a maternal-fetal transmission distortion of the 677T allele. Also, the rate of paternally inherited disease alleles in preeclamptic fetuses was not increased, which makes the involvement of fetal MTHFR disease alleles in the etiology of preeclampsia unlikely. In summary, no association of the MTHFR C677T polymorphism with preeclampsia on the maternal or fetal level was found in our investigation.

Kaiser et al33 could recently exclude an association of A1298C, another MTHFR polymorphism that reduces MTHFR activity and also of the combination of C677T and A1298C with preeclampsia in Australian women. These results and data,34 which suggest that the C677T polymorphism may rather exhibit an indirect effect on cardiovascular disease via increased plasma homocysteine levels in conjunction with low plasma folate levels, make a direct and exclusive involvement of the MTHFR gene in the etiology of preeclampsia ever more unlikely. The fact that different MTHFR genotypes have different folate requirements35,36 might still lead to an increased disease risk for carriers of certain MTHFR polymorphisms. However, effects may be too subtle and too variable to be detectable in small patient samples, and this might especially be true for a contribution of the fetal genotype, if present at all.

Variations of the prevalence of MTHFR polymorphisms in different ethnic populations may also contribute to the discrepant results of available studies on disease associations of genetic MTHFR variants. A meta-analysis by Brattström et al27 on the C677T MTHFR polymorphism in vascular disease reported frequencies between 5–16% for 677T homozygotes and 37–54% for 677T/677C heterozygotes worldwide in healthy controls. However, relatively little information is available about the frequencies of MTHFR polymorphisms in different ethnic groups. The prevalence of 677T/677C genotypes observed in our German/Croatian patient sample lies well within the range reported for other German control populations.37,38 In contrast, the prevalence of the 677T allele and corresponding genotypes was significantly lower in our Indonesian sample. Although no additional data are currently available on Indonesian populations, studies among Chinese in Taiwan,39 Thai,40 Korean,41 and also African26 patients all showed lower frequencies for the 677T allele and the corresponding genotypes than in Europeans, whereas allele frequencies in Japanese were comparable with white populations.24

In conclusion, we found significantly lower rates of the MTHFR 677T allele among Indonesian patients, which are among the lowest reported for a human population. Based on the low rates of MTHFR 677T homozygotes in Indonesians with normal and preeclamptic pregnancies, we can exclude a major influence of this genetic variant on the etiology of preeclampsia in Indonesia. Our findings further underline the need for a clear separation of samples according to ethnicity in the case of the study of disease associations of functional genetic polymorphisms.


   Footnotes
 
D. Prasmusinto is recipient of a DAAD fellowship. This work was additionally funded by BONFOR O1004.0007.

The authors thank Prof. G. Wiknjosastro and his colleagues for their valuable assistance in collecting the samples from Indonesia and G. Engels and A. Maie for technical assistance.

PII S0029-7844(02)01997-X

Received May 30, 2001. Received in revised form December 10, 2001. Accepted January 10, 2002.


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ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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Right arrow Articles by van der Ven, K.

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