MTHFR C677T polymorphism is not associated with placental abruption or preeclampsia in Finnish women.

OBJECTIVE: The aim of our study was to examine genetic variability in the gene encoding methylenetetrahydrofolate reductase (MTHFR) and individual susceptibility to the placental abruption or preeclampsia. METHODS: 362 women (133 with preeclampsia, 117 with placental abruption, and 112 healthy controls) were genotyped for C677T polymorphism in the MTHFR gene. RESULTS: Similar genotype distributions were observed in the frequencies of C/C homozygotes (58.6%, 64.1%, and 57.1% for the three groups, respectively) and mutant homozygotes T/T (9.0%, 5.1% and 5.4%). No significant differences were detected in T allele frequencies (25.2%, 20.5%, and 24.1% for the three groups, respectively). CONCLUSIONS: MTHFR C677T polymorphism does not have a major role in the development of preeclampsia or placental abruption in the Finnish population.

Microdialysis detects postoperative perfusion failure in microvascular flaps.

In microvascular tissue transfers, it is essential postoperatively to follow-up on the perfusion of the transferred flap because of the risk of anastomotic failure. The diagnosis of pedicle obstruction is usually made by clinical observation, but some techniques have been reported as more reliable than clinical observation in detecting perfusion failure. The authors used microdialysis (MD), a method developed to assess in situ tissue metabolism, in the follow-up of 80 consecutive microvascular flaps from October, 2001 to October, 2003. Of the 78 flaps with postoperative data, 58 flaps were uneventful clinically and using MD, and served as the reference material for normal postoperative metabolism. Twenty flaps showed some abnormality in the clinical course or with MD. Of these, 13 flaps were reoperated for anastomosis thrombosis (9 arterial, 4 venous). All thromboses were clearly recognized by MD via a decrease in the glucose concentration in the tissue (< 2.7 mmol/l) and an increase in the lactate concentrations (> 5.7 mmol/l). In some cases, MD indicated a pathological trend in glucose and lactate concentrations hours before there were any clinical signs. A system of alarm levels was developed for the staff: when the limits were reached, a critical evaluation of the situation was undertaken, and the need for reoperation was considered. In the series, the salvage rate of all thrombosed flaps was 77 percent, with a final success rate in microvascular reconstruction of 95 percent. No flap was lost due to a delay in the diagnosis of secondary ischemia, if on-line MD monitoring was available. Microdialysis is a clinically feasible and sensitive monitoring method for all kinds of microvascular flaps, especially for those in which clinical observation is difficult or impossible. The performance of the analysis is easy and can be done by even less experienced nursing staff working in institutes with a low frequency of microsurgery.

Endothelial nitric oxide synthase polymorphism is not associated with placental abruption in Finnish women.

OBJECTIVE: To study whether genetic variability in the gene encoding endothelial nitric oxide synthase (eNOS) affects individual susceptibility to the development of placental abruption during pregnancy. METHODS: One hundred and sixteen pregnant women with placental abruption and 113 healthy controls were genotyped for Glu298Asp polymorphism in the eNOS gene. Chi-square analysis was used to assess the differences in genotype and allele frequencies between the two groups. RESULTS: A statistically similar allelic distribution of eNOS Glu298Asp polymorphism was observed in the two groups, with the frequency of the variant G allele being 66.8% in the abruption group and 68.1% in the control group (OR 0.94, 95% CI: 0.64-1.39; p = 0.76). The genotype distribution of the eNOS polymorphism was also found to be statistically similar (p = 0.72). CONCLUSIONS: The observed genotype data in subjects from eastern Finland suggest that the Glu298Asp polymorphism of the eNOS gene does not contribute to placental abruption in this population.

Low-activity haplotype of the microsomal epoxide hydrolase gene is protective against placental abruption.

OBJECTIVE: We wanted to determine whether genetic variability in the gene encoding microsomal epoxide hydrolase (EPHX) contributes to individual differences in susceptibility to the occurrence of placental abruption. METHODS: The study involved 117 women with placental abruption and 115 healthy control pregnant women who were genotyped for two single nucleotide polymorphisms (SNPs), T-->C (Tyr113His) in exon 3 and A-->G (His139Arg) in exon 4, in the EPHX gene. Chi-square analysis was used to assess genotype and allele frequency differences between the women with placental abruption and the control group. In addition, single-point analysis was expanded to pair of loci haplotype analysis to examine the estimated haplotype frequencies of the two SNPs, of unknown phase, among the women with placental abruption and the control group. Estimated haplotype frequencies were assessed using the maximum-likelihood method, employing an expectation-maximization algorithm. RESULTS: Single-point allele and genotype distributions in exons 3 and 4 of the EPHX gene were not statistically different between the groups. However, in the haplotype estimation analysis we observed a significantly decreased frequency of haplotype C-A (His113-His139) among the placental abruption group compared with the control group (P = .007). The odds ratio for placental abruption associated with the low-activity haplotype C-A (His113-His139) was 0.552 (95% confidence interval, 0.358 to 0.851). CONCLUSIONS: The use of two intragenic SNPs jointly in haplotype analysis of association demonstrated that the genetically determined low-activity haplotype C-A (His113-His139) was significantly less frequent in women with placental abruption.

Susceptibility to pre-eclampsia in Finnish women is associated with R485K polymorphism in the factor V gene, not with Leiden mutation.

This study determines whether genetic variability in the gene-encoding factor V contributes to differences in pre-eclampsia susceptibility. Allele and genotype frequencies of three single-nucleotide polymorphisms (SNPs) in the factor V gene leading to nonsynonymous changes (M385T in exon 8, and R485K and R506Q (Leiden mutation) in exon 10) were studied in 133 Caucasian women with pre-eclampsia and 112 healthy controls. Single-point analysis was expanded to haplotype analysis, and haplotype frequencies were estimated using an expectation-maximization algorithm. Comparison of single-point allele and genotype distributions of SNPs in exons 8 and 10 of the factor V gene revealed statistically significant differences in R485K allele (P=0.003) and genotype (P=0.03) frequencies between the patients and the control subjects. The A allele of SNP R485K was over-represented among the patients (12%) vs the control subjects (4%), at an odds ratio (OR) of 2.8 (95% confidence interval (CI) 1.2-6.2) for combined A genotypes (GA+AA vs GG). Allele and genotype differences between the patients and control subjects as regards M385T and Leiden mutation were not significant. In haplotype estimation analysis, there was a significantly elevated frequency of haplotype T-A-G encoding the M385-K485-R506 variant in the pre-eclamptic group vs the control group (P=0.01), at an OR of 2.6 (95% CI 1.2-5.5). We conclude that the T-A-G haplotype was more frequent among the patient group than in the control group, and genetic variations in the factor V gene other than the Leiden mutation may play a role in disease susceptibility.

Plasminogen activator inhibitor-1 polymorphism in women with pre-eclampsia.

We determined whether or not genetic variability in the promoter region of the gene encoding plasminogen activator inhibitor-1 (PAI1) contributes to individual differences in susceptibility to the development of preeclampsia. The study involved 133 preeclamptic and 115 healthy control pregnant women who were genotyped for a single-nucleotide insertion/deletion polymorphism (4G/5G) at position -675 in the PAI1 gene promoter. Furthermore, the frequencies of the alleles in the general middle-aged population are presented for comparison. Chi-square analysis was used to assess genotype and allele frequency differences between preeclamptic women and controls. A similar allelic distribution of PAI1 4G/5G polymorphism was observed in the two groups, with the frequency of the variant 4G allele being 50.4% in the preeclampsia group and 54.3% in the control group (p = 0.377; OR = 0.85, 95% CI = 0.60-1.22). Accordingly, the genotype distribution of the PAI1 4G/5G polymorphism in the preeclamptic and control groups was found to be similar (p = 0.68). Overall, this genotype data on fertile women is almost identical to that in the general middle-aged Finnish population. The 4G/5G polymorphism of the PAI1 gene promoter is unlikely to be a major genetic predisposing factor as regards preeclampsia in subjects from eastern Finland. These results are not suggestive of an important contribution of the PAI1 genotype on preeclampsia across populations.

Polymorphism in the interleukin 1 receptor antagonist gene in women with preeclampsia.

We have determined whether genetic variability in the gene encoding interleukin 1 receptor antagonist (IL1Ra) contributes to individual differences in susceptibility to the development of preeclampsia. The study involved 133 preeclamptic and 112 healthy control pregnant women who were genotyped for the variable copy number of 86-bp tandem repeats in intron 2 of the IL1Ra gene. Chi-square analysis was used to assess genotype and allele frequency differences between the preeclamptic and control groups. The frequencies were also compared with those in the general population. The frequency of the A2 allele was 38% among women with preeclampsia and 33% in the healthy control women (P=0.18), which was close to the rate in the general population (29%). The distribution of the A2 alleles and pooled homozygous and heterozygous genotypes having this allele was significantly different between the general population and the study group (P=0.006), at an odds ratio of 1.51, whereas the case-control setting was not sufficiently powerful to show a significant association. Using population frequencies as a reference, an association between IL1Ra polymorphism and preeclampsia was apparent, although the clinical importance of this finding is not clear.

Two exonic single nucleotide polymorphisms in the microsomal epoxide hydrolase gene are associated with polycystic ovary syndrome.

OBJECTIVE: To determine whether genetic variability in the gene encoding microsomal epoxide hydrolase (EPHX) contributes to individual differences in susceptibility to the development of polycystic ovary syndrome (PCOS). DESIGN: Retrospective case-control study. SETTING: University-based clinic. PATIENT(S): One hundred twelve white women with PCOS and 115 healthy controls. INTERVENTION(S): None. MAIN OUTCOME MEASURES: The presence of two single nucleotide polymorphisms (SNPs), T-->C (Tyr113His) in exon 3 and A-->G (His139Arg) in exon 4, in the EPHX gene. Single point analysis was expanded to pair of loci haplotype analysis to examine the estimated haplotype frequencies of the two SNPs, of unknown phase, in the PCOS and control groups. Estimated haplotype frequencies were assessed using the maximum-likelihood method, using an expectation-maximization algorithm. RESULT(S): Single point allele and genotype distributions in exon 3 and exon 4 of the EPHX gene were not statistically different between the groups. However, according to the haplotype estimation analysis, we observed a significantly elevated frequency of haplotype C-G (His113-Arg139) in the PCOS group versus the control group. The odds ratio for PCOS associated with the low activity haplotype C-G (His113-Arg139) was 2.28 (95% confidence interval 1.1-4.8). CONCLUSION(S): The use of two intragenic single nucleotide polymorphisms jointly in haplotype analysis of association demonstrated that the genetically determined low activity haplotype C-G (His113-Arg139) was significantly associated with PCOS.

Endothelial nitric oxide synthase polymorphism in preeclampsia.

OBJECTIVE: We wished to determine whether genetic variability in the gene encoding endothelial nitric oxide synthase (eNOS) modifies individual susceptibility to the development of preeclampsia. METHODS: The study involved 132 preeclamptic and 113 healthy control pregnant women who were genotyped for the Glu298Asp polymorphism in the eNOS gene. Chi(2) analysis was used to assess genotype and allele frequency differences between preeclamptic women and controls. RESULTS: A statistically similar allelic distribution of eNOS Glu298Asp polymorphism was observed in the two groups, with the frequency of the variant G allele being 74.6% in the preeclampsia group and 67.7% in the control group (P = .091; odds ratio 1.40, 95% confidence interval 0.95, 2.01). Accordingly, the genotype distribution of the NOS polymorphism in the preeclamptic and control groups was found to be similar (P = .233). CONCLUSION: These genotype data in subjects from eastern Finland were not suggestive of an important contribution of the Glu298Asp polymorphism in the NOS gene on preeclampsia across populations. However, the observed association between the G allele and disease risk, of borderline significance, may imply that other polymorphism(s) in the gene may modify disease risk.

Microsatellite marker association at chromosome region 2p13 in Finnish patients with preeclampsia and obstetric cholestasis suggests a common risk locus.

The pathophysiology of preeclampsia is incompletely understood, but the familial nature of the disease has long been recognized. Recent genome-scan studies have indicated linkage at the p23 region of chromosome 2. We have previously reported microsatellite marker association at chromosome region 2p13 in patients with obstetric cholestasis. We conducted population-based association screening with microsatellite markers to find potential preeclampsia-associated loci on chromosome region 2p13-p12 and to test whether preeclampsia and obstetric cholestasis share a single risk locus. The study was carried out among 115 unrelated control women, 133 preeclamptic women and 57 cholestatic women. Screening with microsatellite markers at the 2p13-p12 region revealed that the marker D2S286 was significantly associated with obstetric cholestasis in the overall association analysis (P=0.03), while it revealed only borderline association with preeclampsia (P=0.08). However, single allele association analysis indicated that both preeclampsia and obstetric cholestasis showed a statistically significant association with a common allele (P < 0.05), which was overrepresented in both the obstetric cholestasis (0.42) and preeclamptic (0.37) groups when compared with the control group (0.28). In conclusion, These findings suggest a possible genetic link between chromosome region 2p13-p12, preeclampsia and obstetric cholestasis. More specifically, these data suggest that there may be a common risk locus associated with both obstetric complications located in the vicinity of the 2p13-p12 association region.

Two exonic single nucleotide polymorphisms in the microsomal epoxide hydrolase gene are jointly associated with preeclampsia.

This study determined whether genetic variability in exons 3 and 4 of the microsomal epoxide hydrolase gene jointly modifies individual preeclampsia risk. The study also determined whether genetic variability in the gene encoding for microsomal epoxide hydrolase (EPHX) contributes to individual differences in susceptibility to the development of preeclampsia. The study involved 133 preeclamptic and 115 healthy control pregnant women who were genotyped for two single nucleotide polymorphisms (SNPs), T-->C (Tyr113His) in exon 3 and A-->G (His139Arg) in exon 4, in the EPHX gene. Chi-square analysis was used to assess genotype and allele frequency differences between the preeclamptic and control groups. In addition, single-point analysis was expanded to pair of loci haplotype analysis to examine the estimated haplotype frequencies of the two SNPs, of unknown phase, among the preeclamptic and control groups. Estimated haplotype frequencies were assessed using the maximum-likelihood method, employing an expectation-maximization (EM) algorithm. Single-point allele and genotype distributions in exons 3 and 4 of the EPHX gene were not statistically different between the groups. However, according to the haplotype estimation analysis, we observed a significantly elevated frequency of haplotype T-A (Tyr113-His139) among the preeclampsia group vs the control group (P=0.01). The odds ratio for preeclampsia associated with the high-activity haplotype T-A (Tyr113-His139) was 1.61 (95% CI: 1.12-2.32). The use of two intragenic SNPs jointly in haplotype analysis of association demonstrated that the genetically determined high-activity haplotype T-A (Tyr113-His139) was significantly associated with preeclampsia.

Polymorphism in the tumor necrosis factor-alpha gene in women with preeclampsia.

PURPOSE: We determined whether genetic variability in the gene encoding for tumor necrosis factor-alpha (TNF-alpha) contributes to individual differences in susceptibility to the development of preeclampsia. METHODS: The study involved 133 preeclamptic and 115 healthy control pregnant women who were genotyped for C-850T polymorphism in the TNF-alpha gene promoter. Chi-square analysis was used to assess genotype and allele frequency differences between preeclamptic women and controls. RESULTS: A significantly different genotype distribution of C-850T polymorphism was observed between the two groups, with the frequency of the variant T allele being significantly reduced in the preeclamptic group (4.5%) when compared with the control group (9.6%) (P = 0.03; OR = 0.45, 95% CI = 0.22-0.92). Accordingly, the odds ratio for preeclampsia associated with the pooled TT and CT genotypes was 0.367 (P = 0.02; 95% CI = 0.159-0.847). CONCLUSIONS: The T allele of the TNF-alpha gene may modify individual preeclampsia risk, being protective against the development of the complication.