Hannele Laivuori

Evidence of a state of increased insulin resistance in preeclampsia

Similarities in certain biochemical variables between preeclampsia and the insulin resistance syndrome imply a possible link between insulin resistance and preeclampsia. We measured insulin sensitivity by the minimal model technique between 29 and 39 weeks of gestation in 22 preeclamptic and 16 control women, whose glucose tolerance was first confirmed as normal by an oral glucose tolerance test. In addition, we measured the fasting levels of serum C-peptide, uric acid, lipids, and lipoproteins. Preeclamptic women showed a higher insulin response (P = .001) during the oral glucose tolerance test than the controls. Insulin sensitivity in preeclamptic women (1.11+/-0.15 x 10(-4) x min(-1) x microU/mL) was 37% lower (P = .009) than in control women (1.77+/-0.19 x 10(-4) x min(-1) x microU/mL). The free fatty acid (FFA) concentration in preeclamptic women (0.17+/-0.01 g/L, P = .0004) was 70% higher than in control women (0.10+/-0.01 g/L). Also, baseline serum levels of C-peptide, uric acid, and triglyceride were higher in preeclamptic women. Insulin sensitivity increased fourfold to fivefold within the first 3 postpartum months, but insulin sensitivity in preeclamptic women was still 26% lower (P = .04) than in control women. Preeclampsia is a state of increased insulin resistance, and it persists for at least 3 months after pregnancy. This may be a pathogenetic factor in preeclampsia and may contribute to the excess cardiovascular morbidity among women with prior preeclampsia.

Susceptibility Loci for Preeclampsia on Chromosomes 2p25 and 9p13 in Finnish Families

Preeclampsia is a common, pregnancy-specific disorder characterized by reduced placental perfusion, endothelial dysfunction, elevated blood pressure, and proteinuria. The pathogenesis of this heterogeneous disorder is incompletely understood, but it has a familial component, which suggests that one or more common alleles may act as susceptibility genes. We hypothesized that, in a founder population, the genetic background of preeclampsia might also show reduced heterogeneity, and we have performed a genomewide scan in 15 multiplex families recruited predominantly in the Kainuu province in central eastern Finland. We found two loci that exceeded the threshold for significant linkage: chromosome 2p25, near marker D2S168 (nonparametric linkage [NPL] score 3.77; P=.000761) at 21.70 cM, and 9p13, near marker D9S169 (NPL score 3.74; P=.000821) at 38.90 cM. In addition, there was a locus showing suggestive linkage at chromosome 4q32 between D4S413 and D4S3046 (NPL score 3.13; P=.003238) at 163.00 cM. In the present study the susceptibility locus on chromosome 2p25 is clearly different (21.70 cM) from the locus at 2p12 found in an Icelandic study (94.05 cM) and the locus at 2q23 (144.7 cM) found in an Australian/New Zealand study. The locus at 9p13 has been shown to be a candidate region for type 2 diabetes in two recently published genomewide scans from Finland and China. The regions on chromosomes 2p25 and 9p13 may harbor susceptibility genes for preeclampsia.

Strategy for Standardization of Preeclampsia Research Study Design

Preeclampsia remains a major problem worldwide for mothers and babies. Despite intensive study, we have not been able to improve the management or early recognition of preeclampsia. At least part of this is because of failure to standardize the approach to studying this complex syndrome. It is possible that within the syndrome there may be different phenotypes with pathogenic pathways that differ between the subtypes. The capacity to recognize and to exploit different subtypes is of obvious importance for prediction, prevention, and treatment. We present a strategy for research to study preeclampsia, which will allow discrimination of such possible subtypes and also allow comparison and perhaps combinations of findings in different studies by standardized data and biosample collection. To make studies relevant to current clinical practice, the definition of preeclampsia can be that currently used and accepted. However, more importantly, sufficient data should be collected to allow other diagnostic criteria to be used and applied retrospectively. To that end, we present what we consider to be the minimum requirements for a data set in a study of preeclampsia that will facilitate comparisons. We also present a comprehensive or optimal data set for in-depth investigation of pathophysiology. As we approach the definition of phenotypes of preeclampsia by clinical and biochemical criteria, adherence to standardized protocols will hasten our understanding of the causes of preeclampsia and development of targeted treatment strategies

Gestational Diabetes Mellitus Can Be Prevented by Lifestyle Intervention: The Finnish Gestational Diabetes Prevention Study (RADIEL): A Randomized Controlled Trial.

OBJECTIVE To assess whether gestational diabetes mellitus (GDM) can be prevented by a moderate lifestyle intervention in pregnant women who are at high risk for the disease. RESEARCH DESIGN AND METHODS Two hundred ninety-three women with a history of GDM and/or a prepregnancy BMI of ≥30 kg/m2 were enrolled in the study at <20 weeks of gestation and were randomly allocated to the intervention group (n = 155) or the control group (n = 138). Each subject in the intervention group received individualized counseling on diet, physical activity, and weight control from trained study nurses, and had one group meeting with a dietitian. The control group received standard antenatal care. The diagnosis of GDM was based on a 75-g, 2-h oral glucose tolerance test at 24–28 weeks of gestation. RESULTS A total of 269 women were included in the analyses. The incidence of GDM was 13.9% in the intervention group and 21.6% in the control group ([95% CI 0.40–0.98%]; P = 0.044, after adjustment for age, prepregnancy BMI, previous GDM status, and the number of weeks of gestation). Gestational weight gain was lower in the intervention group (−0.58 kg [95% CI −1.12 to −0.04 kg]; adjusted P = 0.037). Women in the intervention group increased their leisure time physical activity more and improved their dietary quality compared with women in the control group. CONCLUSIONS A moderate individualized lifestyle intervention reduced the incidence of GDM by 39% in high-risk pregnant women. These findings may have major health consequences for both the mother and the child.

Aspirin in the prevention of pre‐eclampsia in high‐risk women: a randomised placebo‐controlled PREDO Trial and a meta‐analysis of randomised trials

Objective  To study the effect of aspirin in the prevention of pre‐eclampsia in high‐risk women.

Leptin during and after preeclamptic or normal pregnancy: its relation to serum insulin and insulin sensitivity.

Hyperleptinemia may be part of the insulin resistance syndrome. We studied serum leptin in preeclampsia, which is an insulin-resistant state, and sought associations between leptin and insulin or insulin sensitivity during and after pregnancy. Twenty-two proteinuric preeclamptic women and 16 normotensive controls were studied during the third trimester. Leptin was higher in preeclampsia (mean +/- SE, 34.6 +/- 3.9 v 20.0 +/- 3.3 microg/L, P = .002) and correlated directly with the level of proteinuria (r = .47, P = .03) and normal pregnancy (r = .52, P = .04), whereas insulin sensitivity as assessed by an intravenous glucose tolerance test showed no relationship to leptin. Leptin was 19.0 +/- 3.6 microg/L in 14 preeclamptic women and 10.1 +/- 2.0 microg/L (P = .11) in 11 controls 3 months after delivery. Leptin correlated directly with insulin both in preeclamptic puerperal women (r = .63, P = .02) and in controls (r = .81, P = .003). Leptin and insulin sensitivity correlated only in preeclamptic puerperal women (r = -.59, P = .02). In conclusion, (1) serum leptin is elevated in preeclampsia, (2) insulin is an important determinant of serum leptin in preeclamptic and normotensive women both during pregnancy and in the puerperium, and (3) hyperleptinemia may be part of the insulin resistance syndrome also in women with prior preeclampsia.

Adiponectin concentrations in maternal serum: elevated in preeclampsia but unrelated to insulin sensitivity.

Objective: Adiponectin is an adipocyte-derived protein with profound insulin-sensizing, anti-inflammatory, and antiatherogenic effect. Surprisingly, recent evidence suggests that adiponectin concentrations are increased during preeclampsia, which is characterized by insulin resistance. We studied whether serum adiponectin is related to insulin sensitivity in preeclamptic and normotensive pregnant women. Methods: We measured serum adiponectin concentrations and insulin sensitivity (intravenous glucose tolerance test/minimal model) in 22 women with preeclampsia and 15 normotensive controls with similar pre-pregnancy body mass index (BMI) (range 18-29 kg/m2) between 29 and 39 weeks of gestation. Fourteen cases and 10 controls were also studied 6-22 weeks after delivery. No subject had gestational diabetes. Results: During pregnancy, the mean adiponectin concentration in preeclamptic women was 10.3 (SD 4.2) μg/mL as compared to 7.9 (SD 2.9) μg/mL in normotensive controls (95% confidence interval [CI] for difference 0.1-5.3 μg/mL; P = .04). Adiponectin concentrations were unrelated to insulin sensitivity both in preeclamptic and normotensive subjects; insulin sensitivity was decreased in preeclampsia (P = .01). After delivery, mean adiponectin concentration was lower than during pregnancy: 7.4 (SD 3.0) μg/mL in preeclamptic subjects (P = .001) and 7.1 (SD 1.6) μg/mL in normotensive controls (P = .06) and similar in cases and controls (95% CI for difference - 1.7-2.3 μg/mL, P = .7). Conclusions: Despite their reduced insulin sensitivity, preeclamptic women have higher adiponectin concentrations than normotensive pregnant women. These concentrations are unrelated to insulin sensitivity. After pregnancy, the difference in adiponectin concentrations is no longer present between the two groups. These findings are consistent with a role of adiponectin in the pathophysiology of preeclampsia.

677 C-->T polymorphism of the methylenetetrahydrofolate reductase gene and preeclampsia.

Objective To evaluate C to T substitution at nucleotide 677 of N5,N10-methylenetetrahydrofolate reductase gene in women with prior preeclamptic or normotensive pregnancies. Methods Methylenetetrahydrofolate reductase genotypes were determined in 113 Finnish women with preeclamptic first pregnancies and 103 controls with one or more normotensive pregnancies, using polymerase chain reaction and restriction enzyme analysis. Preeclampsia was defined as severe in 100 women who fulfilled one or more of the subsequent criteria: systolic blood pressure (BP) at least 160 mmHg, diastolic BP at least 110 mmHg, or proteinuria at least 2 g per 24-hour urine collection. Results There were no significant differences in prevalences of the methylenetetrahydrofolate reductase genotypes (CC, CT, and TT) between groups (57%, 40%, and 3% in the preeclamptic group and 54%, 39%, and 7%, respectively, in controls). The frequency of the T677 allele was 0.23 in the preeclamptic group and 0.26 in the control group (difference 0.03; 95% confidence interval −0.08, 0.14; P = .51). Our sample had 60% power to detect a difference of the allele frequencies similar to that (0.12) reported previously. The result was similar when analysis was restricted to patients with severe preeclampsia (T677 allele frequency 0.22). Conclusion A carrier status for the T677 allele of the methylenetetrahydrofolate reductase gene does not predispose to preeclampsia, at least in the Finnish population.

Large genomic rearrangements and germline epimutations in Lynch syndrome.

In one‐third of families fulfilling the Amsterdam criteria for hereditary nonpolyposis colorectal cancer/Lynch syndrome, and a majority of those not fulfilling these criteria point mutations in DNA mismatch repair (MMR) genes are not found. The role of large genomic rearrangements and germline epimutations in MLH1, MSH2 and MSH6 was evaluated in 2 such cohorts. All 45 index patients were mutation‐negative by genomic sequencing and testing for a prevalent population‐specific founder mutation, and selectively lacked MMR protein expression in tumor tissue. Eleven patients (“research cohort”) represented 11 mutation‐negative families among 81 verified or putative Lynch syndrome families from the nation‐wide Hereditary Colorectal Cancer Registry of Finland. Thirty‐four patients from 33 families (“clinic‐based cohort”) represented suspected Lynch syndrome patients tested for MMR gene mutations in a diagnostic laboratory during 2004–2007. Multiplex ligation‐dependent probe amplification (MLPA) and methylation‐specific (MS)‐MLPA were used to detect rearrangements and epimutations, respectively. Large genomic deletions occurred in 12/45 patients (27%), being present in 3/25 (12%), 9/16 (56%) and 0/4 (0%) among index patients lacking MLH1, MSH2 or MSH6 expression, respectively. Germline epimutations of MLH1, one of which coexisted with a genomic deletion, occurred in 2 patients (4%) and were accompanied by monoallelic expression in mRNA. Large genomic deletions (mainly MSH2) and germline epimutations (MLH1) together explain a significant fraction of point mutation‐negative families suspected of Lynch syndrome and are associated with characteristic clinical and family features. Our findings have important implications in the diagnosis and management of such families.

Genome-Wide Association Scan Identifies a Risk Locus for Preeclampsia on 2q14, Near the Inhibin, Beta B Gene

Elucidating the genetic architecture of preeclampsia is a major goal in obstetric medicine. We have performed a genome-wide association study (GWAS) for preeclampsia in unrelated Australian individuals of Caucasian ancestry using the Illumina OmniExpress-12 BeadChip to successfully genotype 648,175 SNPs in 538 preeclampsia cases and 540 normal pregnancy controls. Two SNP associations (rs7579169, p = 3.58×10−7, OR = 1.57; rs12711941, p = 4.26×10−7, OR = 1.56) satisfied our genome-wide significance threshold (modified Bonferroni p<5.11×10−7). These SNPs reside in an intergenic region less than 15 kb downstream from the 3′ terminus of the Inhibin, beta B (INHBB) gene on 2q14.2. They are in linkage disequilibrium (LD) with each other (r2 = 0.92), but not (r2<0.80) with any other genotyped SNP ±250 kb. DNA re-sequencing in and around the INHBB structural gene identified an additional 25 variants. Of the 21 variants that we successfully genotyped back in the case-control cohort the most significant association observed was for a third intergenic SNP (rs7576192, p = 1.48×10−7, OR = 1.59) in strong LD with the two significant GWAS SNPs (r2>0.92). We attempted to provide evidence of a putative regulatory role for these SNPs using bioinformatic analyses and found that they all reside within regions of low sequence conservation and/or low complexity, suggesting functional importance is low. We also explored the mRNA expression in decidua of genes ±500 kb of INHBB and found a nominally significant correlation between a transcript encoded by the EPB41L5 gene, ∼250 kb centromeric to INHBB, and preeclampsia (p = 0.03). We were unable to replicate the associations shown by the significant GWAS SNPs in case-control cohorts from Norway and Finland, leading us to conclude that it is more likely that these SNPs are in LD with as yet unidentified causal variant(s).