The Norwegian preeclampsia family cohort study: a new resource for investigating genetic aspects and heritability of preeclampsia and related phenotypes.

BACKGROUND: Preeclampsia is a major pregnancy complication without curative treatment available. A Norwegian Preeclampsia Family Cohort was established to provide a new resource for genetic and molecular studies aiming to improve the understanding of the complex pathophysiology of preeclampsia. METHODS: Participants were recruited from five Norwegian hospitals after diagnoses of preeclampsia registered in the Medical birth registry of Norway were verified according to the study's inclusion criteria. Detailed obstetric information and information on personal and family disease history focusing on cardiovascular health was collected. At attendance anthropometric measurements were registered and blood samples were drawn. The software package SPSS 19.0 for Windows was used to compute descriptive statistics such as mean and SD. P-values were computed based on t-test statistics for normally distributed variables. Nonparametrical methods (chi square) were used for categorical variables. RESULTS: A cohort consisting of 496 participants (355 females and 141 males) representing 137 families with increased occurrence of preeclampsia has been established, and blood samples are available for 477 participants. Descriptive analyses showed that about 60% of the index women's pregnancies with birth data registered were preeclamptic according to modern diagnosis criteria. We also found that about 41% of the index women experienced more than one preeclamptic pregnancy. In addition, the descriptive analyses confirmed that preeclamptic pregnancies are more often accompanied with delivery complications. CONCLUSION: The data and biological samples collected in this Norwegian Preeclampsia Family Cohort will provide an important basis for future research. Identification of preeclampsia susceptibility genes and new biomarkers may contribute to more efficient strategies to identify mothers "at risk" and contribute to development of novel preventative therapies.

Refined phenotyping identifies links between preeclampsia and related diseases in a Norwegian preeclampsia family cohort.

OBJECTIVE: Preeclampsia is a complex genetic disease of pregnancy with a heterogenous presentation, unknown cause and potential severe outcomes for both mother and child. Preeclamptic women have increased risk for atherothrombotic cardiovascular disease. We aimed to identify heritabilities and phenotypic correlations of preeclampsia and related conditions in the Norwegian Preeclampsia Family Biobank. METHODS: By applying a variance components model, a total of 493 individuals (from 138 families with increased occurrence of preeclampsia) were classified according to 30 disease-related phenotypes. RESULTS: Of parous women, 75.7% (263/338) had experienced preeclampsia and 35.7% of women with and 22.4% without preeclampsia delivered children small for gestational age (SGA). We identified 11 phenotypes as heritable. The increased occurrence of preeclampsia was reflected by the presence [heritability (H2r) = 0.60)] and severity (H2r = 0.15) of preeclampsia and being born in a preeclamptic pregnancy (H2r = 0.25). Other heritable phenotypes identified included SGA (H2r = 0.40), chronic hypertension (H2r = 0.57), severity of atherothrombotic cardiovascular disease (H2r = 0.31), BMI (H2r = 0.60) and pulmonary disease (H2r = 0.91). The heritable phenotype preeclampsia overlapped with SGA (P = 0.03), whereas pulmonary disease was phenotypically correlated with atherothrombotic cardiovascular disease (P < 0.01), SGA (P = 0.02) and BMI (P = 0.02). CONCLUSION: This is the first study identifying the H2r of a range of health-related conditions in preeclamptic families. Our study demonstrates how refinement of phenotypes leads to better H2r estimation and the identification of a biological relationship between preeclampsia and related traits.

OP006. A preeclampsia genome-wide linkage scan in norwegian families.

INTRODUCTION: Several maternal susceptibility loci for preeclampsia (PE) have been discovered amongst Icelandic, Australian/New Zealand, Dutch and Finnish family cohorts, implicating locus heterogeneity. Through candidate gene studies, allele-specific heterogeneity in different populations is also evident. It is therefore likely that numerous population specific PE susceptibility variants exist, differing in their effect size. Despite on-going efforts to identify susceptibility genes for PE, the causal genetic variants still remain obscure. OBJECTIVES: The aim of this study is to interrogate the genetic architecture of PE susceptibility by performing a genome-wide linkage scan in a novel familial cohort from Norway. METHODS: A total of 480 DNA samples from The Norwegian PE Family Biobank were genotyped at Genomic Core Facility at NTNU. Genome-wide genotyping was performed with the Infinium HumanExome BeadChip (>240,000 markers) (Illumina, USA) that delivers focused coverage of exonic regions of the human genome. RESULTS: A total of 137 families are represented with 222 women with a valid PE diagnosis (SBP⩾140mmHg DBP⩾90mmHg, ⩾2 measurements at least 4h apart with documented proteinuria at ⩾2 occasions occurring after 20weeks of pregnancy), 44 with self-reported PE and 72 women with a healthy pregnancy. The genotyping has just recently been completed with an average call rate of 99.96%. Data and statistical analysis is now underway using MERLIN, R and SOLAR. A description of the Norwegian PE familial cohort plus preliminary results will be presented at the Congress. CONCLUSION: To our knowledge this is the first SNP-based genome-wide linkage study on PE, and the first performed in a novel Norwegian PE family cohort. By using an approach focusing on functionally relevant markers we anticipate the identification of susceptibility loci that are of substantial importance for disease development.

A validation of the diagnosis of obstetric sphincter tears in two Norwegian databases, the Medical Birth Registry and the Patient Administration System.

BACKGROUND: The purpose of the present study was to validate the registration of obstetric sphincter tears in 2 registers, the Medical Birth Registry of Norway [MBRN] and Patient Administration System [PAS]. METHODS: A retrospective cohort study of all obstetric sphincter tears that occurred in our department in 1990-1992 and 2000-2002 was performed. The case records of all patients registered either in MBRN, PAS or the birth logs were compared with the information in the medical records, which constituted the 'golden standard'. RESULTS: The incidence of obstetric sphincter tears in 1990-1992 was 5.8% (774/13381), 5.6% (745/13381) had a perineal tear of third degree and 0.2% (29/13381) of fourth degree. In 2000-2002, the total incidence was 6.6% (813/12380), 5.9% (731/12380) was a third degree perineal tear and 0.7% (82/12380) fourth degree, respectively. The sensitivity and specificity of the MBRN database to detect obstetric sphincter tears was 85.3 and 99.5% in 1990-1992, and 91.8 and 99.7% in 2000-2002, respectively. The positive and negative predictive values of a MBRN-registered diagnosis of obstetric sphincter tears in 1990-1992 were 91.4 and 99.1%, while the corresponding percentages in 2000-2002 were 95.4 and 99.4%, respectively. The sensitivity and specificity of the PAS database was correspondingly 52.1 and 99.0% in 1990-1992, and 84.6 and 98.5% in 2000-2002. The positive and negative predictive values of a PAS-diagnosis of obstetric sphincter tears were 75.8 and 97.1% in 1990-1992. In 2000-2002, they were 92.7 and 98.9%, respectively. CONCLUSION: The validity of a diagnosis of obstetric sphincter tears, based on the MBRN, is sufficiently high to justify future large-scale epidemiologic studies based on this database, while the validity of a PAS diagnosis is lower, but improves.