Preeclampsia Risk Raised by Variant of AGT2R Gene
Preeclampsia Risk Raised by Variant of AGT2R Gene
A polymorphism in a gene that is part of the renin angiotensin system (RAS) is associated with increased risk for preeclampsia in overweight or obese women, according to a study published online November 5 in Placenta.
"Preeclampsia affects up to 7% of nulliparous pregnancies and is a major cause of maternal and perinatal morbidity and mortality worldwide," write the authors, led by Ang Zhou, MD, from the Robinson Institute University of Adelaide in Australia. The cause of preeclampsia, however, remains unknown, they continue. Hypertension is both a symptom and a risk factor for preeclampsia. Variants in the genes whose protein products are part of the RAS, therefore, may be associated with increased risk of developing this life-threatening condition and may possibly provide a genotyping test to identify at-risk pregnant women.
To investigate whether specific gene-environment interactions might elevate risk for preeclampsia, Dr. Zhou and colleagues stratified genotypes in 2 RAS genes by environmental risk factors (body mass index [BMI], maternal age, diet, smoking, and socioeconomic status) for 2121 parent–infant trios in Adelaide and Auckland, New Zealand, who were part of the Screening for Pregnancy Endpoints (SCOPE) study. Of these 2121 trios, 123 (5.8%) experienced preeclampsia, 813 (38.3%) had other complications, and 1185 (55.9%) had uncomplicated pregnancies.
The researchers genotyped the participants for 4 polymorphisms each in the genes AGT1R (angiotensin type 1 receptor) and AGT2R (angiotensin type 2 receptor). Past studies had associated certain genotypes with increased risk for myocardial infarction and coronary artery disease.
The investigators sampled blood for genotyping from both the mother at the fifteenth (±1) week of pregnancy, from the partner at some time during the woman's pregnancy, and from umbilical cord blood at the time of delivery. When partners were unwilling to undergo venipuncture or umbilical cord blood was not collected, buccal swabs were performed on the partner and/or infant instead.
Genotype data were not available for 199 (9.4%) of the women, 470 (22.2%) of the men, and 578 (27.3%) of the infants because of either technical failure or nonpaternity.
The screen revealed significant association for the AGT2R C4599A polymorphism in both parents and the child only when stratified for a maternal BMI of 25 kg/m or higher. The gene is X-linked, so males have a single allele.
A significant increase in preeclampsia risk occurred when the maternal BMI was 25 kg/m or higher for genotype AA for the women (adjusted odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0 - 4.2), and for the pregnant partners of men who had genotype A,, adjusted OR was 1.9 (95% CI, 1.1 - 3.2).
The paternal A allele was also associated with increased risk for uterine artery bilateral notching at 20 weeks (OR, 2.1; 95% CI, 1.3 - 3.4), as seen on Doppler ultrasound. For the newborns, CA and AA genotypes increased preeclampsia risk for mothers with higher BMIs (OR, 3.5 [95% CI, 1.6 - 7.9]; OR, 3.0 [95% CI, 1.4 - 6.5], respectively).
The current study offers several "novelties," the researchers write: "1) paternal and neonatal association of this polymorphism with preeclampsia and 2) modulation of these associations by maternal BMI."
Results of this study add to the evidence that paternal factors influence the risk for preeclampsia in their partners, explain the authors. Although the investigation did not determine the precise mechanism of the elevated risk, the finding of uterine artery bilateral notching suggests arterial resistance and inadequate trophoblast invasion, implicating the placenta, according to the report. "It is tempting to speculate," the researchers write, that accelerated trophoblast apoptosis is behind the increased risk for preeclampsia in individuals with specific genotypes in the AGT2R gene.
A limitation of the study was the inability to obtain genotype information on all participants.
The Australian SCOPE study was funded by the Premier’s Science and Research Fund, Government of South Australia. The New Zealand SCOPE study was funded by New Enterprise Research Fund, Foundation for Research Science and Technology; Health Research Council; and Evelyn Bond Fund, Auckland District Health Board Charitable Trust. Genotyping and data analyses were funded by a National Health and Medical Research Council Australia project grant awarded to 2 of the authors and by the University of Adelaide. One author is supported by a National Health and Medical Research Council Australia Senior Research Fellowship. The other authors have disclosed no relevant financial relationships.
Placenta. Published online November 5, 2012. Abstract
A polymorphism in a gene that is part of the renin angiotensin system (RAS) is associated with increased risk for preeclampsia in overweight or obese women, according to a study published online November 5 in Placenta.
"Preeclampsia affects up to 7% of nulliparous pregnancies and is a major cause of maternal and perinatal morbidity and mortality worldwide," write the authors, led by Ang Zhou, MD, from the Robinson Institute University of Adelaide in Australia. The cause of preeclampsia, however, remains unknown, they continue. Hypertension is both a symptom and a risk factor for preeclampsia. Variants in the genes whose protein products are part of the RAS, therefore, may be associated with increased risk of developing this life-threatening condition and may possibly provide a genotyping test to identify at-risk pregnant women.
To investigate whether specific gene-environment interactions might elevate risk for preeclampsia, Dr. Zhou and colleagues stratified genotypes in 2 RAS genes by environmental risk factors (body mass index [BMI], maternal age, diet, smoking, and socioeconomic status) for 2121 parent–infant trios in Adelaide and Auckland, New Zealand, who were part of the Screening for Pregnancy Endpoints (SCOPE) study. Of these 2121 trios, 123 (5.8%) experienced preeclampsia, 813 (38.3%) had other complications, and 1185 (55.9%) had uncomplicated pregnancies.
The researchers genotyped the participants for 4 polymorphisms each in the genes AGT1R (angiotensin type 1 receptor) and AGT2R (angiotensin type 2 receptor). Past studies had associated certain genotypes with increased risk for myocardial infarction and coronary artery disease.
The investigators sampled blood for genotyping from both the mother at the fifteenth (±1) week of pregnancy, from the partner at some time during the woman's pregnancy, and from umbilical cord blood at the time of delivery. When partners were unwilling to undergo venipuncture or umbilical cord blood was not collected, buccal swabs were performed on the partner and/or infant instead.
Genotype data were not available for 199 (9.4%) of the women, 470 (22.2%) of the men, and 578 (27.3%) of the infants because of either technical failure or nonpaternity.
The screen revealed significant association for the AGT2R C4599A polymorphism in both parents and the child only when stratified for a maternal BMI of 25 kg/m or higher. The gene is X-linked, so males have a single allele.
A significant increase in preeclampsia risk occurred when the maternal BMI was 25 kg/m or higher for genotype AA for the women (adjusted odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0 - 4.2), and for the pregnant partners of men who had genotype A,, adjusted OR was 1.9 (95% CI, 1.1 - 3.2).
The paternal A allele was also associated with increased risk for uterine artery bilateral notching at 20 weeks (OR, 2.1; 95% CI, 1.3 - 3.4), as seen on Doppler ultrasound. For the newborns, CA and AA genotypes increased preeclampsia risk for mothers with higher BMIs (OR, 3.5 [95% CI, 1.6 - 7.9]; OR, 3.0 [95% CI, 1.4 - 6.5], respectively).
The current study offers several "novelties," the researchers write: "1) paternal and neonatal association of this polymorphism with preeclampsia and 2) modulation of these associations by maternal BMI."
Results of this study add to the evidence that paternal factors influence the risk for preeclampsia in their partners, explain the authors. Although the investigation did not determine the precise mechanism of the elevated risk, the finding of uterine artery bilateral notching suggests arterial resistance and inadequate trophoblast invasion, implicating the placenta, according to the report. "It is tempting to speculate," the researchers write, that accelerated trophoblast apoptosis is behind the increased risk for preeclampsia in individuals with specific genotypes in the AGT2R gene.
A limitation of the study was the inability to obtain genotype information on all participants.
The Australian SCOPE study was funded by the Premier’s Science and Research Fund, Government of South Australia. The New Zealand SCOPE study was funded by New Enterprise Research Fund, Foundation for Research Science and Technology; Health Research Council; and Evelyn Bond Fund, Auckland District Health Board Charitable Trust. Genotyping and data analyses were funded by a National Health and Medical Research Council Australia project grant awarded to 2 of the authors and by the University of Adelaide. One author is supported by a National Health and Medical Research Council Australia Senior Research Fellowship. The other authors have disclosed no relevant financial relationships.
Placenta. Published online November 5, 2012. Abstract
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