Genetic Predisposition to Pre-eclampsia
Both maternal and fetal genes contribute to pre-eclampsia risk, with family history conferring a 2.9-fold increased risk, though specific causative genes remain inconsistent across studies despite extensive candidate gene research and genome-wide searches. 1, 2
Familial and Genetic Evidence
The genetic basis of pre-eclampsia is strongly supported by epidemiological patterns:
Pre-eclampsia is more common in daughters of pre-eclamptic women and in pregnancies fathered by sons of pre-eclamptic women, demonstrating involvement of both maternal and fetal genetic contributions to the syndrome. 3
Having 2 or more first-degree relatives with cardiovascular risk factors doubles pre-eclampsia risk, while having 2 or more first-degree relatives with heart disease or stroke confers a 3-fold risk, suggesting genetic factors common to both pre-eclampsia and atherosclerotic disease. 1
A family history of pre-eclampsia conveys a relative risk of 2.9 for developing the condition, establishing familial clustering as a significant risk factor. 1, 4
Current State of Gene Identification
Despite strong evidence for genetic predisposition, specific gene identification has been challenging:
Genome-wide searches have begun but have not yet yielded consistent results across different populations and studies. 3
Function-perturbing polymorphisms have been identified for several candidate genes, but findings are inconsistent and have not been replicated reliably. 3
The pathogenic mechanisms underlying pre-eclampsia include immune maladaptation, inadequate placental development and trophoblast invasion, placental ischemia, oxidative stress, and thrombosis—all of which have genetic factors that may be involved in the pathogenic changes occurring. 5
Complexity of Genetic Analysis
The difficulty in identifying specific genes stems from several factors:
Studies of the epidemiological genetics of the disorder are hampered by the fact that overt disease only occurs in women at the time of reproduction, and information from older records is frequently inadequate to establish family history definitively. 3
The potential contributions of both maternal and fetal genes to disease onset have complicated genetic analysis in humans, as two individuals are involved (mother and baby), each with different genetic makeups. 6, 7
Pre-eclampsia is not a single disorder but rather different pathways converging on a common syndromic endpoint, with the disorder arising from different mixes of environmental and genetic factors, with different contributions from the mother and placenta. 1, 7
Paternal Genetic Contribution
Evidence for paternal genetic involvement includes:
Multigravidas pregnant by a new partner have a risk of pre-eclampsia intermediate between that associated with first pregnancies and subsequent pregnancies with the same partner, suggesting new paternal antigen exposure increases risk. 3, 2
The risk is reduced when there is a longer period of intercourse with the father before conception, and barrier contraceptives that prevent exposure to semen increase the risk of pre-eclampsia, supporting an immunologic basis involving paternal genes. 3
Clinical Implications
Pre-eclampsia can be initiated by at least three independent mechanisms: pre-existing borderline maternal hypertension exacerbated by pregnancy, elevated levels of vasoconstrictor angiotensin II in maternal circulation by placental over-production of renin, and placental pathology. 6
Segregation of the human disease into different subtypes may be a key first step in identifying genetic risk factors, as the pathogenesis cannot be explained by a single mechanism. 6
Both maternal and fetal genes contribute to disease risk, with genetic factors common to both pre-eclampsia and atherosclerotic disease, explaining why women with pre-eclampsia have approximately 75% increased risk of cardiovascular-related mortality. 2, 4