Is Angiotensinogen a Good Candidate Gene for Preeclampsia?

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Abstract
Objective: To test the hypothesis that variants in the angiotensinogen gene are a major genetic cause of preeclampsia (PE). Methods: Ten families with a high incidence of PE were typed for alleles at a microsatellite repeat within the angiotensinogen gene (AGT). Logarithm of odds (LODs) scores were used to examine for cosegregation of AGT alleles with the disease under several models of inheritance. Both recessive and dominant modes of inheritance with penetrances ranging from 0.9 to 0.5 were considered for a range of disease gene frequencies. A model-independent analysis, affected pedigree member method (AFFPED), was also used. Results: There was no indication of cosegregation between preeclampsia and angiotensinogen alleles under any model. Under most dominant models the preeclampsia gene was excluded from a 5 centimorgan region around angiotensinogen (LOD < -2). AFFPED also does not support close linkage of AGT and the preeclampsia gene. Conclusions: Variants at the angiotensinogen gene are not responsible for the preeclampsia in these families. We are unable to verify the reports of two groups suggesting that susceptibility to preeclampsia is correlated with variation at the angiotensinogen locus. Distinguishing preeclampsia from other hypertensive disorders of pregnancy has long been a difficult problem, and still remains to be solved. Raised blood pressure is almost certainly a secondary event in the PE causal chain. The pathophysiology of preeclampsia suggests that genes involved in specifying products which affect the interaction of trophoblast and decidua are better candidates for the origin of the fundamental lesion than are genes involved in controlling blood pressure.