1 Department of Nephrology 3 Department of Gynecology, University Hospital Charité, Homboldt University of Berlin 2 Institute of Molecular Biology and Biochemistry, Free University of Berlin, Berlin, Germany
Sir,
Low birthweight, thinness and short body length at birth are associated with markedly increased rates of cardiovascular disease and non-insulin dependent diabetes in adult life. The fetal programming hypothesis proposes that these diseases originate through adaptation which the fetus makes when it is undernourished. These adaptations may be vascular, metabolic or endocrine. They permanently change the function and the structure of the body in adult life [1, 2].
Recently, Siffert reviewed current knowledge concerning the 825T allele of the GNB3 gene which encodes the ß3 subunit of heterotrimeric G proteins. The molecular phenotype of this allele is characterized by enhanced signal transduction via G proteins through the generation of a splice variant termed Gß3s. This allele is associated with hypertension and the development of obesity, and it predisposes patients with type 2 diabetes to end-stage renal disease [3].
Our own study, on the other hand, showed that the maternal 825T allele of the GNB3 gene in healthy pregnant women without any other detectable risk factors for impaired fetal growth was also associated with a lower birthweight [4]. Low birthweight as just mentioned, has been associated with a higher risk for diabetes type 2 and hypertension. This principal relationship, which was first described by Barker et al. [1], has been confirmed since in about 250 000 people studied worldwide.
Thus we postulate based on our study [4], that it is not only the patient's G protein ß3 subunit (825T) allele on its own causing an association with hypertension and obesity, but in addition causing the higher chance for a G protein ß3 subunit (825T) allele carrier to be a child of a mother with this allele. A mother with at least one ß3 subunit (825T) allele hasas a matter for courseinfants with an increased incidence of the (825T) allele. The classic fetal programming hypothesis proposes that exogenous maternal malnutrition during pregnancy causes a lifelong, persisting adaptation of the fetus resulting in low birthweight, increased cardiovascular risk, and non-insulin dependent diabetes in adult life. Based on our data [4], we suggest an advanced fetal programming hypothesis: maternal genes such as the G protein ß3 subunit (825T) allele might contributebeside maternal malnutrition during pregnancyto fetal malnutrition as well and therefore induce an adaptation of the fetus which causes cardiovascular disease in adult life. This hypothesis is illustrated in Figure 1.
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Institut für Pharmakologie, Universitätsklinikum Essen, Essen, Germany
Sir,
The G protein ß3 subunit 825T allele is associated with obesity, hypertension, diabetes, and, potentially diabetic nephropathy [1]. Hocher et al. have conducted a very interesting study that may link low birthweight with the 825T allele which in turn represents a cardiovascular risk factor [2]. As stated by Hocher et al., evidence is overwhelming that low birthweight or impaired fetal growth is associated with an increased life-time risk for cardiovascular events and type 2 diabetes. Hocher et al. found that maternal 825T carrier status but not fetal 825T carrier status was associated with reduced birthweight [2]. They concluded that the maternal 825T allele could contribute somehow to fetal malnutrition which would induce persisting fetal programming through an as yet unknown mechanism. Although attractive, this hypothesis neglects one important aspect. Children from homozygous or heterozygous 825T allele carriers, who have been found to have reduced birthweight, have a very high likelihood of being 825T allele carriers themselves. The 825T allele indicates increased G protein activation and is associated with many cellular phenotypes which contribute to an increased cardiovascular risk. Such phenotypes include an augmented constriction of coronary arteries [3], an increased activation of immune cells [4, 5], enhanced platelet aggregation [6], and abnormal regulation of cardiac potassium channels [7]. These effects are not seen in homozygous C825 allele carriers although the possibility exists that these had a mother carrying one 825T allele. In view of these considerations I would rather propose that the fetal 825T allele could be a risk for low birthweight. Increased cardiovascular risk in adult life does not result from fetal programming but from the high likelihood for babies from 825T allele carriers to carry at least one 825T allele.
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