The advanced fetal programming hypothesis

Berthold Hocher1,2, Torsten Slowinski1,2, Christian Bauer2 and Horst Halle3

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 has—as a matter for course—infants 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 contribute—beside maternal malnutrition during pregnancy—to 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 1Go.



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Fig. 1. Maternal genes like the G protein ß3 subunit (825T) allele and/or maternal nutrition during pregnancy determines fetal nutrition. Impaired fetal nutrition causes an adaptation, which improves the chance for survival of the fetus. These adaptations may be vascular, metabolic or endocrine. They permanently change the function and the structure of the body in adult life. In combination with adverse adult life-style risk factors, these adaptations increase the risk for adult diseases such as hypertension, type 2 diabetes and hypercholesteraemia.

 

References

  1. Barker DJP, Osmond C, Winter PD, Margetts B, Simmonds SJ. Weight in infancy and death from ischaemic heart disease. Lancet1989; 2: 577–580[ISI][Medline]
  2. Barker DJP. Fetal origin of cardiovascular disease. Ann Med1999; 31 Suppl 1: 3–6[ISI][Medline]
  3. Siffert W. G protein ß3 subunit 825T allele, hypertension, obesity and diabetic nephropathy. Nephrol Dial Transplant2000; 15: 1298–1306[Abstract/Free Full Text]
  4. Hocher B, Slowinski T, Stolze T, Pleschka A, Neumayer HH, Halle H. Association of maternal G protein ß3 subunit 825T allele with low birthweight. Lancet2000; 355: 1241–1242[ISI][Medline]

 

Reply

Winfried Siffert

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.

References

  1. Siffert W. G protein ß3 subunit 825T allele, hypertension, obesity and diabetic nephropathy. Nephrol Dial Transplant2000; 15: 1298–1306[Abstract/Free Full Text]
  2. Hocher B, Slowinski T, Stolze T, Pleschka A, Neumayer HH, Halle H. Association of maternal G protein ß3 subunit 825T allele with low birthweight. Lancet2000; 355: 1241–1242[ISI][Medline]
  3. Baumgart D, Naber C, Haude M, Oldenburg O, Erbel R, Heusch G, Siffert W. G protein ß3 subunit 825T allele and enhanced coronary vasoconstriction on alpha(2)-adrenoceptor activation. Circ Res1999; 85: 965–969[Abstract/Free Full Text]
  4. Virchow S, Ansorge N, Rosskopf D, Rübben H, Siffert W. The G protein ß3 subunit splice variant Gbeta3-s causes enhanced chemotaxis of human neutrophils in response to interleukin-8. Naunyn Schmiedebergs Arch Pharmacol1999; 360: 27–32[ISI][Medline]
  5. Virchow S, Ansorge N, Rübben H, Siffert G, Siffert W. Enhanced fMLP-stimulated chemotaxis in human neutrophils from individuals carrying the G protein ß3 subunit 825T-allele. FEBS Lett1998; 436: 155–158[ISI][Medline]
  6. Naber C, Hermann BL, Vietzke D, Altmann C, Haude M, Mann K, Rosskopf D, Siffert W. Enhanced epinephrine-induced platelet aggregation in individuals carrying the G protein ß3 subunit 825T allele. FEBS Lett2000; 484: 199–201[ISI][Medline]
  7. Dobrev D, Wettwer E, Himmel HM, Kortner A, Kuhlisch E, Schuler S, Siffert W, Ravens U. G-protein ß3-subunit 825T allele is associated with enhanced human atrial inward rectifier potassium currents. Circulation2000; 102: 692–697[Abstract/Free Full Text]




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