title: New evidence for the fetal insulin hypothesis: fetal angiotensinogen M235T polymorphism is associated with birth weight and elevated fetal total glycated hemoglobin at birth.
abstract: BACKGROUND
  Low birth weight is associated with an increased risk of cardiovascular events in later life. Insulin resistance is a key finding in adult patients with cardiovascular diseases. The neonatal phenotype of an individual with insulin resistance might be low birth weight, as insulin influences fetal growth. The renin-angiotensin-aldosterone system has been associated with cardiovascular disease and insulin resistance. We analyzed whether fetal polymorphisms of the angiotensinogen (AGT) and angiotensin-converting enzyme genes influence birth weight and/or fetal total glycated hemoglobin (fTGH), a surrogate parameter of fetal insulin resistance at birth.
  
  
  METHODS
  In 1132 white women delivering singletons, neonatal umbilical blood samples and clinical data of the mothers and newborns were obtained. Newborns were genotyped with respect to the AGT M235T and angiotensin-converting enzyme insertion/deletion polymorphism.
  
  
  RESULTS
  The AGT M235T TT polymorphism is associated with reduced birth weight (TT: 3288 g versus TM + MM: 3435 g, P < 0.05). Furthermore, newborns with a high percentage of fTGH (>6.5%) are more likely to have the TT genotype than those with normal fTGH (<or=6.5%, P < 0.05). With higher cutoffs for fTGH, the significance increases to P less than 0.005. No association was seen between these parameters and the fetal angiotensin-converting enzyme insertion/deletion phenotype.
  
  
  CONCLUSIONS
  The fetal AGT M235T polymorphism is associated with low birth weight and elevated fetal fTGH at birth. Previous findings show that elevated fetal fTGH correlates with low birth weight and that higher activity of the renin-angiotensin-aldosterone system is an independent risk factor for the development of diabetes mellitus and coronary artery disease. Therefore, our data are supportive of the fetal insulin hypothesis.
authors.affiliation: Center for Cardiovascular Research/Institute of Pharmacology, Charité, Berlin, Germany.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Schlemm
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Haumann
authors.forename: Maja
authors.initials: M
authors.lastname: Ziegner
authors.forename: Bulza
authors.initials: B
authors.lastname: Stirnberg
authors.forename: Andreas
authors.initials: A
authors.lastname: Sohn
authors.forename: Markus
authors.initials: M
authors.lastname: Alter
authors.forename: Thiemo
authors.initials: T
authors.lastname: Pfab
authors.forename: Karim D
authors.initials: KD
authors.lastname: Kalache
authors.forename: Florian
authors.initials: F
authors.lastname: Guthmann
authors.forename: Berthold
authors.initials: B
authors.lastname: Hocher
mesh_terms: D000328:Adult; D000808:Angiotensinogen / Q000235:genetics*; D001724:Birth Weight / Q000235:genetics*; D005260:Female; D005319:Fetal Hemoglobin / Q000235:genetics; D005838:Genotype; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn; D007328:Insulin / Q000235:genetics*; D016254:Mutagenesis, Insertional / Q000235:genetics; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D011110:Polymorphism, Genetic; D012084:Renin-Angiotensin System / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics
chemical_list: D000808:Angiotensinogen; D005319:Fetal Hemoglobin; D006442:Glycated Hemoglobin; D007328:Insulin; D007703:Peptidyl-Dipeptidase A