title: Association of congenital cardiovascular malformations with 33 single nucleotide polymorphisms of selected cardiovascular disease-related genes.
abstract: BACKGROUND
  Clark (1996) proposed that abnormal blood flow is related to some congenital cardiovascular malformations (CCVMs), particularly CCVM with obstruction to blood flow. Our hypothesis is that CCVMs may relate to genes that affect blood coagulation or flow. We studied whether polymorphisms of such genes are related to CCVMs; previous association of these SNPs to conotruncal CCVMs is described.
  
  
  METHODS
  We assessed risk of pulmonary stenosis (PS, N = 120), atrial septal defect (ASD, N = 108), aortic stenosis (AS, N = 36), and coarctation of the aorta (CoAo, N = 64), associated with 33 candidate genes, selected for their relationship to blood flow affected by homocysteine metabolism, coagulation, cell-cell interaction, inflammation, or blood pressure regulation.
  
  
  RESULTS
  Effects were specific to cardiac phenotype and race. CoAo was associated with MTHFR (-667) C>T (odds ratio [OR] for TT 3.5, 95% confidence limits [CI] 1.4-8.6). AS was associated with a polymorphism of SERPINE1, G5>G4, OR = 5.6 for the homozygote with 95% CI 1.4-22.9. Unique polymorphisms were associated with increased risk of ASD and PS: NPPA 664G>A with ASD (OR of 2.4, 95%CI 1.3-4.4) and NOS3 (-690) C>T with PS (OR 6.1; 95% CI 1.6-22.6 in the African American population only). For ASD, the NPPA (-664) G>A SNP there was increased risk from the variant genotype only in maternal smokers (OR 2.6; 95% CI 1.0-7.2).
  
  
  CONCLUSIONS
  Genes affecting vascular function and coagulation appear to be promising candidates for the etiology of cardiac malformations and warrant further study.
authors.affiliation: Children's National Heart Institute, Washington, DC 20010, USA. kkuehl@cnmc.org
authors.forename: Karen
authors.initials: K
authors.lastname: Kuehl
authors.forename: Christopher
authors.initials: C
authors.lastname: Loffredo
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Lammer
authors.forename: David M
authors.initials: DM
authors.lastname: Iovannisci
authors.forename: Gary M
authors.initials: GM
authors.lastname: Shaw
mesh_terms: D001017:Aortic Coarctation / Q000235:genetics; D001024:Aortic Valve Stenosis / Q000235:genetics; D001777:Blood Coagulation / Q000235:genetics; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology; D002450:Cell Communication / Q000235:genetics; D019587:Dietary Supplements; D005260:Female; D006330:Heart Defects, Congenital / Q000235:genetics*; D006344:Heart Septal Defects, Atrial / Q000235:genetics; D006710:Homocysteine / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011446:Prospective Studies; D011666:Pulmonary Valve Stenosis / Q000235:genetics; D044469:Racial Groups / Q000235:genetics
chemical_list: D006710:Homocysteine; D042965:Methylenetetrahydrofolate Reductase (NADPH2)