Association of congenital cardiovascular malformations with 33 single nucleotide polymorphisms of selected cardiovascular disease-related genes.
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.
Kuehl
Karen
K
Children's National Heart Institute, Washington, DC 20010, USA. kkuehl@cnmc.org
Loffredo
Christopher
C
Lammer
Edward J
EJ
Iovannisci
David M
DM
Shaw
Gary M
GM
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
D006710:Homocysteine; D042965:Methylenetetrahydrofolate Reductase (NADPH2)