Infant TGF-alpha genotype, orofacial clefts, and maternal periconceptional multivitamin use.
OBJECTIVE
We previously demonstrated a strong association between periconceptional maternal cigarette smoking, infant transforming growth factor-alpha (TGFa) genotype, and risk of orofacial clefts. Because serum folate may be decreased by cigarette smoking and because maternal periconceptional use of multivitamins containing folic acid has been associated with a reduced risk of clefting, we explored whether a potential relation existed between infant TGFa genotype, maternal multivitamin use, and risk of orofacial cleft phenotypes.


METHODS
Data were derived from a population-based case-control study of fetuses and live-born infants among a cohort of 1987 to 1989 California births (n = 548,844). Information concerning periconceptional multivitamin use was obtained via telephone interviews with mothers of 731 (84.7% of eligible) orofacial cleft case infants, and of 734 (78.2%) nonmalformed control infants. DNA was obtained from newborn screening bloodspots and genotyped for the Taql polymorphism of TGFa. Among infants of interviewed mothers, genotypes were available for 571 (78.1%) case infants and 640 (87.2%) control infants.


METHODS
The study encompassed all hospitals in selected California counties.


METHODS
The main outcome measures were the risks of specific cleft phenotypes among infants with uncommon TGFa genotypes and whose mothers did not use multivitamins periconceptionally.


RESULTS
Compared with infants homozygous for the common TGFa genotype and whose mothers used multivitamins, increased clefting risks were observed for infants with the A2 genotype (homozygous or heterozygous) and whose mothers did not use multivitamins. Risk estimates were 3.0 (1.4-6.6 [95% confidence interval]) for isolated cleft lip with or without cleft palate (CLP), 2.4 (0.69-11.6) for multiple CLP, 2.6 (0.97-7.7) for isolated cleft palate (CP), 4.2 (1.3-16.2) for multiple CP, and 8.1 (2.6-27.7) for "known-syndrome" clefts. Clefting risks for infants with the A2 genotype and whose mothers used multivitamins were substantially smaller, as were the risks for infants with the A1 genotype whose mothers did not use multivitamins.


CONCLUSIONS
These data provide preliminary evidence for a gene-nutrient interaction in risk of clefting.
March of Dimes Birth Defects Foundation, California Birth Defects Monitoring Program, Emeryville, California 94608, USA.
G M
GM
Shaw
C R
CR
Wasserman
J C
JC
Murray
E J
EJ
Lammer
D000328:Adult; D016022:Case-Control Studies; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D015331:Cohort Studies; D016001:Confidence Intervals; D004247:DNA / Q000235:genetics; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D007407:Interviews as Topic; D008297:Male; D016017:Odds Ratio; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics; D011159:Population Surveillance; D016742:Preconception Care; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects / Q000097:blood; D016211:Transforming Growth Factor alpha / Q000235:genetics*; D014815:Vitamins / Q000008:administration & dosage / Q000627:therapeutic use*
D016211:Transforming Growth Factor alpha; D014815:Vitamins; D004247:DNA; D005492:Folic Acid