Retinoic acid receptor alpha gene variants, multivitamin use, and liver intake as risk factors for oral clefts: a population-based case-control study in Denmark, 1991-1994

Am J Epidemiol. 2003 Jul 1;158(1):69-76. doi: 10.1093/aje/kwg102.


Previous studies suggest that the risks of nonsyndromic cleft lip with or without cleft palate (CL+/-P) and isolated cleft palate are influenced by variation at several loci and that these loci interact with environmental factors to determine disease risk. One putative genetic risk factor for these conditions is the retinoic acid receptor alpha (RARA) locus, which is involved in cell-specific responses to retinoic acid. Hence, RARA may influence disease risk via an interaction with vitamin A and related compounds. Data from a Danish case-control study (1991-1994) were used to evaluate the relations between oral clefts, RARA, and maternal vitamin A exposure from multivitamins and liver. Analyses provided no compelling evidence that the risks of CL+/-P or isolated cleft palate are related to the RARA variant analyzed. Consistent with several previous studies, the authors' analyses indicated that maternal multivitamin supplement use protects against CL+/-P. Within the range observed in this population, higher levels of vitamin A intake from multivitamins and liver sources also seemed to protect against CL+/-P. Exploratory analyses suggested that the latter association was not entirely explained by the association between CL+/-P and multivitamin use, indicating that adequate levels of vitamin A may be required for normal development of the primary palate.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Case-Control Studies
  • Cleft Lip / epidemiology*
  • Cleft Lip / etiology
  • Cleft Lip / genetics
  • Cleft Palate / epidemiology*
  • Cleft Palate / etiology
  • Cleft Palate / genetics
  • DNA Primers
  • Denmark / epidemiology
  • Diet*
  • Dietary Supplements*
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Humans
  • Infant, Newborn
  • Liver
  • Male
  • Maternal Exposure / statistics & numerical data
  • Meat*
  • Odds Ratio
  • Polymerase Chain Reaction
  • Pregnancy
  • Receptors, Retinoic Acid / genetics*
  • Risk Factors
  • Vitamin A / administration & dosage*
  • Vitamin A / adverse effects


  • DNA Primers
  • Receptors, Retinoic Acid
  • Vitamin A