Centers for Disease Control and Prevention
Centers for Disease Control and Prevention
Centers for Disease Control and Prevention CDC Home Search CDC CDC Health Topics A-Z    
Office of Genomics and Disease Prevention  
Office of Genomics and Disease Prevention
e-Journal Club

SLC19A1 (RFC1) A80G Polymorphism, Maternal Multivitamin with Folate Use, and Orofacial and Conotruncal Heart Defects

October 22, 2004

Reviewed by:
Mindy Clyne, MS1
Cynthia A. Moore, M.D., Ph.D.2

Office of Genomics and Disease Prevention1,2, and National Center on Birth Defects and

Developmental Disabilities2,
Centers for Disease Control and Prevention

The Health Outcome

Conotruncal heart defects and orofacial clefts are common birth defects. The birth prevalence of conotruncal heart defects and orofacial clefts are 0.8 in 1,000 and 2 in 1,000 births, respectively. Treatment is costly and may involve multiple surgical interventions. Conotruncal heart defects include truncus arteriosus, transposition of the great arteries, double outlet right ventricle, tetralogy of Fallot, pulmonary atresia with ventricular septal defect and aortopulmonary window . Orofacial clefts include cleft lip with or without cleft palate, or cleft palate alone.

The Finding

Several epidemiologic studies have evaluated the association of periconceptional folic acid with conotruncal heart defects and orofacial clefts (Botto et al., 2000 (1) ; Botto et al., 1996 (2) ; Shaw et al., 1995 (3) ; Shaw et al., 1995;(4) ) . Studies evaluating the thermolabile or C677T allele of 5,10-methylenetetrahydrofolate (MTHFR), one gene in the folate metabolic pathway, have shown increased risk for congenital heart defects (Junker, et al, 2001(5); Wenstrom, et al, 2001(6); Martinelli et al., 2001(7)) and orofacial clefts (Mills et al., 1999 (8) ; Gaspar et al., 1999 (9) ) , but don’t account for a large proportion of these defects. Positive results were reported for the homozygous 677TT individuals in some studies, and combined homozygous and heterozygous individuals in other studies, however, none reported a higher risk in the heterozygous group.

In this case-control study (10), the risks of conotruncal heart defects and orofacial clefts were evaluated in infants genotyped for a variant of the reduced folate carrier-1 gene (RFC-1 or SLC19A1). The gene product is a transporter for the uptake of folate. The gene variant is an A-to-G (A80G) single nucleotide change at position 80, replacing a histidine (CAC) with an arginine (CGC). This variant has been associated with increased homocysteine levels [Chango, et al, 2000(11), and elevated risk of spina bifida was found in homozygous G80/G80 infants whose mothers did not use vitamin supplements (Shaw, et al, 2002(12)).

Study participants were liveborn infants in California between 1987-1989. Cases included infants diagnosed with either of the above defects before 1 year of age. Controls were non-malformed infants randomly selected from the same geographic area and time period as cases. An increased risk for conotruncal heart defects was found with both the G80/G80 and G80/A80 genotypes; the estimated relative risk for the heterozygous group was slightly higher than for the homozygous group (2.3 vs. 1.6). No increased risk was observed for orofacial clefts. The study also evaluated gene-nutrient interaction, assessing maternal folic acid intake for each defect type. Some evidence suggestive of an interaction between the infant G80/G80 genotype and maternal supplemental vitamin use was observed, but only for conotruncal defects. The authors suggest that the study was limited because of small sample size and the findings must be replicated. Studies of genes specifically involved with folate metabolism and “correction” by maternal supplemental vitamin use are important because they may help us understand how to prevent some birth defects.


Public Health Implications

This study evaluates an association between a gene other than MTHFR involved in the folate metabolic pathway. Although the findings were only ‘suggestive’ of an interaction between RFC-1genotype and perinatal folic acid intake in association with conotruncal heart defects, they further support the value of food fortification with folic acid and maternal periconceptional vitamin use. Future studies should evaluate additional genes in the folate metabolic pathway. Because food fortification with folic acid is now in place and women are receiving folic acid in their diet, maternal plasma folate will also be an important measurement to include. As the authors indicated, maternal genotype may offer additional information in these studies.


References

  1. Botto LD, Mulinare J, Erickson JD. Occurrence of congenital heart defects in relation to maternal mulitivitamin use. Am J Epidemiol 2000;151:878-84.
  2. Botto LD et al. Periconceptional multivitamin use and the occurrence of conotruncal heart defects: results from a population-based, case-control study. Pediatrics 1996;98:911-7.
  3. Shaw GM et al. Maternal periconceptional use of multivitamins and reduced risk for conotruncal heart defects and limb deficiencies among offspring. Am J Med Genet 1995;59:536-45.
  4. Shaw GM et al. Risks of orofacial clefts in children born to women using multivitamins containing folic acid periconceptionally. Lancet 1995;346:393-6.
  5. Junker R et al. Infant methylenetetrahydrofolate reductase 677TT genotype is a risk factor for congenital heart disease. Cardiovasc Res 2001;51:251-4.
  6. Wenstrom KD et al. Association of the C677T methylenetetrahydrofolate reductase mutation and elevated homocysteine levels with congenital cardiac malformations. Am J Obstet Gynecol 2001;184:806-17.
  7. Martinelli M et al. C677T variant form at the MTHFR gene and CL/P: a risk factor for mothers? Am J Med Genet 2001;98:357-60.
  8. Mills JL et al. Methylenetetrahydrofolate reductase thermolabile variant and oral clefts.
  9. Am J Med Genet 2000 May 1;92(1):79-80.
  10. Gaspar DA et al. Role of the C677T polymorphism at the MTHFR gene on risk to nonsyndromic cleft lip with/without cleft palate: results from a case-control study in Brazil . Am J Med Genet 1999 Nov 19;87(2):197-9.
  11. Shaw GM et al. Genetic variation of infant reduced folate carrier (A80G) and risk of orofacial and conotruncal heart defects. Am J Epidemiol 2003;158:747-52.
  12. Chango A, Emeryet al. A polymorphism (80G à A) in the reduced folate carrier gene and its association with folate status and homocysteinemia. Mol Genet Metab 2000 Aug;70(4):310-5.
  13. Shaw GM, et al. Maternal periconceptional vitamin use, genetic variation of infant reduced folate carrier (A80G), and risk of spina bifida. Am J Med Genet 2002;108:1-6.
Last Updated October 22, 2004