Analysis of seven maternal polymorphisms of genes involved in homocysteine/folate metabolism and risk of Down syndrome offspring.
OBJECTIVE
We present a case-control study of seven polymorphisms of six genes involved in homocysteine/folate pathway as risk factors for Down syndrome. Gene-gene/allele-allele interactions, haplotype analysis and the association with age at conception were also evaluated.


METHODS
We investigated 94 Down syndrome-mothers and 264 control-women from Campania, Italy.


RESULTS
Increased risk of Down syndrome was associated with the methylenetetrahydrofolate reductase (MTHFR) 1298C allele (OR 1.46; 95% CI 1.02-2.10), the MTHFR 1298CC genotype (OR 2.29; 95% CI 1.06-4.96), the reduced-folate-carrier1 (RFC1) 80G allele (1.48; 95% CI 1.05-2.10) and the RFC1 80 GG genotype (OR 2.05; 95% CI 1.03-4.07). Significant associations were found between maternal age at conception > or = 34 years and either the MTHFR 1298C or the RFC 180G alleles. Positive interactions were found for the following genotype-pairs: MTHFR 677TT and 1298CC/CA, 1298CC/CA and RFC1 80 GG/GA, RFC1 80 GG and methylenetetrahydrofolate-dehydrogenase 1958 AA. The 677-1298 T-C haplotype at the MTHFR locus was also a risk factor for Down syndrome (P = 0.0022). The methionine-synthase-reductase A66G, the methionine-synthase A2756G and the cystathionine-beta-synthase 844ins68 polymorphisms were not associated with increased risk of Down syndrome.


CONCLUSIONS
These results point to a role of maternal polymorphisms of homocysteine/folate pathway as risk factors for Down syndrome.
Scala
Iris
I
Department of Pediatrics, Federico II University of Naples, via S. Pansini 5, 80131 Naples, Italy.
Granese
Barbara
B
Sellitto
Maria
M
Salomè
Serena
S
Sammartino
Annalidia
A
Pepe
Antonio
A
Mastroiacovo
Pierpaolo
P
Sebastio
Gianfranco
G
Andria
Generoso
G
D000328:Adult; D016022:Case-Control Studies; D002869:Chromosome Aberrations; D004314:Down Syndrome / Q000235:genetics*; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006710:Homocysteine / Q000378:metabolism*; D006801:Humans; D008423:Maternal Age; D026901:Membrane Transport Proteins / Q000235:genetics*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008954:Models, Biological; D011110:Polymorphism, Genetic; D012307:Risk Factors
D026901:Membrane Transport Proteins; C120043:SLC19A2 protein, human; D006710:Homocysteine; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2)