A common variant in MTHFD1L is associated with neural tube defects and mRNA splicing efficiency.
Polymorphisms in folate-related genes have emerged as important risk factors in a range of diseases including neural tube defects (NTDs), cancer, and coronary artery disease (CAD). Having previously identified a polymorphism within the cytoplasmic folate enzyme, MTHFD1, as a maternal risk factor for NTDs, we considered the more recently identified mitochondrial paralogue, MTHFD1L, as a candidate gene for NTD association. We identified a common deletion/insertion polymorphism, rs3832406, c.781-6823ATT(7-9), which influences splicing efficiency and is strongly associated with NTD risk. Three alleles of rs3832406 were detected in the Irish population with varying numbers of ATT repeats: Allele 1 consists of ATT(7), whereas Alleles 2 and 3 consist of ATT(8) and ATT(9), respectively. Allele 2 of this triallelic polymorphism showed a decreased case risk as demonstrated by case-control logistic regression (P=0.002) and by transmission disequilibrium test (TDT) (P=0.001), whereas Allele 1 showed an increased case risk. Allele 3 showed no influence on NTD risk and represents the lowest frequency allele (0.15). Additional single nucleotide polymorphism (SNP) genotyping in the same genomic region provides additional supportive evidence of an association. We demonstrate that two of the three alleles of rs3832406 are functionally different and influence the splicing efficiency of the alternate MTHFD1L mRNA transcripts.
Parle-McDermott
Anne
A
Nutritional Genomics Group, School of Biotechnology, Dublin City University, Dublin 9, Ireland. anne.parle-mcdermott@dcu.ie
Pangilinan
Faith
F
O'Brien
Kirsty K
KK
Mills
James L
JL
Magee
Alan M
AM
Troendle
James
J
Sutton
Marie
M
Scott
John M
JM
Kirke
Peadar N
PN
Molloy
Anne M
AM
Brody
Lawrence C
LC
D017398:Alternative Splicing / Q000235:genetics*; D001483:Base Sequence; D016022:Case-Control Studies; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics*; D015778:Minor Histocompatibility Antigens; D008954:Models, Biological; D008969:Molecular Sequence Data; D009436:Neural Tube Defects / Q000201:enzymology* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
D015778:Minor Histocompatibility Antigens; C539735:MTHFD1 protein, human; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP)