title: Association between selected folate pathway polymorphisms and nonsyndromic limb reduction defects: a case-parental analysis.
abstract: Inadequate folate status resulting from either genetic variation or nutritional deficiencies has been associated with an increased risk of congenital malformations including orofacial clefting, limb, cardiac and neural tube defects. Few epidemiological studies have examined the association between limb reduction defects (LRDs) and folate-related genetic polymorphisms other than MTHFR 677C→T. We conducted a case-parental analysis of 148 families who participated in the National Birth Defects Prevention Study to examine the association between nonsyndromic transverse and longitudinal LRDs with five single nucleotide polymorphisms (SNPs) in genes encoding enzymes in folate and methionine pathways. Log-linear Poisson regression, adapted for analysis of case-parental data assuming an additive genetic model, was used to estimate genetic relative risks and 95% confidence intervals for the association between LRDs and each SNP. Among women who did not take multivitamin supplements, the MTHFR 677T variant acts via the offspring's genome to increase the risk of LRDs. No association between LRDs and any fetal SNP was found among women who used multivitamin supplements. These results suggest the possibility that initiating folic acid supplementation prior to pregnancy may reduce the risk of having a LRD-affected pregnancy, especially in women whose offspring inherit one or two copies of the MTHFR 677T variant.
authors.affiliation: Arkansas Center for Birth Defects Research and Prevention, Department of Pediatrics, University of Arkansas for Medical Sciences, and Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, USA. clevesmarioa@uams.edu
authors.forename: Mario A
authors.initials: MA
authors.lastname: Cleves
authors.forename: Charlotte A
authors.initials: CA
authors.lastname: Hobbs
authors.forename: Weizhi
authors.initials: W
authors.lastname: Zhao
authors.forename: Patrycja A
authors.initials: PA
authors.lastname: Krakowiak
authors.forename: Stewart L
authors.initials: SL
authors.lastname: MacLeod
mesh_terms: D000293:Adolescent; D000328:Adult; D001835:Body Weight; D019587:Dietary Supplements; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006801:Humans; D017880:Limb Deformities, Congenital / Q000235:genetics*; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D010375:Pedigree; D016012:Poisson Distribution; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016742:Preconception Care / Q000379:methods; D011247:Pregnancy; D012307:Risk Factors; D055815:Young Adult
chemical_list: D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2)