Effect of common polymorphisms in folate uptake and metabolism genes on frequency of micronucleated lymphocytes in a South Australian cohort.
Single nucleotide polymorphisms (SNPs) in genes that control folate uptake and metabolism may have an important effect on chromosomal stability. The present study investigated the effect of common SNPs in some of these critical genes on frequency of lymphocytes with micronuclei, a biomarker of chromosome breakage or loss. 164 individuals (94 males and 70 females) of different age ranging from 18 to 73 years participated in this study. Polymorphisms in GCPII (C1561T), RFC (G80A), MTR (A2756G), MTRR (A66G and C524T), TS (tandem repeats, 6bp deletion in 3'-UTR region) and MTHFR (C677T and A1298C) were detected using PCR-based methods. Frequency of binucleated (BN) lymphocytes containing one or more micronuclei (BN-MN) was determined using the cytokinesis-block micronucleus (CBMN) assay and adjusted for the effects of age and gender. We did not find any significant association between BN-MN frequency and the common SNPs in GCPII, MTRR, TS and MTHFR genes. BN-MN frequency in individuals who carried at least one copy of the rarer G allele for MTR (A2756G) or were homozygotes for the more common G allele for RFC (G80A) had a 14% or 19% lower BN-MN frequency compared to the alternative genotypes for that SNP respectively. It was evident from genotype combination analyses that BN-MN frequency per 1000 BN cells was highest in those with the combined MTR (2756) AA and RFC (80) GA or AA genotype (13.6 per thousand) and lowest in those with the combined MTR (2756) AG or GG and RFC (80) GG genotypes (9.5 per thousand) (P trend=0.015). The RFC G80A and MTR A2756G polymorphisms and their combinations may be important variables that substantially affect lymphocyte BN-MN frequency in this South Australian cohort.
Genome Health and Nutrigenomics Laboratory, CSIRO Human Nutrition, A Centre of Food Science Australia, Adelaide BC, SA, Australia.
Varinderpal
V
Dhillon
Philip
P
Thomas
Michael
M
Fenech
D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001483:Base Sequence; D001693:Biological Transport, Active / Q000235:genetics; D015331:Cohort Studies; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism* / Q000648:ultrastructure*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D048629:Micronuclei, Chromosome-Defective; D015162:Micronucleus Tests; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D058978:Reduced Folate Carrier Protein; D013021:South Australia; D055815:Young Adult
D017931:DNA Primers; D026901:Membrane Transport Proteins; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; D005492:Folic Acid; D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase