Thymidylate synthase polymorphisms and risk of conotruncal heart defects

Abstract

In this study, we investigated whether the two TYMS functional variants (28bp VNTR and 1494del6) (275 cases and 653 controls) and six selected SNPs (265 case infants, 535 control infants; 169 case mothers and 276 control mothers) were associated with risks of conotruncal heart defects. Further, we evaluated interaction effects between these gene variants and maternal folate intake for risk of CTD. Cases with diagnosis of single gene disorders or chromosomal aneusomies were excluded. Controls were randomly selected from area hospitals in proportion to their contribution to the total population of live-born infants. DNA samples were collected using buccal brushes or drawn from the repository of newborn screening blood specimens when available. Genetic variants were treated as categorical variables (homozygous referent, heterozygote, homozygous variant). Odds ratios and 95% confidence intervals (CI) were computed to estimate risks among all subjects, Hispanic and non-Hispanic whites, respectively using logistic regression. Gene-folate interactions were assessed for these variants by adding an interaction term to the logistic model. A dichotomized composite variable, “combined folate intake”, was created by combining maternal peri-conceptional use of folic acid-containing vitamin supplements with daily dietary intake of folate. In general, the results do not show strong gene-only effects on risk of CTD. We did, however, observe a 3.6-fold increase in CTD risk (95%CI:1.1 – 11.9) among infants who were homozygotes for the 6bp deletion in the 3’-untranslated region (UTR) (1694del6) and whose mothers had low folate intake during the peri-conceptional period.

Association of Genetic Polymorphisms in Genes Involved at the Branch Point of Nucleotide Biosynthesis and Remethylation with Down Syndrome Birth Risk: A Case-Control Study

“…It is associated with reduced risk for spina bifida in a study from Calfornia [31]. TYMS 6bpdel/6bp genotype has been reported to associate to have increased risk over TYMS 6bp/6bp in case of conotruncal heart defect in population of California [32]. In our case, TYMS 3'UTR 6bp/6bpdel polymorphism didn't turn out significantly associated with increased genetic risk in DS mothers.…”

“…It is obvious from this interaction that TYMS 5'UTR 3R allele and TYMS 3'UTR 6bp allele synergistically are protective in control mothers. Linkage disequilibrium has been reported for TYMS 3'UTR 6bpdel allele and TYMS 5'UTR 3R allele [33,34] but weak linkage diseulilibrium was reported for this haplotype revealing protective effect in another study by Zhu et al, [32]. To the best of our knowledge, there is only one study [8] so for available for association of these two polymorphisms in case of DS.…”

Conotruncal heart defects and common variants in maternal and fetal genes in folate, homocysteine, and transsulfuration pathways

“…Statistically significant associations were observed for SNPs within the MTHFD2 ( rs702465 , rs7571842 ) and TYMS ( rs2847159 , rs1001761 , rs502396 ) genes for spina bifida, but no statistically significant associations were observed for CTDs and the 118 SNPs. Zhu and colleagues investigated whether two CTD were associated with two TYMS functional variants (rs4544694: a variable number of tandem repeats polymorphism; rs16430: a six base‐pair deletion) (Zhu et al, ). The investigators did not find a gene‐only effect of either variant.…”

TYMS 2R3R polymorphism and DPYD [IVS]14+1G>A mutation genes in Mexican colorectal cancer patients

“…The 2R/3R polymorphism is a variable tandem repeat sequence (VNTR; rs45445694) associated with the regulation of TYMS expression. It is localized at 5'-untranslated region (UTR) and has 2 to 9 repeats, of which 2 and 3 repeats (2R and 3R) are the most frequent alleles, with an increment of expression from 2-to 4-fold of the 3R/3R genotype when compared with the 2R/2R genotype (Trinh et al, 2002;Zhu et al, 2012;Wang et al, 2016,).…”

“…It has been hypothesized that the TYMS polymorphisms can influence the enzyme activity, which would affect plasma folate levels and, indirectly, the plasma homocysteine levels (Trinh et al, 2002;Zhu et al, 2012;Wang et al, 2016). The 2R allele (rs45445694) showed a frequency of 18% among Hispanic infants and 26.3% in non-Hispanic white infants (Zhu et al, 2012 ).…”