Association between maternal reduced folate carrier gene polymorphisms and congenital heart disease in offspring: a case-control study / 中国当代儿科杂志

OBJECTIVE@#To study the association between maternal reduced folate carrier (@*METHODS@#A hospital-based case-control study was conducted. The mothers of 683 infants with CHD who attended the Department of Cardiothoracic Surgery, Hunan Children's Hospital, from November 2017 to March 2020 were enrolled as the case group. The mothers of 740 healthy infants without any deformity who attended the hospital during the same period of time were enrolled as the control group. A questionnaire survey was performed to collect the exposure data of subjects. Venous blood samples of 5 mL were collected from the mothers for genetic polymorphism detection. A multivariate logistic regression analysis was used to evaluate the association of @*RESULTS@#After control for confounding factors, the multivariate logistic regression analysis showed that maternal @*CONCLUSIONS@#Maternal

Methionine synthase A2756G and reduced folate carrier1 A80G gene polymorphisms as maternal risk factors for Down syndrome in Egypt

Background: Polymorphisms of genes encoding enzymes involved in folate metabolism have long been hypothesized to be maternal risk factors for Down syndrome, however, results are conflicting and inconclusive

Aim of the study: To analyze the effect of methionine synthase [MTR] A2756G, and reduced folate carrier [RFC1] A80G gene polymorphisms on the maternal risk for DS

Patients: This study was conducted in the Medical Genetics Center, Ain-Shams University hospitals, on a total of 170 mothers of children, diagnosed with Down syndrome, who were attending the center. Eighty-five control mothers were also enrolled in the study

Methods: Genotype analyses were performed using PCR-RFLP to detect RFC1A80G and MTRA2756G gene polymorphisms in all case and control mothers

Results: Comparing RFC1A80G genotype frequency between both groups revealed, that the frequency of the AA genotype in case mothers [94.11%] is highly significantly [p< 0.001] greater than its frequency in control mothers [74.11%], with no significant difference between the two groups regarding GG genotype. Comparing RFC1 A80G allele frequency between the two groups revealed a high frequency of the A allele among case mothers [94.11%], which showed a highly statistically significant difference [p<0.001] from the control group [55.29%], meanwhile the G allele showed a low frequency of 5.88% in DS mothers compared to 22.35% in the control mothers, with a highly statistically significant difference [p<0.001] between the two groups. Regarding MTRA2756G polymorphism, it was found that the AA genotype predominated in the control group [65.88%] with a highly statistically significant difference [p< 0.001] from case mothers group [5.88%]. Comparing MTR allele frequency between the two groups revealed predominance of the G allele among mothers of DS children [76.47%]

Conclusion: Current results provide strong evidence that the MTRA2756G, and RFC1 80 A genotypes could be considered as maternal risk factors for DS in Egyptian mothers

Association of single nucleotide polymorphism of reduced folate carrier gene with susceptibility to acute leukemia / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate the allele and genotype frequencies of reduced folate carrier gene (RFC) 80G/A polymorphism in Chinese patients with acute leukemia (AL) and healthy control children, and to provide clue for association between the single nucleotide polymorphism (SNP) of RFC and the occurrence of AL.</p><p><b>METHODS</b>Bone marrow samples from 98 childhood patients with AL and peripheral blood samples from 135 healthy children were obtained to prepare complementary DNAs (cDNAs). The cDNAs were analyzed for the polymorphisms in RFC 80G/A by reverse transcriptase-polymerase chain reaction-denaturing gradient gel electrophoresis (RT-PCR-DGGE) and direct sequencing.</p><p><b>RESULTS</b>The A allele frequencies of the AL patients and control children were 0.515 and 0.415, respectively (P< 0.05). Chi-square test confirmed a statistical significance of the association between RFC80 G/A and AL.</p><p><b>CONCLUSION</b>RFC 80AA or GA genotype may contribute to increasing the susceptibility to AL.</p>

Influence of Reduced Folate Carrier and Dihydrofolate Reductase Genes on Methotrexate-Induced Cytotoxicity / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The aim of this study is to investigate the effect of genetic variations and the expression of the reduced folate carrier (RFC) and dihydrofolate reductase (DHFR) on the drug sensitivity to methotrexate (MTX) in different cancer cell lines. MATERIALS AND METHODS: We examined the six human cancer cell lines (MCF-7, AGS, A549, NCI-H23, HCT-116 and Saos-2). The cytotoxicity of MTX was measured by sulforhodamine B (SRB) assay. The expressions of the DHFR and RFC were evaluated by real-time PCR and western blotting. Four single nucleotide polymorphisms (SNPs) of the DHFR and two SNPs of the RFC were genotyped. RESULTS: The IC50s of MTX was in an extensively broad range from 6.05+/-0.81 nM to>1,000 nM in the cell lines. The Saos-2 (>1,000 nM) and MCF-7 (114.31+/-5.34 nM) cells were most resistant to MTX; in contrast, the AGS and HCT-116 cells were highly sensitive to MTX with an IC50 of 6.05+/-0.81 nM and 13.56+/-3.76 nM, respectively. A reciprocal change of the RFC and DHFR mRNA expression was found between the MTX-sensitive AGS and MTX-resistant Saos-2 cells. There was no significant difference in the expression levels of RFC protein in both the AGS and Saos-2 cells, whereas DHFR protein was more increased in the MTX-resistant Saos-2 cells treated with MTX. The genotype of the MTX-sensitive AGS cells were mutant variants of the DHFR; in contrast, the Saos-2 cells had the wild-type of the DHFR. CONCLUSION: In conclusion, this study showed that inverse change of the RFC and DHFR mRNA and protein expression was associated with RFC and DHFR polymorphisms and it is postulated that this phenomenon might play an important role in sensitivity of certain cancers to MTX.

A parental case control study on the association between reduced folate carrier gene polymorphism and neural tube defects / 中华流行病学杂志

<p><b>OBJECTIVE</b>To study the association between reduced folate carrier gene (RFC1 A80G) polymorphism and the risk for child with neural tube defects (NTDs), and to provide epidemiological evidence for the existence of NTDs genetic marker.</p><p><b>METHODS</b>RFC1 (A80G) genotypes were detected using RFLP-PCR for blood DNA of 104 families with NTDs-affected children and 100 control families with no history of child-affected birth defects. Case-control study and transmission/disequilibrium test(TDT) for the RFC1 genotype of NTDs pedigree were carried out.</p><p><b>RESULTS</b>The G allele frequency of children with NTDs was higher than that of controls when compared to A allele( OR = 1. 64, 95% CI :1.08-2.49). The offspring of the GG genotype were associated with a 2.56-fold increased risk of NTDs when compared to the AA genotype (OR = 2.56, 95% CI: 1.04-6.36) in our study population. There was evidence of association between G allele and the risk of parent having a child with NTDs (OR = 1.56, 95% CI: 1.07-2.28) in the TDT analysis.</p><p><b>CONCLUSION</b>Our findings indicated that there was potential association between offspring RFC1 GG genotype and the risk of NTDs, and the G allele was a possible susceptible gene marker for an increased NTDs risk in the Chinese population.</p>

Interaction between maternal periconceptional supplementation of folic acid and reduced folate carrier gene polymorphism of neural tube defects / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To search the interaction between reduced folate carrier gene (RFC1 A80G) polymorphism of children with neural tube defects (NTDs) and maternal periconceptional no supplementation of folic acid. The purpose is to provide the epidemiological evidence for finding genetic marker of NTDs.</p><p><b>METHODS</b>RFC1 (A80G) genotype was detected using PCR-restricted fragment length polymorphism for the blood DNA of 104 trios with NTDs-affected child, and 100 control families with non-malformed control children. The authors investigated the gene-environment interactions between the offspring RFC1 genotype and maternal periconceptional folic acid supplementation through a case-control study.</p><p><b>RESULTS</b>It was observed that the offspring with the GG genotype were associated with a 2.56-fold increased risk of NTDs when compared to those with the AA genotype (OR = 2.56; 95% CI = 1.04-6.36) in this population under investigation. The risk of mothers who did not take folic acid for having an NTDs-affected infants was 7.69 (95% CI = 2.86-21.75). Among the mothers who did not utilize folic acid supplements, the NTDs risk was 3.30 (95% CI = 1.15-9.65) for offspring with the GG genotype, compared to the reference (AA) genotype. Children who had the GG genotype and whose mothers did not take folic acid had an elevated risk for NTDs (OR = 8.80, 95% CI = 2.86 - 29.82), compared to "offspring with AA or GA genotype" and "maternal folic acid use", the interactive coefficient being 1.45.</p><p><b>CONCLUSION</b>The above findings indicate that the RFC1 genotype (GG) is a possible susceptible gene marker for an increased NTDs risk in Chinese population, and there is a potential gene-nutrient interaction between offspring RFC1 GG genotype and maternal periconceptional intake of folic acid on the risk of NTDs. However,the sample size of this study was limited, a larger sample of population-based study is required to pursue the initial observation.</p>

Study on the association between reduced folate carrier gene polymorphism and congenital heart defects and cleft lip with or without cleft palate / 中华流行病学杂志

<p><b>OBJECTIVE</b>To study the association between reduced folate carrier gene (RFC1) polymorphism and congenital heart defects (CHD) as well as cleft lip with or without cleft palate (CLP) and to provide epidemiological evidence on genetic markers of CHD and CLP.</p><p><b>METHODS</b>RFC1 (A80G) genotype was detected using RFLP-PCR for blood DNA of the 67 triads with nonsyndromic CHD-affected child, the 82 triads with child-affected cleft lip with or without CLP and the 100 control families without child-affected birth defects. We performed a family-based association test and analyzed the interaction between RFC1 A80G genotype and maternal periconceptional supplementation of folic acid.</p><p><b>RESULTS</b>Offspring of mothers who did not take folic acid had an elevated risk for CHD when comparing with offspring of mothers who did (OR = 2.68, 95% CI: 1.14 - 6.41). There was a statistical association between the risk of CHD and maternal periconceptional folic acid supplementation (chi(2) = 6.213, P < 0.05). In the family-based association test, G allele was positively associated with an increased risk for children CHD (Z = 2.140, P < 0.05) while G allele of RFC1 (A80G) polymorphism might increase the risk for CHD. Elevated risks for either CLP group were not observed between RFC1 genotype using or not using folic acid.</p><p><b>CONCLUSION</b>Our findings suggested that the G allele was likely to be a genetically susceptible allele for CHD. There was possible association between offspring with GG, GA genotype and maternal periconceptional folicacid deficiency.</p>