Genetic Variants in the Folate Pathway and the Risk of Neural Tube Defects: A Meta-Analysis of the Published Literature

Background

Neural Tube Defects (NTDs) are among the most prevalent and most severe congenital malformations worldwide. Polymorphisms in key genes involving the folate pathway have been reported to be associated with the risk of NTDs. However, the results from these published studies are conflicting. We surveyed the literature (1996–2011) and performed a comprehensive meta-analysis to provide empirical evidence on the association.

Methods and Findings

We investigated the effects of 5 genetic variants from 47 study populations, for a total of 85 case-control comparisons MTHFR C677T (42 studies; 4374 cases, 7232 controls), MTHFR A1298C (22 studies; 2602 cases, 4070 controls), MTR A2756G (9 studies; 843 cases, 1006 controls), MTRR A66G (8 studies; 703 cases, 1572 controls), and RFC-1 A80G (4 studies; 1107 cases, 1585 controls). We found a convincing evidence of dominant effects of MTHFR C677T (OR 1.23; 95%CI 1.07–1.42) and suggestive evidence of RFC-1 A80G (OR 1.55; 95%CI 1.24–1.92). However, we found no significant effects of MTHFR A1298C, MTR A2756G, MTRR A66G in risk of NTDs in dominant, recessive or in allelic models.

Conclusions

Our meta-analysis strongly suggested a significant association of the variant MTHFR C677T and a suggestive association of RFC-1 A80G with increased risk of NTDs. However, other variants involved in folate pathway do not demonstrate any evidence for a significant marginal association on susceptibility to NTDs.     

Methylenetetrahydrofolate reductase C677T and methionine synthase A2756G polymorphisms influence on leukocyte genomic DNA methylation level

Methionine synthase (MTR) and methylenetetrahydrofolate reductase (MTHFR) enzymes are involved in the metabolism of methyl groups, and thus have an important role in the maintenance of proper DNA methylation level. In our study we aimed to evaluate the effect of the polymorphism A2756G (rs1805087) in the MTR gene on the level of human leukocyte genomic DNA methylation. Since the well-studied polymorphism C677T (rs1801133) in the MTHFR gene has already been shown to affect DNA methylation, we aimed to analyze the effect of MTR A2756G independently of the MTHFR C677T polymorphism. For this purpose, we collected the groups of 80 subjects with the MTR 2756AA genotype and 80 subjects with the MTR 2756GG genotype, having equal numbers of individuals with the MTHFR 677CC and the MTHFR 677TT genotypes, and determined the level of DNA methylation in each group. Individuals homozygous for the mutant MTR 2756G allele showed higher DNA methylation level than those harboring the MTR 2756AA genotype (5.061 ± 1.761% vs. 4.501 ± 1.621%, P = 0.0391). Individuals with wild-type MTHFR 677СC genotype displayed higher DNA methylation level than the subjects with mutant MTHFR 677TT genotype (5.103 ± 1.767% vs. 4.323 ± 1.525%, P = 0.0034). Our data provide evidence that the MTR A2756G polymorphism increases the level of DNA methylation and confirm the previous reports that the MTHFR C677T polymorphism is associated with DNA hypomethylation.     

The MTRR 66A>G polymorphism and maternal risk of birth of a child with Down syndrome in Caucasian women: a case–control study and a meta-analysis

We performed a large case–control study and a meta-analysis of the literature to address the role of the methionine synthase reductase (MTRR) c.66A>G polymorphism as a maternal risk factor for the birth of a child with Down Syndrome (DS) among Caucasian women. A total of 253 mothers of a DS child (MDS) and 298 control mothers of Italian origin were included in the case–control study. The meta-analysis of previous and present data involved a total of seven studies performed in Caucasian populations (971 MDS and 1,387 control mothers). Results from the meta-analysis indicated overall a positive significant association between MTRR c.66A>G genotype [OR 1.36 (95 % CI 1.10–1.68), dominant model] and allele frequencies [OR 1.26 (95 % CI 1.04–1.51), allele contrast model] and maternal risk of birth of a child with DS. A sensitivity analysis revealed some interesting differences between Europeans, Caucasians of European descent, and inhabitants of Mediterranean regions, suggesting the possibility of population-specific modifying factors. The case–control study revealed association of the polymorphism with increased folate levels, and a possible interaction with the methionine synthase (MTR) c.2756A>G one, that resulted in a borderline significant maternal risk of birth of a child with DS for the double heterozygous MTR 2756AG/MTRR 66AG genotype [OR 1.79 (95 % CI 1.00–3.18)]. Overall, present data suggest that the MTRR c.66A>G polymorphism represents a risk factor for the birth of a child with DS among white Caucasian women. However, the combined presence of other genetic factors and interactions with geographic and environmental ones, can modify the effect of the single polymorphism alone, leading to population specific effect sizes.     

Hyperhomocysteinemia and related genetic polymorphisms correlate with ulcerative colitis in Chinese Han population in Central China [corrected

Increased levels of homocysteine are found systemically and in intestinal mucosa of patients with inflammatory bowel disease, and, specifically, in ulcerative colitis (UC). However, there are controversial reports regarding the factors contributing to increased levels of homocysteine in UC. Furthermore, little information is available regarding the relationship between hyperhomocysteinemia (HHcy), vitamin status, and genetic polymorphisms of homocysteine-related enzymes in these patients. This study examined four functional polymorphisms linked to homocysteine metabolism (MTHFR C677T and A1298C, MTR A2756G and MTRR A66G), and evaluated plasma levels of homocysteine, folate, and vitamin B₁₂ in 310 consecutive patients with UC and 936 age- and sex-matched healthy controls from southeast China. The variant allele and genotypic frequencies in MTHFR A1298C, MTR A2756G and MTRR A66G genes were significantly higher in patients with UC compared to healthy controls. Further, HHcy and low levels of folate and vitamin B₁₂ were more frequent in patients with UC. The MTR 2756G allele, extent of the disease, and gender were the independent determinants of HHcy in these patients. These findings suggest that genetic and nutritional factors have a synergetic effect on HHcy in patients with UC. In conclusion, our data highlight a prevention strategy for moderation of HHcy and supplementation with folate and vitamine B₁₂ in patients with UC from Southeast China.     

The <Emphasis Type="Italic">MTR</Emphasis> 2756A&gt;G polymorphism and maternal risk of birth of a child with Down syndrome: a case–control study and a meta-analysis

Methionine synthase (MTR) is required for the conversion of homocysteine (hcy) to methionine in the one-carbon metabolic pathway. Previous studies investigating a common MTR 2756A>G polymorphism as a maternal risk factor for the birth of a child with Down syndrome (DS) are conflicting and limited by small case–control cohorts, and its contribution to circulating hcy levels is still debated. We performed a large case–control study and a meta-analysis of the literature to further address the role of MTR 2756A>G as a maternal risk factor for the birth of a child with DS. 286 mothers of a DS child (MDS) and 305 control mothers of Italian origin were included in the case–control study. Genotyping was performed by means of PCR/RFLP technique. Data on circulating levels of hcy, folates, and vitamin B12 were available for 189 MDS and 194 control mothers. The meta analysis of previous and present data involved a total of 8 studies (1,171 MDS and 1,402 control mothers). Both the case–control study and the meta-analysis showed no association of MTR 2756A>G with the maternal risk of birth of a child with DS (OR = 1.15; 95 % CI 0.85–1.55, and OR = 1.08; 95 % CI 0.93–1.25, respectively), even after stratification of the overall data available for the meta-analysis into ethnic groups. No association of the studied polymorphism with circulating levels of hcy, folates, and vitamin B12 was observed. Present data do not support a role for MTR 2756A>G as independent maternal risk factor for a DS birth.     

Association between folate metabolism polymorphisms and breast cancer: a case-control study

We investigated the association between methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthetase (MTR A2756G), and methionine synthase reductase (MTRR A66G) polymorphisms involved in folate pathway and breast cancer risk, and the interaction between these polymorphisms and tobacco and alcohol consumption. Furthermore, we evaluated the association between these polymorphisms and clinicopathological variables. This case-control study included 606 Brazilian women, comprising 128 patients with breast cancer and 478 controls. MTHFR and MTR polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and MTRR polymorphisms using real-time PCR. Age ≥50 years (odds ratio [OR]: 2.65; 95% confidence interval [CI]: 1.65-4.26; p<0.001) and alcohol consumption (OR: 1.76; 95% CI: 1.0-2.85; p=0.021) were associated with an increased risk of breast cancer. For MTHFR A1298C, we observed a reduced risk of developing breast cancer in the codominant model (genotype CC-OR: 0.22; 95% CI: 0.06-0.74; p=0.014), recessive model (OR: 0.22; 95% CI: 0.07-0.76 p=0.004), and log-additive model (OR: 0.70; 95% CI: 0.49-0.98; p=0.035). Women aged ≥50 years and those who are alcohol consumers had increased susceptibility to breast cancer, and MTHFR A1298C modulated the risk for this disease. This is the first study to evaluate the association between polymorphisms in folate metabolism and breast cancer in the northwest region of São Paulo State, Brazil.     

Polymorphisms in the MTHFR and MTR genes and the risk of varicose veins in ethnical Russians

Objectives: The objective of this study was to study the association of polymorphisms MTHFR C677T (rs1801133) and MTR A2756G (rs1805087) with the risk of varicose veins in ethnical Russians.

Methods: We genotyped 475 patients with varicose veins, 168 individual without chronic venous disease, and the population-based group of 896 subjects. Association was studied using logistic regression analysis adopting co-dominant, additive, recessive, and dominant models of inheritance.

Results: None of the polymorphisms showed a statistically significant association with the risk of varicose veins.

Conclusions: Our results provide evidence that the studied polymorphisms do not contribute to genetic susceptibility to varicose veins in ethnical Russians.     

Associations of polymorphisms of folate cycle enzymes and risk of breast cancer in a Brazilian population are age dependent

Polymorphisms in genes involved in folate metabolism have been shown to be implicated in breast cancer risk but with contradictory results. In this case–control study, we investigated the association between MTHFR C677T and A1298C, TYMS 5′-UTR, MTR A2756G and cSHMT C1420T and also the folate carrier (RFC1 G80A) and breast cancer risk in a northeastern Brazilian population. The study included 183 women diagnosed with breast cancer and 183 controls volunteers without any history of cancer. Also a significant number of healthy individuals were included for allelic frequency in the population studied. Risk of breast cancer was estimated by conditional logistic regression. An association with risk was found for women carrying the MTR A2756G polymorphic allele (AG, P = 0.0036; AG/GG, P = 0.0040), and a protective effect in carriers of the RFC1 G80A polymorphic allele (GA, P = 0.0015; AA, P = 0.0042). Stratifying the data by age (cutoff point of 50 years old), different distributions were observed for breast cancer risk. For women ≤50 years, the risk observed in the presence of the polymorphic allele MTR 2756 (AG/GG) in the general analysis was, restricted to this age group (P = 0.0118). Conversely, for women over 50, the risk of breast cancer development was statistically associated with the MTHFR 677CT genotype, but especially significant was risk associated with the presence of the polymorphic allele of cSHMT C1420T (P = 0.0120) and the protective effect associated with the RFC1 G80A polymorphism allele (P = 0.0021), was restrict to this age group. These data indicate that the cutoff age used (50 years old) was appropriate, since it was able to discriminate risk in each age group in the population studied and also to point to the importance of age in the analyses of cancer-associated polymorphisms.     

Reduced folate carrier-1 G80a gene polymorphism is associated with neuroblastoma’s development

Neuroblastoma is a malignant embryonal tumor of neural crest cells that give rise to the sympathetic nervous system, responsible for 10–70 % of all cases of childhood cancer. Because of its early appearance, it has been suggested that risk factors active in the prenatal can be associated with the pathogenesis of neuroblastoma. The aim of this study was to investigate whether the genetic polymorphisms MTHFR C677T and A1298C, MTR A2756G, TYMS 2R/3R and SLC19A1 G80A, involved in folate metabolism, increase the risk of neuroblastoma in Brazilian children. This study comprised 31 Brazilian children (0–14 years old) diagnosed with neuroblastoma compared with 92 controls. Investigation of polymorphisms MTHFR C677T, MTR A2756G and SLC19A1 A80G was performed using PCR–RFLP, the TYMS 2R/3R using PCR and MTHFR A1298C using AS-PCR. The SLC19A1 A80A genotype was significantly associated with the development of neuroblastoma, compared with the control group (Williams G-Test = 0.0286; OR = 5.1667; 95 % CI = 1.4481–18.4338; p = 0.0175). When analyzed together, the 80AG+AA genotypes showed a trend toward association (OR = 3.3033; 95 % CI = 1.0586–10.3080; p = 0.0563). Our results suggest that individuals carriers of genotype AA for the SLC19A1 gene present risk for the development of neuroblastoma and possibly have difficulty in absorption of folic acid by the cells, and this may adversely affect the metabolism of folate causing genomic instability and promoting the development of cancer. This is the first retrospective/prospective study to examine the relationship between polymorphisms of folate pathway genes and risk of neuroblastoma.     

Methylenetetrahydrofolate reductase gene C677T,A1298C polymorphisms and pre-eclampsia risk: a meta-analysis

To determine whether methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms are associated with pre-eclampsia susceptibility. Literature searches of the Pubmed, Embase, BIOSIS Previews and Web of Science were conducted to identify all eligible articles up to January 18th, 2013. The pooled odds ratios (ORs) with 95 % confidence intervals (CIs) of five genetic models were calculated by fixed-effects or random-effects model. Publication bias, subgroup analysis, meta-regression and sensitivity analysis were also performed. A number of 49 studies including 51 samples consisted of 18,009 subjects (6,238 patients and 11,771 controls) were finally included. MTHFR C677T allele (TT or CT) carriers were 1.12 times more likely to develop pre-eclampsia (95 % CI 1.04–1.21) compared with 677CC homozygous individuals. Similar results were obtained under other genetic models. Restricted to severe pre-eclampsia, there was an increased risk for 677TT homozygotes compared with 677CC homozygotes (OR 1.43; 95 % CI 1.12–1.83). Subgroup analysis revealed a significant positive association between the C677T polymorphism (TT or CT) and pre-eclampsia in Asians (OR 1.41; 95 % CI 1.11–1.79) and white population (OR 1.14; 95 % CI 1.03–1.25). Meta-regression showed that study population, blinded genotyping, matching of cases and controls were not substantial sources of heterogeneity. For the MTHFR A1298C, ORs for all genetic models yielded a null association. This meta-analysis suggests that the MTHFR 677T allele might be associated with increased pre-eclampsia risk in Asian and white ethnicity and the subgroup of severe pre-eclampsia, while no association is observed between the MTHFR A1298C polymorphism and pre-eclampsia.     

Complex interaction between serum folate levels and genetic polymorphisms in folate pathway genes: biomarkers of prostate cancer aggressiveness

Little is known about the role of folate and polymorphisms associated with folate metabolism on prostate cancer risk in populations of African origin. We examined the relationship between serum folate and prostate cancer and whether any association was modified by genetic polymorphisms for folate metabolism. The study was case–control in design and consisted of 218 men 40–80 years old with newly diagnosed, histologically confirmed prostate cancer and 236 cancer-free men attending the same urology clinics in Jamaica, March 2005–July 2007. Serum folate was measured by an immunoassay method and genomic DNA evaluated for MTHR (C677T and A1298C), MTRR A66G, and MTR A2756G polymorphisms. Mean serum folate concentration was higher among cases (12.3 ± 4.1 nmol/L) than controls (9.7 ± 4.2 nmol/L). Serum folate concentration showed a positive association with prostate cancer (OR, 4.41; CI, 2.52–7.72 per 10 nmol/L) regardless of grade. No interactions were observed between genotype and folate concentration, but a weak gene effect was observed for MTHFR A1298C and low-grade prostate cancer. Larger studies to investigate the role of gene–gene/gene–diet interactions in Black men are needed.     

Association between MTR A2756G and MTRR A66G polymorphisms and maternal risk for neural tube defects: A meta-analysis

Background

Methionine synthase (MTR) and methionine synthase reductase (MTRR) genes have been considered to be implicated in the development of neural tube defects (NTDs). However, the results are inconsistent. Accordingly, we conducted a meta-analysis to further investigate such an association.

Methods

Published literature from PubMed and Embase databases was retrieved. All studies evaluating the association between MTR A2756G or MTRR A66G polymorphism and maternal risk for NTDs were included. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using the fixed- or random-effects model.

Results

A total of 11 studies (1005 cases and 2098 controls) on MTR A2756G polymorphism and 10 studies (1211 cases and 2003 controls) on MTRR A66G polymorphism were included. Overall, this meta-analysis revealed no significant association between maternal MTR A2756G polymorphism and NTD susceptibility in either genetic model. A significant association between MTRR A66G polymorphism and maternal risk for NTDs was observed for GG vs. AA (OR = 1.31, 95% CI 1.03–1.67) among Caucasians.

Conclusion

The present meta-analysis indicated that MTRR A66G polymorphism, but not MTR A2756G, is significantly associated with maternal risk for NTDs in Caucasians.     

Association study of folate-related enzymes (MTHFR,MTR, MTRR) genetic variants with non-obstructive male infertility in a Polish population

Spermatogenesis is a process where an important contribution of genes involved in folate-mediated one-carbon metabolism is observed. The aim of the present study was to investigate the association between male infertility and the MTHFR (677C > T; 1298A > C), MTR (2756A > G) and MTRR (66A > G) polymorphisms in a Polish population. No significant differences in genotype or allele frequencies were detected between the groups of 284 infertile men and of 352 fertile controls. These results demonstrate that common polymorphisms in folate pathway genes are not major risk factors for non-obstructive male infertility in the Polish population.     

Variants of the MTHFR gene and susceptibility to acute lymphoblastic leukemia in children: a synthesis of genetic association studies

Background: Acute lymphoblastic leukemia (ALL) is a complex disease with genetic background. The genetic association studies (GAS) that investigated the association between ALL and the MTHFR C677T and A1298C gene variants have produced contradictory or inconclusive results. Materials and methods: In order to decrease the uncertainty of estimated genetic risk effects, a meticulous meta-analysis of published GAS related the variants in the MTFHR gene with susceptibility to ALL was conducted. The risk effects were estimated based on the odds ratio (OR) of the allele contrast and the generalized odds ratio (OR_G). Cumulative and recursive cumulative meta-analyses were also performed.ResultsThe analysis showed marginal significant association for the C677T variant, overall [OR = 0.91 (0.82–1.00) and OR_G = 0.89 (0.79–1.01)], and in Whites [OR = 0.88 (0.77–0.99) and OR_G = 0.85 (0.73–0.99)]. The A1298C variant produced non-significant results. For both variants, the cumulative meta-analysis did not show a trend of association as evidence accumulates and the recursive cumulative meta-analysis indicated lack of sufficient evidence for denying or claiming an association. Conclusion: The current evidence is not sufficient to draw definite conclusions regarding the association of MTHFR variants and development of ALL.     

Association study between methylenetetrahydrofolate reductase gene polymorphisms and Graves' disease

5,10‐Methylenetetrahydrofolate reductase (MTHFR) catalyzes the metabolism of folate and nucleotides, which are essential for DNA synthesis and methylation. It is highly polymorphic, and its variant genotypes result in lower enzymatic activity and higher plasma homocysteine. Previous studies have provided evidence that a high prevalence of MTHFR gene polymorphisms is frequently detected in patients with autoimmune disease, suggesting a novel genetic association with autoimmune disorders. However, the genetic association between MTHFR and Graves' disease (GD), one of the most common autoimmune diseases, has not been studied. Here, we designed a clinic‐based case–control study including 199 GD cases and 235 healthy controls to examine the associations between three common MTHFR polymorphisms (i.e., C677T, A1298C, and G1793A) and GD. Surprisingly, logistic regression analysis shows MTHFR 677CT + TT genotypes are associated with an approximately 42% reduction in the risk of GD in women (adjusted OR = 0.58, 95% CI = 0.3–0.9), compared to the CC genotype, indicating a significant protective effect of 677CT + TT genotypes. Our result provides epidemiological evidence that MTHFR mutation (C677T) protects women from GD. The protective effect, possibly obtained by influencing DNA methylation, should be confirmed in a large number of cohorts. Copyright © 2010 John Wiley & Sons, Ltd.     

MDR1 C3435T polymorphism and inflammatory bowel disease risk: a meta-analysis

The C3435T polymorphism of the multidrug resistance gene (MDR1) has been implicated in inflammatory bowel disease (IBD) risk, but the reported results are inconsistent. Here we performed a meta-analysis to evaluate the association between C3435T polymorphism and the risk of IBD using all case–control studies published before February 2013 according to PubMed and Web of Science. A total of 13 case–control studies, including 6,757 cases and 4,295 controls, were included. Pooled odds ratio (OR) with 95 % confidence interval (CI) was calculated using fixed- or random-effects model. Overall, no evidence has indicated that the C3435T polymorphism was associated with the susceptibility to IBD (dominant model: OR = 1.05, 95 % CI: 0.96–1.16; CT vs. CC: OR = 1.06, 95 % CI: 0.95–1.17; TT vs. CC: OR = 1.04, 95 % CI: 0.92–1.17; recessive model: OR = 0.99, 95 % CI: 0.90–1.09). Besides, stratified analysis by clinical type also indicated that no significant association between MDR1 C3435T and the risk of Crohn’s disease and ulcerative colitis was observed. This meta-analysis indicated that the C3435T polymorphism of MDR1 may not confer susceptibility to IBD.     

Evaluation of heterogeneity in the association between congenital heart defects and variants of folate metabolism genes: conotruncal and left-sided cardiac defects

BACKGROUND: Genetic variation in the folate metabolic pathway may influence the risk of congenital heart defects. This study was undertaken to assess the associations between the inherited and maternal genotypes for variants in folate‐related genes and the risk of a composite heart phenotype that included two component phenotypes: conotruncal heart defects (CTDs) and left‐sided cardiac lesions (LSLs). METHODS: Nine folate‐related gene variants were evaluated using data from 692 case‐parent triads (CTD, n = 419; LSL, n = 273). Log‐linear analyses were used to test for heterogeneity of the genotype‐phenotype association across the two component phenotypes (i.e., CTD and LSLs) and, when there was no evidence of heterogeneity, to assess the associations of the maternal and inherited genotypes with the composite phenotype. RESULTS: There was little evidence of heterogeneity of the genotype‐phenotype association across the two component phenotypes or of an association between the genotypes and the composite phenotype. There was evidence of heterogeneity in the association of the maternal MTR A2756G genotype (p = 0.01) with CTDs and LSLs. However, further analyses suggested that the observed associations with the maternal MTR A2756G genotype might be confounded by parental imprinting effects. CONCLUSIONS: Our analyses of these data provide little evidence that the folate‐related gene variants evaluated in this study influence the risk of this composite congenital heart defect phenotype. However, larger and more comprehensive studies that evaluate parent‐of‐origin effects, as well as additional folate‐related genes, are required to more fully explore the relation between folate and congenital heart defects. Birth Defects Research (Part A) 2011. © 2011 Wiley‐Liss, Inc.     

Methionine synthase polymorphisms (MTR 2756 A>G and MTR 2758 C>G) frequencies and distribution in the Jordanian population and their correlation with neural tube defects in the population of the northern part of Jordan

BACKGROUND:

The human methionine synthase gene (MTR) is located on chromosome 1q43; it is of 105.24 kb and is made up of 33 exons. Methionine synthase is a cytoplasmic enzyme that requires methylcobalamin for activity and catalyzes the remethylation of homocysteine to methionine. In this reaction, the methyl group of 5-methyltetrahydrofolate is transferred to the enzyme bond cob(I) alamin to generate methylcobalamin, followed by the transfer of the methyl group to homocysteine to reform methionine.

MATERIALS AND METHODS:

The frequencies of the polymorphisms of MTR 2756A>G and MTR 2758C>G have been determined in this study in a sample of 491 individuals collected from all regions of Jordan and representing the Jordanian population. The different alleles and genotypes at the two polymorphic sites were identified using the Polymerase Chain Reaction - Restriction Fragment Length Polymorphism (PCR-RFLP) analysis.

RESULTS:

Showed that the percentages of the polymorphic alleles at the MTR 2756 position in the north, middle and south regions were 90.38, 92.65 and 83.69%, respectively, for the MTR 2756A allele, and were 9.61, 7.34 and 16.30%, respectively, for the MTR 2756G allele, with overall percentages in the whole Jordanian population of 90.73 and 9.27% for the MTR 2756A and MTR 2756G alleles, respectively. The percentages of the genotype MTR 2756AA were 82.90% in the northern region, 86.72% in the middle region and 71.73% in the southern region, and an overall percentage of MTR 2756AA in the whole Jordanian population was 83.50%. The frequencies of MTR 2756AG genotype in the northern, middle and southern regions were 14.95, 11.84 and 23.91%, respectively, with an overall percentage of 14.46% in the whole Jordanian population. The percentages of the genotype MTR 2756GG in the northern, middle and southern regions were 2.13, 1.42 and 4.34%, respectively, with an overall percentage of 2.04% in the whole Jordanian population. Only the wild type allele (C) of the MTR 2758C>G polymorphism was detected in this study. In addition, the association of MTR 2756A>G and MTR 2758C>G polymorphisms with the development of neural tube defects (NTDs) was examined using 17 cases of mothers from the northern part of Jordan, who gave birth to NTD affected children during the period of this study. Results showed no association between these two examined polymorphisms and the increase in maternal risk for giving birth to NTD children.

CONCLUSION:

results of this study recommend that examination should be done on larger populations to arrive at better conclusions. Also, more studies on gene–gene interaction should be done to examine the associations with NTDs.     

Association between polymorphisms in the promoter region of interleukin-10 and susceptibility to inflammatory bowel disease

The aim of this study was to assess the association of polymorphisms in the promoter region of the IL-10 gene with the risk of inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). Fifteen studies (3,693 cases and 4,574 controls) were included in a meta-analysis of association between IL-10 ?1082G/A, ?819C/T and ?592C/A polymorphisms, and IBD, CD and UC using allele contrast and the recessive, dominant, and additive models. Hardy–Weinberg equilibrium was confirmed for each study. Heterogeneity and study quality were investigated using stratification analyses and sensitivity analyses. Polymorphism ?1082G/A showed significant association with CD, with odds ratios (ORs) for the GG + GA genotype and GG versus AA genotype of 1.278 (1.004–1.627) and 1.238 (1.027–1.492) in all subjects. Significant associations were found in the Caucasian subgroup using the allele contrast, dominant, and additive models. C-allele carriers of the ?819C/T polymorphism were at increased risk of IBD (OR 1.093, 95 % CI 1.004–1.190). Association with the ?819C/T polymorphism was also found in Caucasians with CD (C vs. T: OR 1.104, 95 % CI 1.010–1.206; CC + CT vs. TT: OR 1.328, 95 % CI 1.006–1.754; CC vs. TT: OR 1.339, 95 % CI 1.008–1.778), and with UC (CC vs. CT + TT: OR 1.188, 95 % CI 1.019–1.385). No significant association was found between the ?592C/A polymorphism and IBD, CD or UC. In conclusion, the meta-analysis demonstrated clear association between the IL-10 polymorphisms ?1082G/A and ?819C/T and the risk of IBD.     

Association of the macrophage migration inhibitory factor gene − 173G/C polymorphism with inflammatory bowel disease: A meta-analysis of 4296 subjects

A variety of epidemiologic studies have focused on the association between macrophage migration inhibitory factor (MIF) gene − 173G/C polymorphism and inflammatory bowel disease (IBD). However, results in different studies have been inconsistent. In order to derive a more precise estimation of the associations, we performed this meta-analysis and systematic searches of electronic databases PubMed and Web of Science (up to April 30, 2013). Based on our search criteria, a total of seven eligible studies concerning the MIF − 173G/C polymorphism and IBD risk were included in the final meta-analysis, comprising 2162 IBD cases and 2134 controls. Significant association was found between MIF − 173G/C polymorphism and the risk of IBD when all studies were pooled into the meta-analysis (for C allele vs. G allele: OR = 1.25, 95% CI = 1.12–1.41, p = 0.000; for C/C vs. G/G: OR = 1.71, 95% CI = 1.23–2.39, p = 0.002; for C/C + G/C vs. G/G: OR = 1.24, 95% CI = 1.09–1.42, p = 0.002; for C/C vs. G/C + G/G: OR = 1.67, 95% CI = 1.20–2.33, p = 0.002). Heterogeneity and publication bias did not exist in the overall comparisons. The present meta-analysis suggests an association between the MIF − 173G/C polymorphism and IBD risk. However, due to few studies and the selection bias existed in some studies, the results should be interpreted with caution.