Genetic determinants of folate and vitamin B12 metabolism: a common pathway in neural tube defect and Down syndrome?

One-carbon metabolism is under the influence of folate, vitamin B12 and genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR 677 C --> T and 1298 A --> C), of methionine synthase (MTR 2756 C --> G), methionine synthase reductase (MTRR 66 A --> G) and transcobalamin (TCN 776 C --> G). The pathogenesis of neural tube defect (NTD) may be related to this metabolism. The influence of the MTHFR 677 C --> T polymorphism reported in The Netherlands and Ireland can be questioned in southern Italy, France and Great Britain. MTRR, combined with a low level of vitamin B12, increases the risk of NTD and of having a child with NTD in Canada, while TCN 776 GG and MTRR 66 GG mutated genotypes associated with the MTHFR 677 CC wild-type are predictors of NTD cases in Sicily. Down syndrome (DS) is due to a failure of normal chromosomal segregation during meiosis, possibly related to one-carbon metabolism. MTHFR 677 C --> T and MTRR 66 A --> G polymorphisms are associated with a greater risk of having a child with DS in North America, Ireland and The Netherlands. In contrast, MTHFR 677 C --> T has no influence on DS risk in France and Sicily, while homocysteine and MTR 2756 AG/GG genotypes are predictors of DS risk in Sicily. In conclusion, NTD and DS are influenced by the same genetic determinants of one-carbon metabolism. The distinct data produced in different geographical areas may be explained by differences in the nutritional environment and genetic characteristics of the populations.     

Synergistic effects of the MTHFR C677T and A1298C polymorphisms on the increased risk of micro- and macro-albuminuria and progression of diabetic nephropathy among Iranians with type 2 diabetes mellitus

ObjectivesTo find whether polymorphisms of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C are risk factors for diabetic nephropathy (DN) among type 2 diabetes mellitus (T2DM) patients from Western Iran.Design and methodsThe MTHFR polymorphisms were detected in 72 microalbuminuric, 68 macroalbuminuric and 72 normoalbuinuric T2DM patients by PCR-RFLP.ResultsThe possession of both MTHFR 677T and 1298C alleles increase the risk of microalbuminuria to 4.3-fold (p = 0.007) in T2DM patients. The presence of either MTHFR 677T, 1298C allele is sufficient to increase the risk of macroalbuminuria in T2DM patients by 4.1 and 5.5 times (p = 0.027, and p = 0.006, respectively). The concomitant presence of both 677T and 1298C alleles act in synergy to increase the risk of macroalbuminuria by 20.4-fold (p < 0.001) and progression of DN from microalbuminuria to macroalbuminuria (OR = 4.73, p = 0.01).ConclusionBoth MTHFR 677T and 1298C alleles increased the susceptibility to the onset and progression of DN in Iranians with T2DM.     

Influence of Amerindian mitochondrial DNA haplogroups on thrombosis susceptibility and frequency of four genetic prothrombotic variants in Southern Chilean subjects

BackgroundRecent evidence suggests that the ethnic background may determine the susceptibility to cardiovascular diseases. Considering the genetic composition of Chilean population, the aim of the present study was to evaluate the possible association between Amerindian mitochondrial DNA (mtDNA) haplogroups and venous thrombosis susceptibility and the influence on frequency of factor V 1691G > A, prothrombin 20210G > A, methylenetetrahydrofolate reductase (MTHFR) 677C > T and β-fibrinogen ?148C > T polymorphisms in Southern Chilean population.MethodsA total of 172 individuals, 60 patients with diagnosis of deep venous thrombosis (DVT) confirmed by Doppler ultrasonography and 112 controls were included in this study. The single nucleotide polymorphisms (SNP) and the Amerindian mtDNA haplogroups were detected by PCR and PCR-RFLP techniques, respectively.ResultsThe presence of mtDNA haplogroups did not modify the thrombosis susceptibility. Of 4 SNPs genotyped, only the MTHFR 677C > T variant was more frequent in DVT patients when compared to controls (OR 3.46; 95%CI, 1.50–8.00). A lower frequency of 1691G > A (factor V) and a total absence of prothrombin 20210G > A variants were observed in subjects with Amerindian background.ConclusionsThe presence of Amerindian haplogroups did not modify the susceptibility to DVT in the studied subjects. Only MTHFR 677C > T polymorphism was associated to venous thrombosis in Chilean subjects. The lower frequency of factor V 1691G > A and the absence of prothrombin 20210G > A polymorphism confirm the poor utility of the molecular detection of these variants in the thrombophilia study in populations with Amerindian background.     

Relationship between methionine synthase, methionine synthase reductase genetic polymorphisms and deep vein thrombosis among South Indians.

BACKGROUND: The rationale behind this study was to examine the relationship between polymorphisms in genes that regulate remethylation of homocysteine to methionine, i.e., methionine synthase (MTR A2756G) and methionine synthase reductase (MTRR A66G), and risk of deep vein thrombosis (DVT) in a South Indian cohort (163 DVT cases and 163 controls), as elevated homocysteine has been documented as an independent risk factor for DVT in the same cohort. METHODS: Plasma homocysteine analysis was carried out by reverse phase HPLC. The MTR A2756G and MTRR A66G genetic polymorphisms were detected using PCR-restriction fragment length polymorphism method. For statistical analyses, Fisher's exact test was used for categorical variables and Student's t-test and analysis of variance were used for continuous variables. RESULTS: The MTRR 66GG genotype was associated with a 2.74-fold [95% confidence interval (CI): 1.73, 4.34] risk of DVT. The MTR A2756G polymorphism was not a risk factor. MTRR GG/MTR AG and MTRR GG/MTR GG genotypes cumulatively were found to increase the risk of DVT by 2.38-fold (95% CI: 1.43, 3.96). A positive association was observed between plasma homocysteine and the MTRR G allele, and the MTR G allele was shown to have an additive effect. The risk associated with the MTRR 66GG genotype was further increased in subjects compound heterozygous for methylene tetrahydrofolate reductase (MTHFR) [odds ratio (OR): 3.46, 95% CI: 1.38, 8.63]. CONCLUSIONS: The MTRR 66GG genotype is a risk factor for DVT among South Indians. This risk is increased further in the presence of the MTHFR 677CT/1298AC genotype.     

Association of parental hyperhomocysteinemia and C677T Methylene tetrahydrofolate reductase (MTHFR) polymorphism with recurrent pregnancy loss

ObjectivesTo investigate the association of parental hyperhomocysteinemia, C677T Methylene tetrahydrofolate reductase (MTHFR) polymorphism and DNA damage with recurrent pregnancy loss (RPL).Design and methodsA case-control study. Reverse phase HPLC, PCR-RFLP and Cytokinesis blocked micronuclei assay were used to assess total plasma homocysteine, C677T MTHFR polymorphism and DNA damage respectively. Student t-test, ANOVA and Fisher exact test were used for statistical analysis.ResultsMaternal [mean: 11.6 ± 5.0 versus 8.6 ± 4.2 μmol/L, odds ratio (OR): 4.48] and paternal [mean: 19.6 ± 9.5 versus 14.2 ± 7.4 μmol/L, OR: 6.92] hyperhomocysteinemia, paternal age [OR: 1.16], paternal MTHFR 677T allele [OR: 2.30] and DNA damage were found to increase the risk for RPL. DNA damage showed positive correlation with plasma homocysteine and MTHFR 677T allele.ConclusionsParental hyperhomocysteinemia, paternal age, paternal C677T MTHFR polymorphism and DNA damage are risk factors for RPL. DNA damage showed positive correlation with plasma homocysteine and MTHFR 677T allele.     

Endothelial nitric oxide synthetase,methylenetetrahydrofolate reductase polymorphisms,and cardiovascular complications in Tunisian patients with nondiabetic renal disease

ObjectivesThe relationship between endothelial nitric oxide synthase (eNOS), methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and cardiovascular disease (CVD) in Tunisian patients with chronic renal disease (CRD) has not been examined. We investigated (a) the relationship of these gene polymorphisms with the presence and the severity of renal disease, and (b) their relationships with CVD in these patients.Design and methodsWe used PCR-RFLP analysis to detect the eNOS G894T, MTHFR C677T and A1298C variants in 100 patients with CRD and in 120 healthy controls.ResultsMTHFR C677T and A1298C polymorphisms were not associated with the presence of renal disease. However, we found that eNOS G894T polymorphism was associated with the presence and severity of renal disease and with CVD in CRD patients (P = 0.028, P = 0.018, P = 0.016 respectively). We showed that 894T allele was an independent risk factor of severity of renal disease and the incidence of CVD (P = 0.01 and P < 0.01 respectively).ConclusionThe G894T polymorphism of the eNOS gene is associated with severity of renal disease. Presence of the 894T allele aggravated renal damage and increased the incidence of CVD in Tunisian CRD patients.     

Simultaneous detection of CYP3A5 and MDR1 polymorphisms based on the SNaPshot assay

BackgroundThe 6986A> G polymorphism for CYP3A5 and the ?129T> C, 1236C> T, 2677G> T/A, and 3435C> T polymorphisms for MDR1 are considered the major genetic factors affecting a range of drugs' metabolism and transport. Simultaneous genotyping of these five polymorphisms would be useful for estimating the therapeutic effects of their related drugs.Subjects and methodsWe have described a SNaPshot assay that can simultaneously detect all the five polymorphisms based on multiplex PCR and minisequencing reaction. A total of 168 unrelated Chinese DNA samples were used to establish and evaluate the assay.ResultsThe different genotypes of the five polymorphisms could be determined by peak retention time and colors. DNA sequencing was performed on samples randomly selected from each of the genotype groups detected by SNaPshot assay, and the results indicated 100% concordance.ConclusionThe SNaPshot assay for the CYP3A5 and MDR1 five polymorphisms detection was accurate, automated, and cost-effective.     

Low frequency of mutated methylenetetrahydrofolate reductase 677C-->T and 1298A-->C genetics single nucleotide polymorphisms (SNPs) in Sub-Saharan populations.

5,10-Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) are two of the key enzymes in the folate/vitamin B12-dependent remethylation of homocysteine to methionine. The frequencies of MTHFR single nucleotide polymorphisms (SNPs), 677C-->T, 1298A-->C, 1317T-->C and of MTR, 2756A-->G, have been widely studied in Caucasians, but they have never been reported simultaneously in a large population from Sub-Saharan Africa. Presently, we report the prevalence of these SNPs and their relationship to homocysteine in 240 subjects recruited in West Africa. The frequencies of the mutant genotypes 677TT (0.8%) and 1298CC (2%) were lower than that usually observed in Caucasians, while the frequency of the mutant 1317CC was higher (16%). We formed a systematic association of the mutated MTHFR 677C-->T SNP with a 1298A/1317T common haplotype. The MTHFR mutant genotype 677TT was associated with an intermediate hyperhomocysteinemia (92.4 +/- 6.0 micromol/l) higher than that described in Caucasians. The 2756A-->G SNP in the MTR was similarly distributed in Africans compared to Caucasians. In conclusion, the MTHFR 677TTor 1298CC genotypes are much rarer in Africans than in Caucasians. The 677TT low frequency may be related to the high effect of this mutation on homocysteine metabolism in the environmental conditions of this African region.     

Potential role of GABAA receptor subunit; GABRA6, GABRB2 and GABRR2 gene polymorphisms in epilepsy susceptibility and pharmacotherapy in North Indian population

BackgroundGABA_A receptors influence the susceptibility to seizures, and variations in the receptor genes can contribute to antiepileptic drug resistance also.MethodsWe investigated the possible associations of single nucleotide polymorphisms (SNPs) present in GABRA6 c. 1512 T>C, GABRB2 c. 1412 C>T, and GABRR2 c. IVS2C>G genes of GABA_A receptors in epilepsy susceptibility and drug resistance in northern Indian patients with epilepsy. After screening a total of 202 healthy controls and 401 epilepsy patients were enrolled in study. The genotyping was done by PCR-RFLP methods.ResultsThe GABRA6 c. 1512 T>C, polymorphism was conferring risk for epilepsy susceptibility for TC (P = 0.018), CC (P = 0.0001) genotype and for C allele (P = 0.0002). Another polymorphism GABRB2 c. 1412 C>T was also conferring high risk for epilepsy susceptibility CT (P = 0.012), TT (P = 0.778) genotype and for variant T allele (P = 0.034) but was not associated with drug resistance. No association was found with epilepsy susceptibility or with drug resistance in case of GABRR2 c. IVS2C>G gene polymorphism.ConclusionOverall, our findings suggest significant involvement of alpha (GABRA6) and beta (GABRB2) subunits of GABA_A receptor in epilepsy susceptibility in north Indian population.     

Association of STAT4 polymorphisms with susceptibility to primary membranous glomerulonephritis and renal failure

BackgroundMembranous glomerulonephritis (MGN) is one of common causes of idiopathic nephrotic syndrome in adults, and 25% of MGN patients proceed to end-stage renal disease. STAT4 gene polymorphisms have been reported to be associated with many inflammatory diseases. The objective of this study was to clarify the relationship between STAT4 gene polymorphisms and the pathogenesis of MGN.MethodsWe investigated the association of three STAT4 gene polymorphisms (rs3024912, rs3024908, and rs3024877) with the susceptibility to MGN in 403 Taiwanese populations (138 MGN patients and 265 controls).ResultsThe results indicated that the statistically significant difference in genotype frequency distribution was found at rs3024908 SNP in MGN patients and control groups (p = 0.014). In addition, the individuals with the GG genotype at rs3024912 SNP may have a higher risk in kidney failure of MGN patients (adjusted odds ratio [OR] = 3.255; 95% confidence interval [CI] = 1.155–9.176, p = 0.026).ConclusionsOur data provide a new information that the STAT4 (rs3024912 and rs3024908) polymorphisms may be the underlying cause of MGN, and these polymorphisms revealed by this study warrant further investigation.     

Relationship between genetic polymorphisms of angiotensin-converting enzyme and methylenetetrahydrofolate reductase as risk factors for type 2 diabetes in Tunisian patients

Background/aimsThe role of methylenetetrahydrofolate reductase (MTHFR) and angiotensin-converting enzyme (ACE) gene polymorphisms as being risk factors for diabetes is still controversial. The aim was to investigate the distribution of ACE and MTHFR genotypes as well as to evaluate the role of plasmatic total homocysteine levels (tHcy) and ACE activity in Tunisian patients with type 2 diabetes mellitus (T2DM).Design and methods115 T2DM patients compared to 116 healthy volunteers.ResultsThe ACE I/D polymorphism was significantly associated with diabetes (p < 0.0001). The DD genotype and D allele were more frequent in patients compared to control group [DD: OR = 4.93; p < 0.0001; 95 % CI: 2.71–8.97; D: OR = 3.08, 95% CI: 2.09–4.51 p < 0.0001]. MTHFR allele and genotype frequencies did not differ between patients and controls. The susceptibility to diabetes in individuals with genotypes DD +vTT was 13.39 and in the individuals with DD + CT was 6.57 times that of the controls. However, individuals with genotypes ID + CC or II + CT have a protective effect against diabetes. The DD and TT genotypes were associated with significantly higher ACE activity and tHcy levels in diabetics.ConclusionOur data suggest that ACE ID polymorphism may act synergistically with MTHFR C677T polymorphism to assess diabetes risk.     

High-level multiplex genotyping of polymorphisms involved in folate or homocysteine metabolism by matrix-assisted laser desorption/ionization mass spectrometry

BACKGROUND: Increased plasma total homocysteine (tHcy), a risk factor for cardiovascular disease, is related to genetic, environmental, and nutritional factors, in particular folate status. Future large epidemiologic studies of the genetic basis of hyperhomocysteinemia will require high-throughput assays for polymorphisms of genes related to folate and Hcy metabolism. METHOD: We developed a high-level multiplex genotyping method based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) for the detection of 12 polymorphisms in 8 genes involved in folate or Hcy metabolism. The assay includes methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C, methionine synthase (MTR) 2756A>G, methionine synthase reductase (MTRR) 66A>G, cystathionine beta-synthase (CBS) 844ins68 and 699C>T, transcobalamin II (TCII) 776C>G and 67A>G, reduced folate carrier-1 (RFC1) 80G>A, paraoxonase-1 (PON1) 575A>G and 163T>A, and betaine homocysteine methyltransferase (BHMT) 742G>A. RESULTS: The failure rate of the assay was < or = 1.7% and was attributable to unsuccessful DNA purification, nanoliter dispensing, and spectrum calibration. Most errors were related to identification of heterozygotes as homozygotes. The mean error rate was 0.26%, and error rates differed for the various single-nucleotide polymorphisms. Identification of CBS 844ins68 was carried out by a semiquantitative approach. The throughput of the MALDI-TOF MS assay was 1152 genotypes within 20 min. CONCLUSIONS: This high-level multiplex method is able to genotype 12 polymorphisms involved in folate or Hcy metabolism. The method is rapid and reproducible and could facilitate large-scale studies of the genetic basis of hyperhomocysteinemia and associated pathologies.     

Association of hsp70-2 (+1267A/G), hsp70-hom (+2437T/C), HMOX-1 (number of GT repeats) and TNF-alpha (+489G/A) polymorphisms with COPD in Croatian population

ObjectiveTo test for possible association of hsp70-2 (+ 1267A/G), hsp70-hom (+ 2437T/C), HMOX-1 (number of GT repeats) and TNF-α (+ 489G/A) polymorphisms with chronic obstructive pulmonary disease (COPD) in Croatian population.MethodsGenotyping of DNA isolated from whole blood of 130 COPD patients (as defined by spirometry) and 95 healthy controls was performed. Fragment size analysis upon restriction enzyme digestion and/or sequencing was used for genotype/allele definition. Significance of findings was tested using χ² test.Resultshsp70-2 (+ 1267A/G) polymorphism was significantly associated with COPD. Results of genotyping analysis indicated that a genotype carrying G allele was preferentially associated with COPD; odds ratio (OR) = 1.50, 95% confidence interval (CI) = 1.00–2.24 and P = 0.061. OR for the GG genotype was 3.47 with CI = 1.26–9.56 and P = 0.04. No association for hsp70-hom (+ 2437T/C), TNF-α (+ 489G/A) and HMOX-1 (number of GT repeats) polymorphisms were found. In addition, comparison of genotype frequencies among different stages of disease severity (GOLD II-IV) revealed no discrimination for any of the tested polymorphisms.ConclusionThis study is supporting the association of hsp70-2 (+ 1267A/G) polymorphism and COPD. Higher frequency of G allele and GG genotype in Croatian COPD patients was observed. There was no evidence for the association of hsp70-hom (+ 2437T/C), TNF-α (+ 489G/A) SNPs and HMOX-1 (number of GT repeats) polymorphism with COPD. Allele and genotype frequencies for all of the tested polymorphisms show no association with disease severity (GOLD II-IV).     

ChREBP gene polymorphisms are associated with coronary artery disease in Han population of Hubei province

BackgroudChREBP regulates lipogenesis and glucose utilization in the liver. Current reports suggest a contradictive association between rs3812316 of this gene and triglyceride level. We hypothesized the polymorphisms in ChREBP gene were associated with CAD in Chinese population.MethodsThe ChREBP gene polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods in 200 controls and 310 CAD patients. Serum lipids and glucose concentrations were measured in all subjects. Haplotypes were constructed based on rs3812316, rs7798357 and rs1051921. All the data were analyzed using SPSS14.0, PLINK1.07 and SHEsis software.ResultsThe rare allele G of rs3812316 was significantly lower in the CAD group after adjusting for age, sex, BMI, SBP and DBP (OR^a = 0.589, 95%CI = 0.361–0.961, P = 0.034). No significant differences between cases and controls were found in genotype or allele distributions of rs7798357, rs17145750 and rs1051921. Haplotype CGC was significant higher in CAD group (P < 0.01, OR = 2.364, 95%CI = 1.608–3.474), while haplotypes GGC, CGT, CCC were significant lower in CAD group (P < 0.05).ConclusionsThe rs3812316 and the haplotypes in ChREBP gene appeared to be related to high susceptibility to CAD.     

Synergistic effects of the polymorphisms in the PAI-1 and IL-6 genes with smoking in determining their associated risk with coronary artery disease

ObjectivesTo assess the relationship between IL-6 and PAI-1 polymorphisms and coronary artery disease (CAD) and to observe the interactions between these polymorphic variants and smoking in the CAD risk.Design and methodThe study population consisted of 178 patients with angiographically documented CAD and 202 blood donors. The analyses of genetic polymorphisms were performed using the PCR-RFLP method.ResultsThe frequency of PAI-1 5G allele was higher in the entire CAD group than in control group (p = 0.04, OR = 1.35). Also the 5G allele carriers (4G5G + 5G5G) were more frequent in patients than in controls (p = 0.03, OR = 1.93). The number of women carrying 5G allele was again significantly higher among patients (OR = 10.95 p = 0.0075). The IL-6 C allele frequency was higher only in the CAD male subgroup (p = 0.035, OR = 1.44). We found synergistic and cumulative effects between specific genotype patterns and smoking in determining the risk of CAD, especially between PAI-1(4G5G + 5G5G)+IL-6(CC) and smoking (SIM = 4.18 and p = 0.0005, OR = 9.20, respectively).ConclusionsThere are synergistic and cumulative effects of 5G allele of PAI-1 polymorphism and C allele of IL-6 polymorphism with smoking in determining their associated risk with CAD.     

Heritability of genetic variants of resistin gene in patients with coronary artery disease: a family-based study

ObjectiveThe resistin gene (RETN) ?420 C > G and + 299 G > A polymorphism was investigated in a case-control study from forty complex Pakistani families with coronary artery disease (CAD) history. Heritability of the susceptible/variant alleles was investigated from parent–offspring trios in these families.MethodResistin levels were determined from 239 individuals by enzyme-linked immunosorbent assay. Genotyping was performed using polymerase chain reaction and restriction fragment length polymorphism.ResultsElevated resistin levels were observed from CAD cases vs. controls (p < 0.0001). The RETN ? 420 C > G and + 299 G > A polymorphism was more prevalent in cases vs. controls (p < 0.0001). The transmission disequilibrium test revealed a significant association of the ? 420 and + 299 polymorphism with CAD (χ² = 34.4, p < 0.0001 and χ² = 31.6, p < 0.0001, respectively).ConclusionElevated resistin, and the RETN ?420 C > G and + 299 G > A polymorphism may contribute to familial CAD. The ? 420 and + 299 variant alleles are transmitted more frequently from parent to affected offspring. This is the first report on the association of the RETN + 299 G > A polymorphism with CAD.     

Gingival crevicular fluid PGE2, IL-1beta, t-PA, PAI-2 levels in type 2 diabetes and relationship with periodontal disease

ObjectivesTo evaluate if type 2 diabetes mellitus increase gingival crevicular fluid (GCF) levels of prostaglandin E₂ (PGE₂), interleukin-1beta (IL-1ß), tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitor-2 (PAI-2).Design and methodsSeventeen type 2 diabetic patients with periodontal disease (DM), 17 otherwise healthy periodontally diseased patients (PD) and 17 systemically and periodontally healthy control subjects (H) were enrolled. Clinical periodontal measurements were recorded at six sites/tooth. GCF samples were analyzed by ELISA. Data were tested by statistical tests.ResultsDM group revealed lower IL-1ß levels than PD group (p < 0.01). PGE₂, t-PA and PAI-2 levels were similar in DM and PD groups (p > 0.05). PGE₂, t-PA levels were higher in DM and PD groups than H group (p < 0.05). PAI-2 level was higher in DM group than H group (p < 0.05). GCF total amount of PGE₂ in DM group exhibited significant correlations with all clinical periodontal measurements (p < 0.05).ConclusionType 2 diabetes in this study seems not to increase GCF levels of the evaluated inflammatory mediators.     

Evaluation of nutritional and genetic determinants of total homocysteine, methylmalonic acid and S-adenosylmethionine/S-adenosylhomocysteine values in Brazilian childbearing-age women

BACKGROUND: Cobalamin (Cbl) and folate deficiencies and gene polymorphism of key enzymes or carriers can impair homocysteine metabolism and may change the serum values of S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH). We investigated the nutritional and genetic determinants for total homocysteine (tHcy), methylmalonic acid (MMA) and SAM/SAH in healthy Brazilian childbearing-age women. METHODS: Serum concentrations of Cbl, folate, red blood cell folate, ferritin, tHcy, MMA, SAM, SAH and other metabolites were measured in 102 healthy unrelated women. The genotypes for MTHFR C677T, MTHFR A1298C, MTR A2756G, MTRR A66G, TC2 C776G, TC2 A67G and RFC1 A80G gene polymorphisms were identified by PCR-RFLP. RESULTS: Serum folate and Cbl were inversely correlated with tHcy and serum MMA, respectively. Cbl deficiency was associated with increased MMA and reduced alpha-aminobutyrate, serine and N-methylglycine concentrations. No variable was associated with SAM/SAH ratio. In addition, gene polymorphisms were not selected as determinants for tHcy, MMA and SAM/SAH ratio. Iron, Cbl and folate deficiencies were found respectively in 30.4%, 22.5% and 2.0% of individuals studied. CONCLUSIONS: There was a high frequency of Cbl and iron deficiency in this group of childbearing-age women. Serum folate and Cbl were the determinants of serum tHcy and MMA concentration, respectively.     

Association study: SLC6A18 gene and myocardial infarction

ObjectiveSLC6A18 (solute carrier family 6, member 18) acts as a specific transporter for neurotransmitters, amino acids and osmolytes such as betaine, taurine and creatine. The aim of the present study was to investigate the relationship between the human SLC6A18 gene and myocardial infarction (MI) in a Japanese population.MethodsUsing 5 single nucleotide polymorphisms in the SLC6A18 gene (rs7728646, rs4975625, rs12522796, rs4975623 and rs7447815) we performed a case-control study based on each SNP and haplotype in 289 MI patients and 223 controls.ResultsLogistic regression analysis revealed that the frequency of the CC + CG genotype of rs7447815 was significantly higher in all patients and the male MI patients than in controls (P = 0.005, P = 0.036, respectively). The frequency of the T-C haplotype (rs7728646–rs7447815) was significantly higher for the MI patients when compared with controls (P = 0.037).ConclusionsThese results suggest that SLC6A18 or neighboring genes are associated with increased susceptibility to MI.