Cystathionine Beta-synthase 844ins68 Research Articles

Folate gene polymorphisms CBS 844ins68 and RFC1 A80G and risk of Down syndrome offspring in young Iranian women: A cross-sectional study

Background: Cytogenetics and association studies showed that folate gene polymorphisms can increase the risk of chromosomal nondisjunction and aneuploidies. The folate-metabolizing gene polymorphisms in Down syndrome mothers (DSM) have been assessed in a variety of populations. Reduced folate carrier 1 (RFC1) and cystathionine beta-synthase (CBS) are key enzymes in folate metabolism.
 Objective: 2 common polymorphisms, CBS 844ins68 and RFC1 A80G, were analyzed to determine their probable risk for having Down syndrome (DS) babies in young mothers of Khuzestan province, Iran.
 Materials and Methods: This study was conducted on 100 mothers who had trisomy 21 DS children. 100 age- and ethnic-matched mothers with at least 2 healthy children and no history of abnormal pregnancies were considered as control. The samples were collected from all the mothers from June 2019 to April 2021. Genomic DNA was extracted from peripheral blood. The CBS-844ins68 and RFC1-A80G were genotyped using polymerase chain reaction-electrophoresis and restriction fragment length polymorphism, respectively.
 Results: The frequency of RFC1 AG and GG genotypes in DSM was significantly higher than the control mothers (odds ratio [OR] of 2.38 and 3.07, respectively). The heterozygote genotype of CBS 844ins68 was significantly more prevalent among DSM than the control (OR: 2.419). The OR was significantly increased to 6.667 when the homozygote of both variants was found together.
 Conclusion: Studying polymorphisms possibly increases the susceptibility of having a DS child. However, ethnicity, nutrition, and epistatic interactions are considerable factors to be evaluated in future studies.
 Key words: Down syndrome, Folic acid, Polymorphism, CBS, RFC1.

MTR, MTRR and CBS Gene Polymorphisms in Recurrent Miscarriages: A Case Control Study from North India.

ABSTRACTBackground:According to various epidemiological studies, the aetiology of recurrent miscarriages (RMs) is multifactorial. The goal of this study is to learn more about the link between genetic polymorphisms and RM.Aim:To evaluate the association of 5-Methytetrahydrofolate-Homocysteine Methyltransferase (MTR) A2756G, 5-Methytetrahydrofolate-Homocysteine Methyltransferase Reductase (MTRR) A66G and cystathionine beta-synthase (CBS) 844INS68 genetic polymorphisms with RM and also to understand the combined effect of the selected genotypes.Study Setting and Design:This was a hospital-based, case–control, observational study.Materials and Methods:A total of 516 participants were recruited in the present study, of which 200 RM cases and 258 controls were included in the present study. Fasting blood sample (~5ml) was drawn from all the participants and were screened for genetic polymorphisms of MTR A2756G, MTRR A66G and CBS 844INS68.Statistical Analysis:The frequency, odd's ratio and Hardy-Weinberg equilibrium were evaluated. SPSS (version 21.0) was used for the data analysis.Results:MTR A2756G genetic polymorphism was not associated with the risk of RM. The ancestral allele of MTRR A66G and the mutant allele of CBS 844INS68 was causing an increased risk of more than two folds for RM. CBS 844INS68 in combination with MTR A2756G was found to pose an increased risk of more than two folds for RM.Conclusion:Genetic polymorphisms particularly MTRR A66G and CBS 844INS68 seems to be elevating the risk and hence making women susceptible for RM.

CBS 844ins68, MTR A2756G and MTHFR C677T gene polymorphisms in hyperhomocysteinemia: A study among a non-tribal population group with East Asian ancestry (India)

Hyperhomocysteinemia (Hhcy) is reported to be one of the non-traditional risk factors for cardiovascular diseases. Mutation of genes in one-carbon metabolic pathway (homocysteine metabolism pathway) like methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR) and cystathionine beta synthase (CBS) have been implicated in hyperhomocysteinemia. The present study is an attempt to understand the association of CBS 844ins68, MTR A2756G and MTHFR C677T gene polymorphisms with hyperhomocysteinemia among a non-tribal population of Manipur, India. A total of 200 individuals from both sexes age ranging between 35 yrs. to 65 yrs. were randomly recruited for the present study. Genotyping of MTHFR C677T, MTR A2756G and CBS 844ins68 gene polymorphisms and analysis of homocysteine levels were done using standard protocols. Of the recruited individuals, 70% were classified as hyperhomocysteinemia cases and 30% were classified as normal homocysteine controls. Results indicate that none of the selected gene polymorphisms were found to be associated with hyperhomocysteinemia in the presently studied population group. However, individuals with TT genotype of MTHFR C677T gene polymorphism are bound to have hyperhomocysteinemia. Further, this TT genotype mediated hyperhomocysteinemia could be lethal among the individuals who have NI genotype of CBS 844ins68 gene polymorphism.

CBS 844INS68 and MS D919G polymorphism: early pregnancy loss risk

Cystathionine beta synthase (CBS) and Methionine synthase (MS) maintains the level of homocysteine in blood. Our objective was to study the genetic association of CBS 844ins68 and MS D919G polymorphism with early pregnancy loss (EPL) and Recurrent pregnancy loss (RPL). We investigated 174 EPL patients in which 130 were RPL patients and 180 healthy controls. Genotyping was done through PCR-RFLP for MS D919G polymorphism whereas that for CBS 844ins68 was performed in duplex PCR reaction. Age adjusted odds ratios (AORs) were calculated by logistic regression analysis. The CBS 844ins68 was found to have protective effect rather than having risk for RPL (AORs = 0.49, 95% CI=0.22-1.08, p=0.07). The MS D919G polymorphism also did not differ significantly between patients and controls. This is the first study to see the association of CBS and MS with EPL and more study in ethically different population is needed to confirm its association with EPL.

Increased Plasma Homocysteine Level isAssociated with Executive Dysfunction inType 2 Diabetic Patients with Mild Cognitive Impairment.

Homocysteine (Hcy) is involved in the pathogenesis of type 2 diabetes mellitus (T2DM) and Alzheimer's disease. We aimed to investigate the role of Hcy in T2DM patients with mild cognitive impairment (MCI), and to determine whether methylene tetrahydrofolate reductase (MTHFR) C677T or cystathionine beta-synthase (CBS) 844ins68 polymorphism is related to T2DM-associated MCI. We recruited 285 T2DM patients and divided them into two groups, 140 patients with MCI, and 145 healthy-cognition controls, on the basis of Montreal Cognitive Assessment (MoCA) scores. Demographic characteristics, clinical parameters, and neuropsychological tests were assessed. MTHFR C677T and CBS 844ins68 polymorphisms were analyzed. The MCI group exhibited significantly higher plasma total Hcy (tHcy) levels than control group (p < 0.001). Plasma tHcy level was negatively correlated with MoCA scores (p = 0.002), but positively associated with Trail Making Test A and B scores (p = 0.044; p = 0.005, respectively). Multivariable logistic regression model showed that high tHcy level was an independent factor for MCI in T2DM patients. No significant difference was observed in the genotype or allele distributions of MTHFR and CBS between MCI and control groups. We did not find significant MCI risks in MTHFR T allele compared with C allele, and in CBS I allele compared with D allele (OR = 1.361, p = 0.067; OR = 1.048, p = 0.909, respectively). Increased plasma tHcy level was significantly related to T2DM-associated MCI, especially executive dysfunction. Further investigation with a large population size should be conducted to confirm these findings.

CBS c.844ins68 Polymorphism Frequencies in Control Populations: Implications on Nonsyndromic Cleft Lip with or without Cleft Palate

Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect with substantial clinical and social impact. Folate deficiency is one of the factors that have been associated with increased risk for NSCLP. Polymorphisms in folate and homocysteine pathway genes may act as susceptibility factors. The objective of this study was to evaluate prevalence estimates of cystathionine beta-synthase (CBS) insertion of 68-bp (c.844ins68) polymorphisms and their correlation with NSCLP. A total of 236 unrelated individuals from seven Indian populations and an additional 355 cases with NSCLP and 357 controls without NSCLP were included in this study. We investigated the CBS c.844ins68 polymorphism in all samples. Genotyping was performed with polymerase chain reaction and electrophoresis. The data were statistically analyzed using the chi-square test. The CBS c.844ins68 allele is present in six of the seven populations analyzed, and allele frequencies range from 1.5% in Balija to 9.1% in Sugali populations. The CBS c.844ins68 polymorphism showed a significant protective effect on NSCLP at both genotype (WW versus WI: odds ratio [OR] = 0.54, 95% confidence interval [CI] = 0.31 to 0.95, P = .149) and allele levels (W versus I: OR = 0.56, 95% CI = 0.32 to 0.96, P = .033). The current study observed significant differences in the frequency of the CBS 844ins68 allele across populations. There is a significant association between CBS c.844ins68 polymorphism and cleft lip and palate in the Indian population. Additional studies are warranted to identify the functional variants in the genes controlling homocysteine as etiological contributors to the formation of oral clefts.

The association between CBS 844ins68 polymorphism and head and neck squamous cell carcinoma risk – a case-control analysis

IntroductionSusceptibility to head and neck squamous cell carcinoma may be modified by functional polymorphisms in genes involved in the folate pathway, such as cystathionine beta-synthase (CBS). The CBS 844ins68 polymorphism is associated with DNA methylation changes and cancer development.Material and methodsA case-control retrospective study was conducted in 322 patients with head and neck squamous cell carcinoma and in 531 control subjects without cancer. The polymerase chain reaction-restriction fragment length polymorphism technique was used to genotype the polymorphism. For statistical analysis, χ2 test was conducted to examine whether the genotypic frequency of CBS 844ins68 was in Hardy-Weinberg equilibrium and multiple logistic regression was used for comparisons between groups, and for interactions between the polymorphism and risk factors and clinical histopathological parameters.ResultsNo significant difference in CBS 844ins68 genotypic distribution was observed between the groups. Age > 50 years, male gender and tobacco consumption were predictors of the disease with increased risk of 7.89 (95% CI: 5.56-11.21), 2.49 (95% CI: 1.72-3.62), 6.44 (95% CI: 4.63-8.96) and 2.29 times (95% CI: 1.71-3.06) respectively. There was no association between the distribution of the CBS 844ins68 genotype and risk factors for this disease. According to clinical histopathological parameters, CBS 884ins68 polymorphism presented high frequency in oral cavity (p < 0.05) and patients with the polymorphism presented less survival time (p < 0.05).ConclusionsWe concluded that the CBS 844ins68 polymorphism is not associated with HNSCC risk and there is increased risk of this disease in male gender individuals smokers aged over 50 years. In adittion, the polymorphism is more frequent in patients with oral cavity as primary site and in patients with less survival time.

The 844ins68 polymorphism of the cystathionine beta-synthase gene is associated with schizophrenia

A subtle genetic defect in homocysteine metabolism is thought to play an etiologic role in schizophrenia. Cystathionine-beta-synthase (CBS) is a key enzyme related to homocysteine levels. The aim of the present study was to search for association between the 844ins68 polymorphism of the CBS gene and schizophrenia in a large Russian sample using case-control and family-based designs. The sample comprised 1135 patients, 626 controls and 172 families. There was a trend for association between the 844ins68 polymorphism and schizophrenia in the case-control study, with higher frequency of the insertion in the control group. The FBAT revealed a statistically significant difference in transmission of alleles from parents to the affected proband, with preferential transmission of the variant without insertion. When the sample of patients was stratified by sex and forms of schizophrenia, the significantly lower frequency of insertion was observed in the group of female patients with chronic schizophrenia ( n = 180) as compared to psychiatrically well women. The insertion variant has been reported earlier to be related to decreased levels of homocysteine and thus thought to play a protective role. In conclusion, our study revealed a possible relation of the CBS 844ins68 polymorphism to schizophrenia.

Influence of the cystathionine β-synthase 844ins68 and methylenetetrahydrofolate reductase 677C&gt;T polymorphisms on folate and homocysteine concentrations

A high homocysteine, low folate phenotype is a feature of many diseases. The effect of the cystathionine beta-synthase (CBS) 844ins68 polymorphism on homocysteine and folate concentrations was examined alone and in the context of the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism in a Northwestern European male population. The MTHFR 677TT genotype is known to be associated with increased homocysteine and decreased folate relative to CT heterozygotes and CC homozygotes in this and other populations. MTHFR 677TT homozygotes who were also CBS 844ins68 carriers had homocysteine and folate concentrations similar to those of individuals with the MTHFR 677CT and CC genotypes. Homocysteine levels in MTHFR 677TT subjects carrying the CBS 844ins68 allele were 24.1% lower than in non-carriers (6.66 vs 8.77 micromol/l, P=0.045), and serum folate levels were 27.7% higher (11.16 vs 8.74 nmol/l, P=0.034). These findings suggest that the CBS 844ins68 allele 'normalizes' homocysteine and folate levels in MTHFR 677TT individuals.

Polymorphisms in genes involved in folate metabolism as risk factors for oedematous severe childhood malnutrition: a hypothesis-generating study

Severe childhood malnutrition (SCM) occurs as both oedematous and non-oedematous syndromes. The reasons why some children develop oedematous SCM (OSCM) have remained elusive but differences in clinical presentation among malnourished children from similar backgrounds suggests that there might be inter-individual variation in susceptibility to OSCM. To estimate the strength of the association between variants of three genes involved in folate/methyl group metabolism [methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR) and cystathionine beta-synthase (CBS)] and risk of OSCM. Patients previously admitted to the Tropical Metabolism Research Unit (TMRU) for treatment of either OSCM (cases, n = 74) or non-oedematous SCM (NOSCM, controls, n = 50) were recruited. Genotypes at four sites within the three genes (MTHFR C677T, MTHFR A1298C, MTR A2756G and CBS 844ins68) were determined using PCR-based assays. The MTHFR 677T [odds ratio (OR) 0.63, 95% CI 0.2-1.7] and MTR 2756G (OR 0.74, 95% CI 0.4-1.4) alleles were associated with moderate reduction in risk of OSCM whereas the CBS 844ins68 allele (OR 1.4, 0.7-2.4) was associated with an increased risk. None of these risks was significant at the 5% level. Genetic variation within folate/methyl group metabolic pathways might have a small but potentially important influence on risk of OSCM. Additional, larger data-sets will be required to test the specific hypotheses (about the putative effect size and direction of association) generated in this preliminary study. Such observations have the potential to improve our understanding of the pathogenesis of clinical heterogeneity in severe malnutrition.

Polymorphisms of Genes Controlling Homocysteine Levels and IQ Score Following the Treatment for Childhood ALL

One of the causes of long-term morbidity associated with the treatment of acute lymphoblastic leukemia (ALL) is late neurotoxicity manifesting as impairment of higher cognitive functions. Cranial radiation therapy (CRT) and chemotherapeutic agents, particularly methotrexate (MTX), are often suggested to be major contributing factors for its development. Homocysteinemia that arises as a result of MTX-induced folate depletion was proposed to play a role in MTX-related neurotoxicity. Several enzymes are essential to maintain the homocysteine levels. Their different functional forms, associated with common genetic polymorphisms, may modulate homocysteine levels and thereby influence MTX-associated neurotoxicity. To test this hypothesis we assessed whether the variants of the methylene tetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), cystathionine beta-synthase (CBS) and endothelial nitric acid synthase (eNOS, NOS3) genes, acting either independently or in conjunction with other risk factors, influenced the cognitive functioning in ALL patients. The influence of the genes was measured by estimating the change in IQ scores over a period of 4 years post ALL diagnosis. Two variants, the CBS 844ins68 polymorphism and NOS3 894T homozygosity, were associated with a change in IQ scores (p = 0.01 and 0.007, respectively). A multivariate model obtained through step-wise selection pointed to the importance of the NOS3 894TT genotype only. This effect appears to be dependent on CRT; IQ decline was apparent among individuals with the 894TT genotype who received radiation therapy (p = 0.03). Furthermore, additional factors affecting IQ were identified, including the treatment administered (i.e., CRT; p = 0.02) and a younger age at diagnosis (p = 0.003), and the modifying effect of the treatment protocols was also noted (p = 0.04). The results suggest that NOS3 genotyping might identify individuals that are susceptible to intellectual impairment following ALL treatment.

Homocysteine concentrations in adults with trisomy 21: effect of B vitamins and genetic polymorphisms

The effects of supplementation with B vitamins and of common polymorphisms in genes involved in homocysteine metabolism on plasma total homocysteine (tHcy) concentrations in trisomy 21 are unknown. We aimed to determine the effects of orally administered folic acid and of folic acid combined with vitamin B-12, vitamin B-6, or both on tHcy in adults with trisomy 21. The study was also intended to analyze the possible influence of gene polymorphisms. One hundred sixty adults with trisomy 21 and 160 healthy, unrelated subjects aged 26 +/- 4 y were included. Plasma tHcy, red blood cell folate, serum folate, and vitamin B-12 were measured. Genotyping for the common methylenetetrahydrofolate reductase (MTHFR) 677C-->T, MTHFR 1298A-->C, cystathionine beta-synthase 844Ins68, methionine synthase 2756A-->C, methionine synthase reductase 66A-->G, and reduced folate carrier 80G-->A polymorphisms was carried out. The mean tHcy concentration (9.8 +/- 0.7 micromol/L) of cases who did not use vitamins was not significantly different from that of controls (9.4 +/- 0.3 micromol/L). Plasma tHcy concentrations (7.6 +/- 0.3 mmol/L) in cases who used folic acid were significantly lower than in cases who did not. Folic acid combined with vitamin B-12 did not significantly change tHcy concentrations compared with those in cases who used only folic acid. Folic acid combined with vitamins B-6 and B-12 significantly lowered tHcy (6.5 +/- 0.5 micromol/L). The difference in tHcy according to MTHFR genotype was not significant. However, tHcy concentrations were slightly higher in TT homozygotes among the controls but not among the cases. This study provides information on the relation between several polymorphisms in genes involved in homocysteine and folate metabolism in adults with trisomy 21.

Genetic determinants of fasting and post-methionine hyperhomocysteinemia in patients with retinal vein occlusion

Introduction: Moderate hyperhomocysteinemia is considered a risk factor for both venous and arterial thrombosis. A prevalence of up to 30% of fasting hyperhomocysteinemia has been recently reported in patients with retinal vein occlusion (RVO) whereas conflicting data exist on the role of C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene as a risk factor for RVO. No report has been published on cystathionine beta-synthase (CBS) 844ins68 polymorphism (another genetic determinant of blood Hcy levels) in RVO patients. Moreover, scarce information is available on the usefulness of measuring homocysteine also after methionine loading to increase the diagnostic efficacy of hyperhomocysteinemia in RVO patients. Materials and methods: In 55 consecutive patients with diagnosis of RVO and 65 matched controls, plasma fasting total homocysteine (Hcy) levels and CBS and MTHFR polymorphisms were evaluated. In patients with normal fasting Hcy levels, post-methionine Hcy levels were determined. Results: Moderate fasting hyperhomocysteinemia was detected in 18/55 patients (32.7%). In the remaining 37 patients, Hcy was measured again post-methionine loading (PML). Only 3/37 (8.1%) patients had PML hyperhomocysteinemia. Thus, the total prevalence of moderate hyperhomocysteinemia in this cohort of RVO patients was 21/55 (38.2%). The prevalence of homozygosity for C677T MTHFR genotype, but not that of heterozygosity for CBS844ins68, was significantly higher in RVO patients than in controls. Conclusions: Differently from what has been reported for arterial and/or venous thrombosis, a single fasting Hcy measurement is able to detect most of RVO patients (85.7%) with moderate hyperhomocysteinemia. C677T MTHFR, but not CBS 844ins68, genotype may play a role as risk factor for RVO.

Homocysteine and atheromatous renal artery stenosis.

Hyperhomocysteinemia is an independent risk factor for vascular disease, frequently observed in patients with severe renal impairment. Hyperhomocysteinemia has never been considered as a possible risk factor in renal artery stenosis. We investigated plasma folate and vitamin B12, methylenetetrahydrofolate reductase (MTHFR) C677T and cystathionine beta-synthase (CBS) 844ins68 polymorphisms, and homocysteine levels before and after methionine (100 mg/kg) loading in 58 patients with angiographically documented renal artery stenosis and mildly impaired renal function. One hundred and two normotensive subjects with angiographically normal coronary arteries and no history or clinical or angiographic evidence of atherosclerosis in other vascular districts, were considered as a control group. Mean total homocysteine levels were significantly higher in patients than in controls (P<0.01), as was the prevalence of hyperhomocysteinemia (51.7% vs. 32.3%, P<0.05). However, MTHFR alleles and genotypes as well as CBS 844ins68 mutation frequencies were similar in the two groups, whereas a lower folate level was observed in the patients. Moreover, patients with MTHFR A/A genotype showed a poorer folate status than control subjects, suggesting that a subclinical folate deficiency may be very frequent in renal artery stenosis, regardless of C677T mutation. In conclusions, hyperhomocysteinemia is common in patients with atheromatous renal artery stenosis; a subclinical folate deficiency seems to be involved, regardless of MTHFR thermolabile or CBS insertion genotypes. Folate supplementation might be useful in the management of overall vascular risk of these patients.

Interaction of folate and homocysteine pathway genotypes evaluated in susceptibility to neural tube defects (NTD) in a German population

Neural tube defects (NTD) are likely to result from an interaction of several genes and environmental factors. Because periconceptional folate intake reduces the NTD risk in the fetus, and because mothers of children with NTD showed elevated plasma homocysteine levels, gene polymorphisms of the folate and homocysteine pathway, such as 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C-->T, MTHFR 1298A-->C and cystathionine beta-synthase (CBS) 844ins68, have been implicated in the etiology of NTD. Several studies have demonstrated that these polymorphisms may indeed be associated with NTD in some populations. In order to evaluate the role of these polymorphisms and their interaction in NTD, we genotyped 417 individuals for case-control studies and 129 families for transmission disequilibrium tests. We are the first to present detailed data on MTHFR haploid genotypes in combination with CBS 844ins68. The MTHFR risk genotype 677CT/1298AC, known to be associated with decreased enzyme activity and increased homocysteine, was found significantly more often in patients than in controls (P = 0.02). A CBS insertion allele in addition to MTHFR 677CT/ 1298AC heterozygosity or MTHFR 677TT/1298AA homozygosity did not result in an increased risk for NTD. This is in agreement with the recently reported homocysteine-lowering effect of the CBS 844ins68 allele in carriers of MTHFR variants.