Congenital heart defects and genetic variants in the methylenetetrahydroflate reductase gene

Hobbs, Charlotte A.; James, S. Jill; Parsian, Azemat J.; Krakowiak, Patrycja A.; Jernigan, Stefanie; Greenhaw, J J; Lu, Yunxia; Cleves, Mario A.

doi:10.1136/jmg.2005.032656

Cited by 62 publications

(80 citation statements)

References 21 publications

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“…[3][4][5]10,11,23 However, previous efforts on several folate-related gene variants have yielded conflicting or negative results. [13][14][15][16][17][18]25,26 For example, in the case of the most extensively studied MTHFR c.677 CϾT variant, the data published so far do not provide strong evidence for an overall significant association with the CHD risk in either mothers or their offspring with CHD. Limited studies have been conducted on variants of the MTRR gene.…”

Section: Discussionmentioning

confidence: 85%

“…However, studies analyzing the association between the MTHFR polymorphism and CHD have yielded controversial results. [13][14][15][16][17][18] Increased maternal homocysteine levels were also found to be associated with an increased risk of CHD in the offspring. 12,19 The remethylation of homocysteine to form methionine is catalyzed by methionine synthase (MTR).…”

Section: Clinical Perspective On P 490mentioning

confidence: 96%

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Functional Variant in Methionine Synthase Reductase Intron-1 Significantly Increases the Risk of Congenital Heart Disease in the Han Chinese Population

Zhao

Yang²,

Gong³

et al. 2012

Circulation

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Background— Homocysteine is known to be an independent risk factor for congenital heart disease (CHD). Methionine synthase reductase ( MTRR ) is essential for the adequate remethylation of homocysteine, which is the dominant pathway for homocysteine removal during early embryonic development. Methods and Results— Here, we report that the c.56+781 A>C (rs326119) variant of intron-1 of MTRR significantly increases the risk of CHD in the Han Chinese population. In 3 independent case-control studies involving a total of 2340 CHD patients and 2270 healthy control participants from different geographic areas, we observed that patients carrying the heterozygous AC and homozygous CC genotype had a 1.40-fold (odds ratio=1.40; P =2.32×10 −7 ) and 1.84-fold (odds ratio=1.84; P =2.3×10 −11 ) increased risk, respectively, of developing CHD than those carrying the wild-type AA genotype. Both in vivo quantitative real-time polymerase chain reaction analysis of MTRR mRNA in cardiac tissue samples from CHD patients and in vitro luciferase assays in transfected cells demonstrated that the c.56+781 C allele profoundly decreased MTRR transcription. Further analysis demonstrated that the c.56+781 C allele manifested reduced CCAAT/enhancer binding protein-α binding affinity. In addition, healthy individuals with the homozygous CC genotype had significantly elevated levels of plasma homocysteine compared with the wild-type AA carriers. Conclusions— We have demonstrated that the MTRR c.56+781 A>C variant is an important genetic marker for increased CHD risk because this variant results in functionally reduced MTRR expression at the transcriptional level. Our results accentuate the significance of functional single-nucleotide polymorphisms in noncoding regions of the homocysteine/folate metabolism pathway core genes for their potential contributions to the origin of CHD.

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Section: Discussionmentioning

confidence: 85%

Section: Clinical Perspective On P 490mentioning

confidence: 96%

Functional Variant in Methionine Synthase Reductase Intron-1 Significantly Increases the Risk of Congenital Heart Disease in the Han Chinese Population

Zhao

Yang²,

Gong³

et al. 2012

Circulation

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“…Interesting results sprouted in the North Europe and PCR-TAQMAN subgroup; a protective role for the CA+AA and CA genotypes was observed. Several studies also report the protective role of 1298C allele, and Hobbs et al suggested three possible explanations for the phenomenon, including: (i) an unknown functional polymorphism in linkage disequilibrium with A1298C, (ii) error-free DNA synthesis with abundant purines and pyrimidines caused by the lower activity of the MTHFR enzyme, and (iii) the selective survival of the 1298A allele [49-51]. In summary, the CC genotype of the MTHFR A1298C polymorphism had an increased risk of CHD, but the protective role of 1298C allele should be interpreted with caution.…”

Section: Discussionmentioning

confidence: 99%

Two Common MTHFR Gene Polymorphisms (C677T and A1298C) and Fetal Congenital Heart Disease Risk: An Updated Meta-Analysis with Trial Sequential Analysis

Zhang

Cai-hong

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Published studies indicated that the MTHFR gene polymorphisms C677T and A1298C are associated with congenital heart disease (CHD) risk in children, but obtained inconsistent results. Our study aims to reach a more accurate association between these two polymorphisms and CHD risk. Methods: Eligible studies were obtained by screening the PubMed, Embase, China National Knowledge Infrastructure, Wan Fang and VIP databases based on designed searching strategy. The odds ratio (OR) and 95% confidence interval (CI) were calculated. Moreover, a trial sequential analysis was introduced to confirm the positive results and an RNA secondary structure analysis was also applied to discover the potential molecular mechanism. Results: Based on thirty-two published articles, involving 6988 congenital heart disease subjects and 7579 healthy controls, the pooled results from the C677T polymorphism in the fetal population showed increased risks in allelic model (OR=1.32, 95%CI=1.14-1.53), recessive model (OR=1.69, 95%CI=1.25-2.30), dominant model (OR=1.35, 95%CI=1.11-1.64), heterozygote model (OR=1.20, 95%CI=1.01-1.41) and homozygote model (OR=1.75, 95%CI=1.31-2.33). An increased risk was only detected in the A1298C polymorphism in the overall fetal popalation in a recessive model (OR=1.42, 95%CI=1.10-1.84). In the subgroup stratified by region, sample size, genotyping method and source of controls, the increased risks were widely observed in both the C677T and A1298C polymorphisms with CHD risk. Furthermore, trial sequential analysis confirmed our positive results, and the RNA secondary structure analysis detected the changes in the RNA secondary structure caused by the mutant 677T allele and 1298C allele. Conclusion: In summary, we found that the MTHFR C677T polymorphism is associated with a significant increased risk in congenital heart disease in the fetal population. Moreover, an increased risk in the CC genotype of MTHFR A1298C polymorphism was observed, but the protective role of the 1298C allele needs further study.

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“…Novejše metaanalize potrjujejo pozitivno korelacijo med polimorfizmom C677T in pojavom CHD.34 S povečanim tveganjem za CHD je povezan tudi genotip 1298CC. 35 Incidenca orofacialne shize (OFC) je 1 na 700 rojstev v vseh populacijah in je druga najpogostejša prirojena napaka.36,37 V povezavi z OFC je gen MTHFR daleč najbolj raziskan. Novejša metaanaliza, ki je preučila 18 študij, je dokazala pozitivno korelacijo med materinim genotipom 677TT in pojavnostjo OFC, medtem ko korelacije med materinim in otrokovim genotipom ter tveganjem za OFC ni dokazala.37 V študiji slovenske populacije otrok z OFC smo dokazali, da se pri otrocih z genotipi, ki kodirajo manj aktivne oblike encima MTHFR, pojavnost shize poveča do 2,5-krat.…”

Section: Povezanost Polimorfizmov V Genu Za Mthfr S Pojavnostjo šTeviunclassified

Spremenjena aktivnost encima 5,10-metilentetrahidrofolat reduktaze (MTHFR) vpliva na razvoj številnih bolezni

et al. 2016

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IzvlečekPomen folatov v fiziologiji je že dolgo znan, prav tako številne patologije, povezane z znižanim folatnim statusom. Pomanjkanje folatov pri posamezniku je lahko posledica nizkega vnosa folata, genetske zasnove posameznika ali sočasnega zdravljenja z zdravili, ki vplivajo na folatni status. Namen tega prispevka je osvetliti pomen ugotavljanja genetskih polimorfizmov, ki pomembno vplivajo na raven biološko aktivne oblike folata. V procesu pretvorbe 5,10-metilen-THF v 5-metil-THF je ključen encim MTHFR, ki je polimorfen, zato pa ima lahko zmanjšano encimsko aktivnost.V slovenski populaciji ima polno aktivnost encima MTHFR le 9,3 % posameznikov, ki so homozigoti za divji tip alelov, medtem ko je povprečna aktivnost encima pri nosilcih mutiranih alelov med 50-60 %. Prisotnost polimorfizma MTHFR predstavlja tveganje za pojav hiperhomocisteinemije in kardiovaskularnih bolezni, nevroloških bolezni, pojav raznih oblik raka, pri nosečnicah pa tudi večje tveganje za pojav okvar ploda. Za ohranjanje ustreznega folatnega statusa so v nekaterih državah uvedli dodajanje folne kisline v prehrano, vendar se je potrebno zavedati, da ta pristop ne bo odpravil pomanjkljivosti v delovanju encima MTHFR, lahko pa ublaži njihov vpliv na končni fenotip posameznika.Prisotnost polimorfizmov v ključnih genih folatnega cikla je pogosta. Zato je ugotavljanje genetske zasnove posameznika smiselno predvsem pri najbolj ranljivih skupinah prebivalstva, npr. pri noseč-nicah in bolnikih, zdravljenih z zdravili, kot so 5-fluorouracil, metotreksat, 6-merkaptopurin, ki se na različne načine vpletajo v presnovno pot folatov. Genotipizacija bi prispevala k identifikaciji bolnikov, pri katerih je povečano tveganje za neustrezen folatni status in zato pomagala pri preprečenju z njim povezanih patoloških stanj. AbstractThe importance of folates in human physiology is well known, as are various pathologies associated with low folate status. Folate deficiency can occur due to low dietary intake, a genetic predisposition or treatment with medicines affecting the folate status. The aim of this paper is to explore the importance of determining genetic polymorphisms, which influence the levels of biologically active folate. MTHFR is involved in the transformation of 5,10-methylene-THF to 5-methyl-THF. Polymorphisms of the MTHRF gene are associated with decreased enzymatic activity.spremenjena aktivnost encima 5,10-metilentetrahidrofolat reduktaze (MthFr) kot dejavnik tveganja za številne bolezni 325 strokoVni čLanek Prispelo: 25. maj 2016Prispelo: 25. maj , sprejeto: 30. jun. 2016 Only 9.3 % of the population in Slovenia display full activity of the MTHFR enzyme; these subjects are non-mutated homozygotes (wild-type alleles). In contrast, the average enzymatic activity in subjects with mutated alleles is between 50 and 60 %. MTHFR polymorphism is associated with an increased risk of hyperhomocysteinemia and cardiovascular diseases, neurological disorders and various types of cancer. There is also an increased risk for congenital malformations. Folic a...

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Congenital heart defects and genetic variants in the methylenetetrahydroflate reductase gene

Abstract: The apparent protective effect of the MTHFR 1298C allele against CHD could have several explanations and further study is needed.

Cited by 62 publications

References 21 publications

Functional Variant in Methionine Synthase Reductase Intron-1 Significantly Increases the Risk of Congenital Heart Disease in the Han Chinese Population

Functional Variant in Methionine Synthase Reductase Intron-1 Significantly Increases the Risk of Congenital Heart Disease in the Han Chinese Population

Two Common MTHFR Gene Polymorphisms (C677T and A1298C) and Fetal Congenital Heart Disease Risk: An Updated Meta-Analysis with Trial Sequential Analysis

Spremenjena aktivnost encima 5,10-metilentetrahidrofolat reduktaze (MTHFR) vpliva na razvoj številnih bolezni

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