rs1801394
badMag 3.8This is a variant in the MTRR gene that changes a isoleucine to an methionine.
Key Literature Trait Associations
Down syndrome (maternal risk)
Maternal carriage of the MTRR rs1801394 G allele has been associated with increased risk of conceiving a child with Down syndrome (trisomy 21), particularly in Caucasian populations. A meta-analysis of 17 case-control studies (Victorino 2014) found evidence for this association, with the strongest signal in Caucasian subgroup analysis. A family-based study in 183 Down syndrome probands in eastern India (Chatterjee 2020) independently confirmed higher G allele and GG genotype frequencies in cases vs. controls (p<0.0001). The proposed mechanism involves impaired B12-dependent remethylation of homocysteine, which may affect DNA methylation fidelity and chromosome segregation during meiosis. Effect sizes are moderate.
Male infertility
The MTRR 66AA genotype (A allele) is associated with increased idiopathic male infertility risk in Asian populations. A meta-analysis of 22 case-control studies (Shi 2019, n=9,206 Asian subjects: 5,049 cases, 4,157 controls) found that across multiple genetic models, the A allele was overrepresented in infertile men: dominant model OR=0.60 (95% CI 0.45–0.81, p=0.001) for GG vs. AA+AG; allele model OR=0.76 (95% CI 0.66–0.88, p<0.0001). The G allele thus appears protective, while the A allele confers risk. A separate meta-analysis (Ren 2019, n=6,461) found the overall result null but noted a significant association specifically with oligoasthenoteratozoospermia (OAT) in Asian subgroups. The mechanism likely involves MTRR-mediated effects on sperm DNA methylation and one-carbon metabolism.
B12 Recycling / Methionine Synthase Reductase
The MTRR A66G variant (rs1801394) is a missense polymorphism (Ile22Met) in methionine synthase reductase, which regenerates the active form of vitamin B12 needed by methionine synthase. The G allele reduces enzyme efficiency, impairing B12 recycling and potentially elevating homocysteine. A meta-analysis found homozygous GG carriers have ~1.31-fold increased maternal risk for neural tube defects in Caucasian populations.
Neural tube defects
The MTRR rs1801394 G allele has been associated with increased neural tube defect (NTD) risk in several Asian studies. A case-control study in 152 NTD cases and 169 controls from northern China found G allele carriers had OR 1.533 (allele model) and GG homozygotes had OR 2.355 for NTD risk. A separate Chinese study (n=61 NTD pregnancies vs. 61 controls) reported OR 1.763 (95% CI 1.023–3.036) for G allele frequency in cases. However, a California-based study (Shaw 2009, n=259 spina bifida cases) found a protective OR of 0.7 for MTRR rs1801394, and an Ethiopian study found no significant association, highlighting population heterogeneity. The association is most consistent in East Asian populations and may reflect gene-nutrient interactions with folate/B12 status.
Lung cancer
MTRR rs1801394 G allele has been associated with increased lung cancer susceptibility in a meta-analysis of 37 genetic association studies (Chen 2020). Significant associations were found across dominant (p=0.01), recessive (p=0.04), and allele (p=0.005) models. The association was notable in smokers, suggesting a gene-environment interaction where impaired one-carbon metabolism compounds carcinogenic risk from tobacco. East Asian populations showed stronger associations. The biological rationale involves MTRR-mediated effects on DNA methylation and genome stability via the methionine cycle, with folate insufficiency potentially unmasking the G allele's effect.
Brain tumors (meningioma and glioma)
The MTRR rs1801394 G allele is associated with modestly increased susceptibility to meningioma and glioma based on a meta-analysis of published folate metabolism studies (Chen 2017). Effect sizes were: G vs. A OR=1.11 (p=0.020); GG vs. AA OR=1.22 (p=0.023); GG vs. AA+AG OR=1.17 (p=0.043). The findings are consistent across multiple genetic models, though specific ORs for meningioma and glioma separately were not reported. Impaired MTRR-mediated one-carbon metabolism may disrupt DNA methylation patterns in neural tissue, contributing to tumorigenesis.
Nonsyndromic cleft lip with or without cleft palate
The MTRR rs1801394 GG genotype (homozygous G) appears protective against nonsyndromic cleft lip with or without cleft palate (NSCL/P) in Asian populations, while the AA genotype confers risk. A meta-analysis (Li 2020) found GG vs. AA OR=0.520 (95% CI 0.321–0.841, p=0.008) in Asian subjects. An earlier meta-analysis (Lei 2018) across all ethnicities found no significant overall association (OR=0.99, p=0.72), suggesting the effect is population-specific. The risk_allele A reflects the genotype with higher NSCL/P risk based on the Asian-specific signal. Evidence is currently limited to Asian populations and requires replication in other groups.
▶ClinVar annotation
Disorders of Intracellular Cobalamin Metabolism; Down syndrome, susceptibility to; Gastrointestinal stromal tumor; Methotrexate response; Methylcobalamin deficiency type cblE (HMAE); Neural tube defects, folate-sensitive, susceptibility to; not specified
View on ClinVar →▶Research that mentions this SNP (13)
▶Gene‐by‐gene interactions associated with the risk of conotruncal heart defectsAssociationN=414Chen Lyu et al.(2020)· Molecular Genetics & Genomic Medicine
This gene-by-gene interaction study of conotruncal heart defects (CTDs) identified one significant SNP pair (rs4764267 in MGST1 and rs6556883 in GLRX) with adjusted p-value of 0.04, and another marginally significant pair (rs11892646 in DNMT3A and rs56219526 in MTRR) with adjusted p-value of 0.06. The analysis combined sequencing (328 case-parental triads) and microarray (86 triads) data, with both SNP pairs located in genes involved in transsulfuration and homocysteine metabolism pathways.
▶A parent‐of‐origin analysis of paternal genetic variants and increased risk of conotruncal heart defectsAssociationN=616Wendy N. Nembhard et al.(2018)· American Journal of Medical Genetics Part A
A family-based case-only study of 616 conotruncal heart defect cases examining paternal genetic variants in folate, homocysteine, and transsulfuration pathways. Among 921 SNPs genotyped in 60 candidate genes, three paternal variants showed statistically significant decreased risk: GLRX rs17085159 (RR=0.23), GLRX rs12109442 (RR=0.27), and GSR rs7818511 (RR=0.31). The study concludes that paternal variants in these metabolic pathways have less influence on conotruncal heart defect risk than maternal variants.
▶Association of main folate metabolic pathway gene polymorphisms with neural tube defects in Han population of Northern ChinaAssociationN=321Yulian Fang et al.(2018)· Child's Nervous System
A case-control study of 152 NTD patients and 169 controls in Han Chinese population identified three folate metabolism pathway SNPs associated with neural tube defects: rs2236225 in MTHFD1 (allele A, OR=1.500; AA genotype OR=2.862), rs1801133 in MTHFR (allele T, OR=1.552; TT genotype OR=2.344), and rs1801394 in MTRR (allele G, OR=1.533; GG genotype OR=2.355). The study demonstrates genetic variation in folate metabolism significantly affects NTD susceptibility.
▶MTHFR rs2274976 polymorphism is a risk marker for nonsyndromic cleft lip with or without cleft palate in the Brazilian populationAssociationN=1,712Sibele Nascimento de Aquino et al.(2014)· Birth Defects Research Part A: Clinical and Molecular Teratology
Case-control study of 501 young stroke patients and 1,211 controls examining 58 polymorphisms in 17 genes involved in methionine metabolism. Multiple logistic regression identified four independent risk factors for early-onset ischaemic stroke: rs10037045 BHMT (OR 1.38, p=0.033), rs682985 BHMT2 (OR 1.46, p=0.017), rs1051319 CBS (OR 3.75, p<0.0001), and rs202680 FOLH1 (OR 3.00, p<0.0001). Haplotype analyses identified significant associations with BHMT, CBS, FOLH1, MTR, PON2, TCN2 and TYMS haplotypes and stroke risk.
▶Possible contribution of GSTP1 and other xenobiotic metabolizing genes to vitiligo susceptibilityAssociationN=200Mikhail M. Minashkin et al.(2013)· Archives of Dermatological Research
A candidate gene association study in 100 Russian vitiligo patients and 100 controls identified a strong novel association between GSTP1 rs1138272 (Ala114Val, OR=13.03, Bonferroni-adjusted P=0.0015) and vitiligo susceptibility. Cumulative analysis of multiple xenobiotic metabolizing genes showed that carrying higher numbers of risk alleles was associated with increased vitiligo risk (9-16 vs 3-8 alleles: OR=2.79, P=0.00063), supporting a polygenic model for vitiligo involving detoxification pathway genes.
▶Folate and vitamin B12-related genes and risk for omphaloceleAssociationN=930James L. Mills et al.(2012)· Human Genetics
Case-control study of 169 omphalocele cases and 761 controls examining variants in folate, vitamin B12, and homocysteine metabolism genes. Variants in transcobalamin receptor (TCblR) rs2232775 (Q8R) and methylenetetrahydrofolate reductase (MTHFR) rs1801131 (1298A>C) were significantly associated with omphalocele (TCblR OR=3.20, p=0.0017; MTHFR OR=2.04, p=0.028). Additional race-ethnicity-specific associations were found with TCN2, BHMT rs3733890, and FOLH1 variants, suggesting disruption of methylation reactions as a potential risk factor.
▶Vascular endothelial growth factor (VEGF) gene polymorphisms may influence the efficacy of thalidomide in multiple myelomaAssociationN=237Niels F. Andersen et al.(2012)· International Journal of Cancer
This case-control association study examined genetic polymorphisms in 237 Russian women to identify variants associated with early reproductive loss and recurrent miscarriage. The study found that DNMT3B rs2424913 (OR=4.44-4.78), DNMT1 rs2228611 (OR=3.0-3.94), and DNMT1 rs8101626 (OR=2.5-3.1) were significantly associated with increased risk of sporadic and recurrent early pregnancy loss, while SYCP3 rs769825641 heterozygotes showed elevated risk of sporadic miscarriage.
▶Genetic Predictors of Response to Photodynamic TherapyReviewFrancesco Parmeggiani et al.(2011)· Molecular Diagnosis & Therapy
Comprehensive review evaluating SNPs as genetic predictors of choroidal neovascularization (CNV) response to photodynamic therapy with verteporfin (PDT-V). The paper examines pharmacogenetic correlations for thrombo-coagulative pathway variants (MTHFR rs1801133, F5 rs6025, F2 rs1799963, F13A1 rs5985), complement/inflammatory variants (CFH, HTRA1, CRP, ARMS2), and VEGFA variants (rs699947, rs2146323), concluding that specific SNPs show clinical plausibility as markers to optimize PDT-V efficacy and guide therapeutic approaches in neovascular macular degeneration.
▶Polymorphisms in CHDH gene and the risk of tooth agenesisAssociationN=344Adrianna Mostowska et al.(2011)· Birth Defects Research Part A: Clinical and Molecular Teratology
This case-control study examined 21 SNPs in 13 folate and choline metabolism genes for associations with tooth agenesis (hypodontia/oligodontia) in a Polish population of 159 cases and 185 controls. The CHDH gene variant rs6445606 showed the strongest association with a protective effect (OR=0.434, p=0.0004), with individuals carrying the C allele having reduced risk of tooth agenesis. Multifactor dimensionality reduction analysis revealed a significant epistatic interaction between CHDH rs6445606 and PLD2 rs3764897 (p=0.004).
▶Variation in folate pathway genes contributes to risk of congenital heart defects among individuals with Down syndromeAssociationN=243Adam E. Locke et al.(2010)· Genetic Epidemiology
This case-control study examined folate pathway gene variants in 121 DS-AVSD cases and 122 DS controls (no CHD). Tag SNPs in MTHFR, MTR, MTRR, CBS, and SLC19A1 were genotyped. SLC19A1 showed significant gene-level association with atrioventricular septal defect (P=0.01), with multiple tag SNPs nominally associated (OR 1.08-1.72). All significant SLC19A1 SNPs showed strong LD (r²≥0.80) with the nonsynonymous variant rs1051266 (c.80A>G, p.H27R). MTHFR c.1298A was over-transmitted to cases (P=0.05) and under-transmitted to controls (P=0.02), showing association in FBAT analysis (P=0.03 dominant, P=0.01 additive). These results suggest folate pathway disruption contributes to AVSD risk in Down syndrome individuals.
▶Genetic variants in one‐carbon metabolism‐related genes contribute to NSCLC prognosis in a Chinese populationAssociationN=564Guangfu Jin et al.(2010)· Cancer
This association study screened 57 SNPs from 11 one-carbon metabolism genes in 564 NSCLC patients to identify genetic variants affecting lung cancer prognosis. Key findings included favorable prognostic associations for MTR rs3768160 A>G (HR=0.78, 95% CI 0.62-0.98), MTRR rs2966952 G>A (HR=0.84, 95% CI 0.71-0.99), and DHFR rs1650697 G>A (HR=0.83, 95% CI 0.70-0.99), with unfavorable prognosis for MTHFD1 rs1950902 G>A (HR=1.18, 95% CI 0.99-1.40). Combined analysis of these four SNPs demonstrated a locus-dosage effect on NSCLC survival (P trend = 6.9×10⁻⁵) and identified combined genotypes as an independent prognostic factor.
▶Folate and one‐carbon metabolism gene polymorphisms and their associations with oral facial cleftsAssociationN=553Abee L. Boyles et al.(2008)· American Journal of Medical Genetics Part A
This family-based association study examined 12 polymorphisms in one-carbon metabolism genes (BHMT, CBS, MTHFD1, MTHFR, MTR, MTRR, SLC19A1, TCN2) and their associations with oral facial clefts in 553 Norwegian families. CBS rs234706 showed a significant maternal protective effect on cleft lip/palate risk (LRT p=0.008), with homozygous carriers of the T allele showing reduced risk (RR=0.50, 95% CI 0.26-0.96). MTHFR rs1801133 demonstrated a protective effect in the low-folate supplementation subset (RR=0.60-0.44), and maternal folic acid supplementation ≥400 μg/day was associated with 39% reduction in cleft lip/palate risk.
▶A Common Variant in Methionine Synthase Reductase Combined with Low Cobalamin (Vitamin B12) Increases Risk for Spina BifidaAssociationN=300Aaron Wilson et al.(1999)· Molecular Genetics and Metabolism
This case-control study identified a common A66G polymorphism (rs1801394) in methionine synthase reductase (MTRR) as a maternal genetic risk factor for spina bifida, particularly when combined with low cobalamin (vitamin B12) status. Mothers carrying the homozygous mutant MTRR genotype with low B12 had a 4.8-fold increased risk (95% CI 1.5-15.8), while affected children had a 2.5-fold increased risk (OR 2.5, 95% CI 0.63-9.7). The study examined 56 spina bifida patients, 58 affected mothers, 97 control children, and 89 control mothers.
Gene information from NCBI Gene. Variant classifications from ClinVar.
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