Rs1801133

rs1801133 is a SNP that is relatively common and has been studied for (relatively) a long time. Also known as C677T, Ala222Val, and A222V, it encodes a variant in the MTHFR gene, which encodes an enzyme involved in folate metabolism.

Homozygous rs1801133(T;T) individuals have ~30% of the expected MTHFR enzyme activity, and rs1801133(C;T) heterozygotes have ~65% activity, compared to the most common genotype, rs1801133(C;C). This reduced activity (i.e. this SNP) has been linked at least once to each of the following disorders (though not necessarily reproducibly):

• autism
• cancer, including
  • gastric cancer
  • lung cancer
  • head and neck cancer
• cleft lip and cleft palate
• coronary artery disease
• depression
• hyperhomocysteinemia
• migraine
• neural tube defects
• pre-eclampsia (gestational hypertension)
• schizophrenia
• thrombosis

These two articles summarize much of what is currently known about the effects of elevated homocysteine levels.

With regard to gastric cancer, a meta-analysis combining 16 studies and ~2,700 patients concluded that the increased risk (odds ratio) associated with rs1801133 (T;T) and (C;T) genotypes, was 1.52 (CI 1.31-1.77) and 1.17 (CI 0.99-1.39), respectively, compared to the (C;C) genotype. Roughly the same risks were seen for Caucasians and Asians. Smoking and having low folate levels (presumably from diets low in fruits and veggies) increased the risk for (T;T) individuals from ~1.5x to ~2x, whereas having high folate levels almost reduced the risk for (T;T) genotypes pretty much down to the (C;C) level, ie. the average risk. [PMID 18162478]

Another meta-analysis of three studies on rs1801133 stratified according to dietary folate intake showed an increased risk for individuals with low folate intake (OR=1.37, CI: 0.92-2.06 for head and neck and OR=1.28, CI: 0.97-1.68 for lung) versus high folate intake (OR=0.85, CI: 0.63-1.16 for head and neck, and OR=0.94, CI: 0.79-1.12 for lung).[PMID 18789576]

rs1801131 and rs1801133 have been linked to increased risk for several types of brain cancer. The highest risk of meningioma was associated with heterozygosity for both MTHFR SNPs (odds ratio 2.11, CI: 1.42-3.12, p=0.002). The corresponding odds ratio for glioma was 1.23 (CI: 0.91-1.66, p=0.02. In general, risks were increased with genotypes associated with reduced MTHFR activity.[PMID 18483342]

Based on a study of 25,000 Caucasian women followed for 11 years (on average), the rs1801133(T;T) genotype individual was less likely to have migraine with aura (odds ratio 0.79, CI: 0.65-0.9 6, p = 0.02) and did not have increased risk for cardiovascular disease. However, if a (T;T) genotype did have migraine with aura, then the risk for cardiovascular disease was increased 3.66 fold (CI: 1.69-7.90, p = 0.001). This was apparently driven by a 4x increased risk for ischemic stroke (multivariable-adjusted relative risk 4.19, CI: 1.38-12.74, p = 0.01).[PMID 18672474]

A study of 677 patients with end-stage renal disease (ESRD) concluded that the adjusted hazard ratio for mortality in all patients was 2.27 (CI: 1.07 - 4.84, p = 0.03) for rs1801133(T;T) homozygotes, in other words, they died at about twice the rate of the other 2 genotypes over the time course of this study.[PMID 19272686]

[PMID 19648163] A 2-year follow-up study of 122 newly diagnosed patients with acute lymphoblastic leukemia (ALL) found that carriers of a rs1801133(T) allele were at increased risk for hepatic toxicity from methotrexate treatment. Hepatic toxicity was increased ~2x and ~5x for heterozygous and homozygous rs1801133(T) genotypes, respectively (p=0.028). If a carrier of a rs1801133(T) allele was also a carrier of a rs70991108 deletion allele, the risk for hepatic toxicity was even higher (odds ratio 6.8, p=0.018).

Note: Another SNP in dbSNP, rs59514310, represents the same location as rs1801133.

blog The MTHFR gene polymorphism is associated with lean body mass but not fat body mass

10.1007/s00223-010-9361-4 rs1801133(T;T) post-menopausal women said to be at 2x higher risk for osteoporosis.

[PMID 19332210] Candidate genetic variants in the fibrinogen, methylenetetrahydrofolate reductase, and intercellular adhesion molecule-1 genes and plasma levels of fibrinogen, homocysteine, and intercellular adhesion molecule-1 among various race/ethnic groups: Data from the Women's Genome Health Study

[PMID 19336565] Folate Intake, Methylenetetrahydrofolate Reductase Polymorphisms, and Breast Cancer Risk in Women from the Malmo Diet and Cancer Cohort.

[PMID 19465420] MTHFR polymorphisms and 5-FU-based adjuvant chemotherapy in colorectal cancer

[PMID 19493349] 118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects

[PMID 19737740] Associations of folate and choline metabolism gene polymorphisms with orofacial clefts

[PMID 19746410] Association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and age of onset in schizophrenia

[PMID 19744961] Genome-wide significant predictors of metabolites in the one-carbon metabolism pathway

[PMID 19759169] Increased breast cancer risk at high plasma folate concentrations among women with the MTHFR 677T allele

[PMID 20031128] Cardiorespiratory fitness modifies the association between the UCP3-55C>T (rs1800849) polymorphism and plasma homocysteine in Swedish youth

GWAS snp
PMID	[PMID 20031578]
Trait	Plasma homocysteine
Title	Novel Associations of CPS1, MUT, NOX4, and DPEP1 With Plasma Homocysteine in a Healthy Population: A Genome-Wide Evaluation of 13 974 Participants in the Women's Genome Health Study
Risk Allele	A
P-val	8E-35
Odds Ratio	0.05 [NR] unit increase in log(homocysteine)

[PMID 20056627] Genetic variability in the MTHFR gene and colorectal cancer risk using the colorectal cancer family registry

[PMID 20154341] Genome-wide association study of homocysteine levels in Filipinos provides evidence for CPS1 n women and a stronger MTHFR effect in young adults

[PMID 20421849] Habituation in prepulse inhibition is affected by a polymorphism on the NMDA receptor 2B subunit gene (GRIN2B)

[PMID 19593234] Association analyses suggest multiple interaction effects of the methylenetetrahydrofolate reductase polymorphisms on timing of menarche and natural menopause in white women

[PMID 20523222] MTHFR genotype and differential evolution of metabolic parameters after initiation of a second generation antipsychotic: an observational study

[PMID 20817226] MTHFR polymorphisms in relation to ovarian cancer risk

[PMID 20863444] Associations between the genetic polymorphisms of MTHFR and outcomes of methotrexate treatment in rheumatoid arthritis

[PMID 20944139] Significant Association of Methylenetetrahydrofolate Reductase Single Nucleotide Polymorphisms with Prostate Cancer Susceptibility in Taiwan

[PMID 20946434] MTHFR 677C>T Polymorphism and Cluster Headache

Gene-wide association study between the methylenetetrahydrofolate reductase gene (MTHFR) and schizophrenia in the Japanese population, with an updated meta-analysis on currently available data. [PMID 20692813]

[PMID 21125565] Folate pathway and nonsyndromic cleft lip and palate

[PMID 21178087] Polymorphisms in Serine Hydroxymethyltransferase 1 and Methylenetetrahydrofolate Reductase Interact to Increase Cardiovascular Disease Risk in Humans

[PMID 21210953] MTHFR polymorphisms and cognitive ageing in the ninth decade: the Lothian Birth Cohort 1921

[PMID 21254359] Folate pathway and nonsyndromic cleft lip and palate

[PMID 21291465] The association of genetic polymorphisms with cerebral palsy: a meta-analysis

[PMID 21302350] rs1801133 shows no consistent association with schizophrenia overall in 12 studies totaling 3,000+ patients

[PMID 21567207] Tetra primer ARMS-PCR relates folate/homocysteine pathway genes and ACE gene polymorphism with coronary artery disease

[PMID 21635773] Methylenetetrahydrofolate Reductase Gene Variant (MTHFR C677T) and Migraine: A Case Control Study and Meta-analysis

[PMID 21980405] A Hypomethylating Variant of MTHFR, 677C>T, Blunts the Neural Response to Errors in Patients with Schizophrenia and Healthy Individuals

[PMID 22015309] MTHFR (677 and 1298) and IL-6-174 G/C genes in pathogenesis of Alzheimer's and vascular dementia and their epistatic interaction

[PMID 21429654] Polymorphic variants of folate and choline metabolism genes and the risk of endometriosis-associated infertility

[PMID 22044028] The C677T polymorphism in the MTHFR gene is associated with the toxicity of methotrexate in a Spanish rheumatoid arthritis population

[PMID 22103680] Folate network genetic variation, plasma homocysteine, and global genomic methylation content: a genetic association study

[PMID 22144047] A single-nucleotide polymorphism in the MTHFR (methylene tetrahydrofolate reductase) gene is associated with risk of radiation pneumonitis in lung cancer patients treated with thoracic radiation therapy

[PMID 22283972] C677T and A1298C Polymorphisms of MTHFR Gene and Their Relation to Homocysteine Levels in Turner Syndrome

[PMID 21913742] Genetic predictors of response to photodynamictherapy

[PMID 22440940] The rs1801133 polymorphism of methylenetetrahydrofolate reductase gene- the association with 5-year survival in patients with ST-elevation myocardial infarction

[PMID 22363213] Homocysteine and Coronary Heart Disease: Meta-analysis of MTHFR Case-Control Studies, Avoiding Publication Bias

[PMID 22457816] Association of the MTHFR A1298C Variant with Unexplained Severe Male Infertility