Rs1801133

From SNPedia

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):

• coronary artery disease
• neural tube defects
• migraine
• thrombosis
• preeclampsia
• cleft lip/palate
• autism
• depression
• schizophrenia
• cancer, including
  • gastric cancer
  • lung cancer
  • head and neck cancer

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

[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