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
 * renal cancer
 * cleft lip and cleft palate
 * coronary artery disease
 * dementia
 * depression
 * hyperhomocysteinemia
 * migraine
 * neural tube defects
 * pre-eclampsia (gestational hypertension)
 * schizophrenia
 * thrombosis
 * down syndrome

PubMed lists over 2,300 studies linking Rs1801133 to a long list of disorders in various populations across the world, of which only some are mentioned above. Considering the central role of MTHFR in folate metabolism and in control of homocysteine levels this is not surprising. A nice summary of the pathological significance of elevated homocysteine levels could be found in this article.

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.

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 cancer 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 cancer, and OR=0.94, CI: 0.79-1.12 for lung).

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.

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).

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.

In a case-control study of 152 cases (men) and 304 age-matched healthy controls conducted in one geographical area of Iran, evidence was seen that the MTHFR polymorphisms might contribute to increased clear cell renal cell carcinoma (CCRCC) risk in men. After controlling for confounding factors, a significant increase in CCRCC risk was found among carriers of the 677CT genotype compared with those with the 677CC genotype (odds ratio 2.21, 95% confidence interval 1.31-3.76), with a significant trend (P=0.014). Statistically significant odds ratios were also found in patients homozygous for MTHFR C677T, who have a 1.58-fold higher risk of developing CCRCC (95% confidence interval=1.21-2.44; P=0.024). Compared with the MTHFR 677CC genotype, the odds ratio (95% confidence interval) for the MTHFR 677TT genotype was 6.18 (95% confidence interval=4.75-8.34) for stage IV cancer and 4.68 (95% confidence interval=2.72-6.54) for grade 3 CCRCC (both P=0.0001). Clin Oncol (R Coll Radiol). 2012 May;24(4):269-81. doi: 10.1016/j.clon.2011.03.005. Epub 2011 Apr 13.

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

rs1801133(T;T) post-menopausal women said to be at 2x higher risk for osteoporosis.

MTHFR 677C&#8594;T polymorphism is more prevalent among mothers of children with Down syndrome than among control mothers, with an odds ratio of 1.91

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.

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