rs2031920 — CYP2E1 *5B (RsaI)

CYP2E1 *5B — When Your Liver Burns Hotter

CYP2E1 is the enzyme your liver uses to metabolize ethanol, acetaminophen, industrial solvents, and dozens of environmental procarcinogens. It is also one of the most prolific generators of reactive oxygen species in the body — every time CYP2E1 processes a substrate, it produces free radicals as a byproduct. The *5B variant (rs2031920) sits 2 kb upstream of the gene in the promoter region, where it alters the transcriptional response to ethanol, ketones, and fasting. Carriers of the T allele have a more inducible CYP2E1 — their enzyme ramps up higher in response to triggers, generating more oxidative stress with each exposure. The variant is rare in Europeans (~3%) and Africans (<1%) but occurs in roughly 1 in 5 East Asians, making it a particularly important pharmacogenomic consideration in those populations.

The Mechanism

The -1053C>T substitution (the *5B RsaI polymorphism) falls within the 5' upstream regulatory region¹¹ upstream regulatory region
non-coding region upstream of the gene that controls how strongly and how often the gene is transcribed of CYP2E1. The T allele creates altered binding affinity for transcription factors that respond to ethanol, starvation, and insulin suppression. The functional result is a higher peak expression level after exposure: when an enzyme surge occurs, the T allele carrier's CYP2E1 climbs higher and stays elevated longer. Because CYP2E1 is an inherently leaky enzyme²² leaky enzyme
CYP2E1 has an unusually high rate of uncoupled catalysis — electrons escape the reaction and reduce oxygen to superoxide rather than finishing the productive catalytic cycle with a high rate of reactive oxygen species³³ reactive oxygen species
ROS: unstable oxygen-containing molecules that damage proteins, lipids, and DNA generation, this induction translates directly into elevated oxidative stress in the liver and other tissues.

The Evidence

Colorectal cancer: A 2013 meta-analysis of 17 studies comprising 17,082 individuals⁴⁴ 2013 meta-analysis of 17 studies comprising 17,082 individuals
Peng H et al. Associations of CYP2E1 rs2031920 and rs3813867 polymorphisms with colorectal cancer risk. Tumour Biology, 2013 found the c2 (T) allele associated with a significant increase in colorectal cancer risk (OR 1.19, 95% CI 1.03–1.37). This was confirmed by a 2022 meta-analysis of 23,598 subjects across 18 studies⁵⁵ 2022 meta-analysis of 23,598 subjects across 18 studies
Sharzehan MA et al. Association between CYP2E1 polymorphisms and colorectal cancer risk. Scientific Reports, 2022, which found an even stronger association in the homozygous model (OR 1.50, 95% CI 1.18–1.90).

Alcoholic liver disease: A case-control study in Indian patients⁶⁶ case-control study in Indian patients
Khan AJ et al. Polymorphism in CYP2E1 and susceptibility to alcoholic liver cirrhosis. Mutation Research, 2009 found the *5B T-A-T haplotype associated with a 4.3-fold increased risk of alcoholic cirrhosis (OR 4.3, 95% CI 1.5–12.4) compared to non-alcoholic controls, rising to 5.4-fold against non-alcoholic cirrhosis patients. A Mexican study found the c2 allele twice as common in cirrhosis patients as in controls (19.5% vs 10.6%)⁷⁷ c2 allele twice as common in cirrhosis patients as in controls (19.5% vs 10.6%)
García-Bañuelos J et al. Genetic polymorphisms of alcohol-metabolizing enzymes in western Mexicans. Alcohol Clin Exp Res, 2012, with c2 carriers also showing worse liver function parameters.

Lung cancer and smoking interactions: A Japanese case-control study of 841 participants⁸⁸ case-control study of 841 participants
Kakino K et al. CYP2E1 rs2031920, COMT rs4680 and lung cancer in Japanese population. Asian Pac J Cancer Prev, 2016 found that the CC genotype (no T allele) in heavy smokers conferred OR 3.57 (95% CI 2.26–5.63) for lung cancer compared to non-smoking T-allele carriers — a complex interaction suggesting that the T allele's role in carcinogen activation depends on exposure context.

Benzene toxicity: The CYP2E1 rapid metabolizer phenotype (which the c2 allele promotes) combined with NQO1 TT genotype (rs1800566) was found to produce 8- to 21-fold increased benzene poisoning risk⁹⁹ 8- to 21-fold increased benzene poisoning risk
Wan J et al. Genetic polymorphisms in CYP2E1, MPO, NQO1, GSTM1, GSTT1 and benzene poisoning. Environ Health Perspect, 2002.

Practical Actions

The *5B variant matters most when CYP2E1 is actively engaged — during alcohol consumption, acetaminophen use, fasting, and occupational chemical exposures. The T allele's higher inducibility means that the same exposure produces greater oxidative stress in a T-carrier's liver than in a CC individual. The most directly modifiable risk factors are acetaminophen dose and alcohol consumption. Antioxidant support (particularly NAC, which replenishes glutathione depleted by CYP2E1-generated ROS) is a targeted intervention specifically relevant to this variant.

Interactions

The most clinically important interaction is with rs1800566 (NQO1 C609T). NQO1 normally detoxifies CYP2E1-generated quinones and reactive metabolites; when both CYP2E1 is overactive (rs2031920 T allele) and NQO1 is absent or reduced (rs1800566 TT), the combined risk for benzene toxicity and related haematotoxicity is multiplicative rather than additive, reaching 8- to 21-fold increased risk in occupationally exposed workers. The companion promoter SNP rs3813867 (CYP2E1 *6, DraI polymorphism) tags the same haplotype block and is often studied together with rs2031920; however, multiple meta-analyses find that rs3813867 alone has no significant effect on cancer risk whereas rs2031920 does.