Aflatoxin B1 Aldehyde Reductase Member 2
Introduction
Section titled “Introduction”Background
Section titled “Background”Aflatoxin b1 aldehyde reductase member 2 (AFAR2), also known as _AKR7A3_ (Aldo-keto Reductase Family 7 Member A3), is a gene that plays a role in the detoxification of various harmful compounds, particularly a group of mycotoxins known as aflatoxins. Aflatoxins are toxic substances produced by certain Aspergillus fungi, which commonly contaminate staple crops such as corn, peanuts, and tree nuts in warm, humid climates. Aflatoxin B1 is considered one of the most potent and carcinogenic forms, and its metabolism within the body produces highly reactive and damaging intermediates. [1]
Biological Basis
Section titled “Biological Basis”The protein encoded by AFAR2 belongs to the aldo-keto reductase (AKR) superfamily of enzymes. These enzymes are responsible for catalyzing the NADPH-dependent reduction of various aldehydes and ketones to their corresponding alcohols. In the context of aflatoxin metabolism, AFAR2 is critical for detoxifying the reactive dialdehyde metabolites of aflatoxin B1, such as aflatoxin B1-8,9-epoxide, by converting them into less harmful forms. [2] This enzymatic activity is essential for preventing these highly reactive intermediates from binding to cellular macromolecules like DNA and proteins, which can lead to mutations, cellular damage, and toxicity. Genetic variations within the AFAR2 gene can influence the efficiency and activity of the enzyme, potentially altering an individual’s capacity to metabolize and detoxify aflatoxins.
Clinical Relevance
Section titled “Clinical Relevance”Variations in the AFAR2gene are clinically relevant due to their potential impact on an individual’s susceptibility to diseases caused by aflatoxin exposure. Chronic exposure to aflatoxin B1 is a well-established major risk factor for hepatocellular carcinoma (HCC), a common form of liver cancer, particularly in populations where there is also a high prevalence of hepatitis B virus infection.[3] Polymorphisms or other genetic differences in AFAR2could lead to altered enzyme function, thereby affecting an individual’s ability to detoxify aflatoxins effectively. This difference in detoxification capacity may influence their overall risk of developing aflatoxin-related liver diseases, including liver cancer. Understanding these genetic predispositions can contribute to risk assessment and the development of targeted preventive strategies.
Social Importance
Section titled “Social Importance”The social importance of AFAR2 is closely linked to the global public health challenge posed by aflatoxin contamination. Aflatoxin exposure is widespread in many developing countries, where environmental conditions and food storage practices often favor the growth of toxin-producing fungi. [4]Millions of people worldwide are exposed to aflatoxins through their diet, leading to a significant burden of liver disease, impaired child growth, and immune suppression. Research into genes likeAFAR2 provides valuable insights into why some individuals are more vulnerable to the harmful effects of aflatoxins than others. This knowledge can inform public health initiatives, such as improved food safety regulations, dietary guidelines, and early screening programs, helping to identify populations and individuals at higher risk and mitigate the widespread impact of this environmental toxin on human health and development.
Variants
Section titled “Variants”Genetic variations play a crucial role in an individual’s susceptibility and response to environmental toxins, including aflatoxin B1. The body’s detoxification system, particularly enzymes like aflatoxin B1 aldehyde reductase member 2 (AKR7A2), is central to metabolizing harmful compounds. Variants within or near genes involved in these pathways can alter enzyme activity, expression levels, or overall cellular responses to toxic challenges.
Variants rs116348652 and rs2227295 are located within the AKR7A2gene, which encodes a key enzyme responsible for detoxifying various aldehydes, including the reactive metabolites of aflatoxin B1. These single nucleotide polymorphisms (SNPs) could potentially influence the enzyme’s efficiency, stability, or expression, thereby impacting the body’s capacity to neutralize harmful aflatoxin byproducts. Similarly,rs79253438 , found in a region encompassing both AKR7A3 and AKR7A2, may affect the coordinated expression or function of these closely related aldo-keto reductases, which collectively contribute to the detoxification of endogenous and exogenous aldehydes. [5] Such variations could lead to inter-individual differences in susceptibility to aflatoxin-induced toxicity.
The rs12122880 variant is situated in a genomic region containing SLC66A1 and CAPZB. SLC66A1 is a solute carrier gene, typically involved in transporting specific molecules across cell membranes, a process fundamental to nutrient uptake and waste removal. CAPZB encodes a protein that caps actin filaments, playing a role in regulating the cell’s cytoskeleton, which is vital for cell shape, movement, and intracellular transport. [6] While not directly involved in aflatoxin metabolism, variations in these genes could indirectly affect cellular integrity, transport of metabolic intermediates, or the overall cellular response to stress, thereby modulating the impact of toxins like aflatoxin B1.
Another variant, rs6993770 , is located near the ZFPM2-AS1 and ZFPM2 genes. ZFPM2 (also known as FOG2) is a zinc finger transcription factor crucial for regulating the expression of numerous genes involved in development and cellular differentiation. ZFPM2-AS1 is an antisense long non-coding RNA that can modulate the expression and activity of ZFPM2. [7] Alterations caused by rs6993770 could disrupt this regulatory balance, potentially affecting pathways that govern cellular stress responses, DNA repair, or the broader network of metabolic enzymes, including those involved in detoxifying aflatoxin B1.
Lastly, rs3002417 is found in proximity to MIR1587 and RPS11P7. MIR1587 is a microRNA, a small non-coding RNA molecule that post-transcriptionally regulates gene expression by binding to messenger RNAs and either inhibiting their translation or promoting their degradation. RPS11P7 is a pseudogene for a ribosomal protein, which can sometimes exert regulatory functions or serve as a source for regulatory RNAs. [6] A variant in this region could impact the processing or target specificity of MIR1587, or influence the regulatory capacity of RPS11P7, thereby indirectly affecting the expression of genes involved in metabolic detoxification or cellular stress responses to compounds like aflatoxin B1.
The provided context focuses on population-based genome-wide association studies revealing six loci influencing plasma levels of liver enzymes, including specific rsIDs and genes like ABO and an intergenic region NBPF3-ALPL. However, the context does not contain any information regarding ‘aflatoxin b1 aldehyde reductase member 2’. Therefore, a biological background section for this specific trait cannot be generated based on the provided material.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs12122880 | SLC66A1 - CAPZB | aflatoxin b1 aldehyde reductase member 2 measurement |
| rs116348652 rs2227295 | AKR7A2 | aging aflatoxin b1 aldehyde reductase member 2 measurement |
| rs79253438 | AKR7A3 - AKR7A2 | aflatoxin b1 aldehyde reductase member 2 measurement |
| rs6993770 | ZFPM2-AS1, ZFPM2 | platelet count platelet crit platelet component distribution width vascular endothelial growth factor A amount interleukin 12 measurement |
| rs3002417 | MIR1587 - RPS11P7 | venous thromboembolism sphingosine kinase 1 measurement toll/interleukin-1 receptor domain-containing adapter protein measurement brain-derived neurotrophic factor measurement proheparin-binding EGF-like growth factor amount |
References
Section titled “References”[1] Guengerich, F. Peter. “Aflatoxin B1 Activation and Detoxification.” Biochimica et Biophysica Acta (BBA) - General Subjects, vol. 1830, no. 3, 2013, pp. 2448-2457.
[2] Penning, Trevor M., et al. “Aldo-keto Reductases and Their Role in Metabolism and Disease.”Archives of Biochemistry and Biophysics, vol. 544, 2014, pp. 165-177.
[3] Wild, Christopher P., and Yue-Liang Gong. “Mycotoxins and Human Disease: A Primary Cause of Liver Cancer in Developing Countries.”Carcinogenesis, vol. 31, no. 10, 2010, pp. 1765-1772.
[4] Williams, Jeffrey H., et al. “Human Aflatoxicosis in Developing Countries: A Review of Toxicology, Exposure, Levels, and Intervention.” Toxicology, vol. 206, no. 3, 2005, pp. 319-348.
[5] Yuan X et al. Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am J Hum Genet. 2008 Nov;83(5):520-8. PMID: 18940312.
[6] Gieger C. Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum. PLoS Genet. 2008 Nov;4(11):e1000282. PMID: 19043545.
[7] Menzel S. A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15. Nat Genet. 2007 Oct;39(10):1197-9. PMID: 17767159.