Rs4880

The rs4880(T) allele, part of the codon for amino acid valine at codon 16 of the antioxidant protein from the mitochrondrial superoxide dismutase 2 SOD2 gene, is the most common in most populations studied. The rs4880(C) allele gives rise to an alanine at this position is it also known as Val16Ala manganese superoxide dismutase.

There appears to be some conflict in the literature over the effect of this SNP. Having a valine at codon 16 is said to reduce enzyme activity [PMID 15864132], and thus lead to increased oxidative stress, yet in at least one study of the actual enzyme levels measured in people, SOD2 activity was 33% higher in (C;T) or (T;T) individuals compared to (C;C) individuals [PMID 16538174]. Regardless of how this resolves, several phenotypic associations have been reported for this SNP, including:

• A 10 fold higher risk for heart disease in hereditary hemochromatosis patients with rs4880(T;T) genotypes compared to similar patients with rs4880(C;T) or rs4880(C;C) genotypes. [PMID 15591282]

• An increased risk of malignant pleural mesothelioma (MPM) was found in individuals with rs4880(C;C) (OR = 3.07, CI: 1.55-6.05) genotypes. Odds ratios for developing mesothelioma were even higher for patients lacking obvious exposure to asbestos fibers. [PMID 17290392]

• Among prostate cancer patients with a rs4880(T;T) genotype, but not the (C;C) genotype, higher iron intake level was associated with a 2.3-fold increase in risk for aggressive forms of the cancer (OR=2.3, CI: 1.0-4.9).[PMID 18296681]

• rs4880(C;T) prostate cancer patients being treated by radiation therapy are more likely (8% compared to 0%, p=0.02) to exhibit a significant increase in grade 2 late rectal bleeding after irradiation than (C;C) or (T;T) patients, based on a study of 135 patients. The odds for this are worse if the patient also has the rs861539(C;T) genotype (14% vs 1%, p=0.002).[PMID 18582155]

• A study of non-Hispanic Caucasians with various types of brain tumors concluded that there was an increased risk of acoustic neuroma (odds ratio 2.0, CI: 1.1-2.7) associated with the alanine-encoding rs4880(C) allele.[PMID 18682580]

• rs4880(C) carriers with breast cancer and being treated with cyclophosphamide had worse survival rates (i.e. didn't benefit as much), based on a study of 248 US and 340 Norwegian patients.[PMID 19509150]

• See also OMIM 147460.0001

• Note: rs1799725 was combined into rs4880 by dbSNP

The C allele of rs4880 appears to be associated with Alzheimer's disease. [PMID 17376152] rs2758346 rs4880 and rs2855116 association with Alzheimer's disease

[PMID 19493484] Association between SNPs in SOD2 and noise-induced hearing loss

[PMID 19706356] Functional polymorphism in manganese superoxide dismutase and antioxidant status: Their interactions on the risk of cervical intraepithelial neoplasia and cervical cancer

[PMID 19753309] SOD2 gene polymorphisms in neovascular age-related macular degeneration and polypoidal choroidal vasculopathy

[PMID 19778569] Oxidative stress in tardive dyskinesia: Genetic association study and meta-analysis of NADPH quinine oxidoreductase 1 (NQO1) and Superoxide dismutase 2 (SOD2, MnSOD) genes

[PMID 19863340] Influence of the polymorphism in candidate genes on late cardiac damage in patients treated due to acute leukemia in childhood

[PMID 20043000] Association of SOD2, a Mitochondrial Antioxidant Enzyme, with Gray Matter Volume Shrinkage in Alcoholics

[PMID 20082738] Inter-individual variation in DNA damage and base excision repair in young, healthy non-smokers: effects of dietary supplementation and genotype

[PMID 20534900] SOD2 V16A SNP in the mitochondrial targeting sequence is associated with noise induced hearing loss in Chinese workers

[PMID 20378690] Genetic variants in selenoprotein genes increase risk of colorectal cancer

[PMID 21062213] Manganese superoxide dismutase dimorphism relationship with severity and prognosis in cardiogenic shock due to dilated cardiomyopathy

[PMID 21567099] Estrogen metabolism genotypes, use of long-term hormone replacement therapy and risk of postmenopausal breast cancer

[PMID 21795425] Genetic Variation in Myeloperoxidase Modifies the Association of Serum {alpha}-Tocopherol with Aggressive Prostate Cancer among Current Smokers

[PMID 21915362] Sequence variants in antioxidant defense and DNA repair genes, dietary antioxidants, and pancreatic cancer risk

[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 22206979] Genetic variants in antioxidant genes are associated with sperm DNA damage and risk of male infertility in a Chinese population

[PMID 21338322] Parameters of oxidative stress, DNA damage and DNA repair in type 1 and type 2 diabetes mellitus

[PMID 21351093] Association of superoxide dismutases and NAD(P)H quinone oxidoreductases with prognosis of patients with breast carcinomas