Rosenblum et al. (1996) identified a 47C-T transition in the SOD2 gene, which resulted in a change from GCT (alanine) to GTT (valine) at codon 16 (ala16 to val; A16V).
Hiroi et al. (1999) observed that processing efficiency of the V-type SOD2 leader peptide in the presence of mitochondria was significantly lower than that of the A type, by 11 +/- 4%.
Bastaki et al. (2006) analyzed SOD2 activity in isolated mitochondria from healthy nonsmokers and found that activity was 15% higher in females than in males, and 33% higher in individuals with the CT or TT genotype of the 47C-T polymorphism versus CC individuals.
Susceptibility to Cardiomyopathy
Hiroi et al. (1999) found an increased frequency for the SOD2-VV genotype (homozygosity for the valine (V) allele vs the alanine allele) in Japanese with nonfamilial idiopathic cardiomyopathy (IDC) and suggested that this polymorphism may collaborate with the DRP1*1401 allele of the HLA-DRB1 gene (142857) in controlling the susceptibility to nonfamilial IDC.
The val16 allele disrupts the alpha-helix structure of SOD2 and causes the protein to be retained at the level of the mitochondrial inner membrane. The mutant protein has 30 to 40% lower activity and increases susceptibility to oxidative stress. Valenti et al. (2004) found a significantly increased frequency of the val16 allele among 217 unrelated patients with hereditary hemochromatosis (235200) who developed dilated or nondilated cardiomyopathy compared to HH patients without cardiomyopathy and controls (frequencies of 0.67, 0.45, and 0.52, respectively). The val/val genotype conferred a 10.1-fold increased risk for cardiomyopathy in the HH patients. The association was independent of cirrhosis, diabetes, arthropathy, and hypogonadism, and did not apply to ischemic heart disease. Valenti et al. (2004) concluded that the val16 allele increased the risk of cardiomyopathy due to iron overload toxicity and oxidation in HH patients as a result of decreased activity of the SOD2 enzyme.
Susceptibility to Microvascular Complications of Diabetes 6
Among Japanese patients with type 2 diabetes (125853), Nomiyama et al. (2003) found a significantly higher frequency of the VV genotype than the AA or VA genotypes in patients with diabetic nephropathy (MVCD6; 612634). They concluded that the A16V polymorphism may be unrelated to the etiology of type 2 diabetes, but is associated with diabetic nephropathy in Japanese patients with type 2 diabetes.
Mollsten et al. (2007) analyzed the SOD2 A16V polymorphism (rs4880) in 1,510 Finnish and Swedish patients with type 1 diabetes (222100), including 955 patients with diabetic nephropathy and 555 controls with diabetes for more than 20 years without albuminuria or antihypertensive treatment. After controlling for age at onset, diabetes duration, hemoglobin A1C, smoking, and gender, the VV genotype was associated with an increase in the risk of diabetic nephropathy (odds ratio, 1.32; p = 0.049). Logistic regression analysis showed that the high-risk group, VV patients who had ever smoked, had a 2.52-fold increased risk for diabetic nephropathy compared to the low-risk group, supporting the hypothesis that oxidative stress contributes to the development of diabetic nephropathy.
