Functional Variants in the Glutathione Peroxidase‐1 (Gpx‐1) Gene Are Associated With an Increased Risk of Keshan Disease

Keshan disease (KD) is an endemic fatal cardiomyopathy in China. Its etiology is unclear, but might associate with the deficiency in selenium and lower activity of glutathione peroxidase‐1 (Gpx‐1), a selenoprotein. In this study, we screened 71 KD patients and 290 controls, and found that levels of blood selenium and Gpx‐1 activity in KD patients were significantly lower. Two variants (Ala 5/6/7 and Pro198Leu) were identified, in which Pro198Leu was statistically differently distributed between the KD patients and the external controls, while the frequency of Ala 5/6/7 allele was extremely low. The level of selenium and Gpx‐1 activity in group with Pro/Leu or Leu/Leu on codon 198 polymorphisms were significantly lower than in group with Pro/Pro. The prevalence of variants inversely increased along with the decrease of selenium level, suggesting that low selenium may increase in susceptibility of genomic mutation. Further analysis revealed a synergistic‐multiplicative interaction between Gpx‐1 codon198 alleles and low blood selenium. An in vitro study in neonatal rat myocytes showed that overexpression of Gpx‐1(198Leu) caused a 30% decrease in enzyme activity and less responsive to increasing concentrations of selenium, when compared with Gpx‐1(198Pro). Thus, low blood selenium in carriers with 198Leu susceptible genotype is associated with lower enzyme activity, which may, in turn, increase the risk of KD.