한국인에서 PGC-1유전자의 G144A 단일염기다형성과 미토콘드리아의 DNA및 제 2형 당뇨병과의 상관관계

Abstract

Objective: It has been reported that mitochondrial dysfunction may cause diabetic development. Mitochondrial dysfuction would be induced by defects in mitochondrial DNA (mtDNA) or the nuclear DNA-encoded proteins required for regulation of mitochondrial biogenesis. One of the cadidate diabetic susceptibility genes is peroxisome proliferation activated receptor-gamma (PPAR-gamma) coactivator-1 (PGC-1), which regulates mitochondrial biogenesis as well as functions in adipogenesis, lipid metabolism and gluconeogenesis. This study was performed to identify the genetic polymorphisms of PGC-1 and their association with diabetes mellitus and insulin-resistant related indices and mtDNA content. Methods: The PGC-1 gene was examined in 49 type 2 diabetic patients and 46 normal controls applying PCR-single strand conformational polymorphism (PCR-SSCP) analysis. The Gly482Ser variant among the identified 4 variants were further genotyped by PCR-RFLP using MspI in 133 offsprings of diabetic patients and 161 gestational diabetic patients. The mtDNA contents of all samples were quantified by real time PCR. The statistical difference in genotype distribution and allele frequencies among groups was assessed by 2 test. Comparison of variables between groups of genotypes was performed by Student's t-test or ANOVA test. Results: A total of four variants G1182A (Thr394Thr), C1428G (Asp476Glu), G1444A (Gly482Ser) and A1584G (Thr528Thr) were identified in exon 8 of PGC-1. No variation was observed in the regions of other exons except exon 8. The frequencies of G1182A, C1428G, G1444A and A1584G were 10%, 18%, 42%, and 15%, respectively. For G1444A (Gly482Ser), as a functional polymorphism, Gly/Ser (G/A) heterozygout frequency was 55% for DM group and 35% for normal subjects. Interestingly, the peripheral blood mtDNA contents of the subjects with Gly/Gly genotype was decreased 20% compared to those with Gly/Ser or Ser/Ser (p=0.011 and p=0.057, respectively). Conclusion: In Korean diabetic patients, Gly/Ser frequency was higher than the caucasians. The mtDNA copy number of Gly/Gly genotype was 20% lower than the genotypes with Ser allele. The results suggest that PGC-1 with the Gly/Gly genotype might impair the regulatory function of mitochondrial biogenesis, resulting in dysfunction of mtDNA replication, insulin resistance, and type 2 diabetes in consequence.