Accumulation of somatic mutation in mitochondrial DNA and atherosclerosis in diabetic patients.
A point mutation of mitochondrial DNA at nucleotide position 3243 A to G is responsible for the genetic cause of diabetes. Otherwise, this mutation is also reported to occur as a somatic mutation, possibility because of oxidative stress. Because diabetes may cause oxidative stress, we hypothesized that accumulation of the somatic A3243G mutation in mitochondrial DNA may be accelerated by diabetes. DNA was extracted from blood samples of 290 nondiabetic healthy subjects (aged 0-60 years) and from 383 type 2 diabetic patients (aged 18-80 years). Then, the extent of somatic A3243G mutation in total mitochondrial DNA was detected by real-time polymerase chain reaction (PCR) using the TaqMan probe. The genotyping of ACE I/D or p22phox C242T was done by PCR or PCR-restriction fragment length polymorphism. Although the level of the A3243G mutation was negligible in the newborn group, it increased in healthy subjects aged 20-29 and 41-60 years. In diabetic patients, the mutational rate increased along with age and the duration of diabetes. In the middle-aged group (41-60 years old), the A3243G mutation accumulates fourfold higher in the diabetic patients than in the healthy subjects. Moreover, multiple regression analysis revealed that the most critical factor associated with this mutation in diabetic patients was the duration of diabetes. Furthermore, the genotype of DD, DI-CC (ACE-p22phox) has the highest mutational rate and the thickest intima-media thickness of the carotid artery. In conclusion, diabetes accelerates the accumulation of the somatic A3243G mutation in mitochondrial DNA, and this somatic mutation may be a marker for the duration of diabetes and atherosclerosis.
Nomiyama
Takashi
T
Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo, Japan.
Tanaka
Yasushi
Y
Piao
Lianshan
L
Hattori
Nobutaka
N
Uchino
Hiroshi
H
Watada
Hirotaka
H
Kawamori
Ryuzo
R
Ohta
Shigeo
S
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001161:Arteriosclerosis / Q000235:genetics / Q000503:physiopathology*; D002648:Child; D002675:Child, Preschool; D004272:DNA, Mitochondrial / Q000235:genetics*; D048909:Diabetes Complications; D003920:Diabetes Mellitus / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D017354:Point Mutation
D004272:DNA, Mitochondrial