hOGG1 polymorphism correlates with progression of IgA nephropathy
Authors: Fukushima T , Sasaki T , Arakawa S , Fujimoto S , Horike H , Hatta H , Kashihara N 
Published: March 2003

DNA damage generated by reactive oxygen species (ROS) has been implicated in ageing and in the pathogenesis of cardiovascular disease. Reactive oxygen species have also been demonstrated to play a crucial role in the pathophysiology of various renal diseases. They are extremely vulnerable to oxidative stress because mitochondria are the major intracellular source of ROS and have limited protection from oxidative stress. We have found increased accumulation of 8‐hydroxy‐2′‐deoxyguanosine (8‐OH‐dG), which is a product and bio‐marker of oxidative DNA damage, in the mitochondria of glomeruli and tubules in patients with IgA GN. The hOGG1 gene encodes a DNA glycosylase that excises 8‐OH‐dG from damaged DNA. Recently, genetic polymorphism of Ser(S)326Cys(C) has been reported. In addition, the enzymatic activity of hOGG1 in the repair of 8‐OH‐dG has been reported to be greater with S than with C.

In this study, we investigated the correlation between hOGG1 polymorphism and the clinical phenotypes in Japanese patients with IgA GN. A total of 100 patients with IgAGN with a clinical course of over 7 years duration whose diagnosis was made by renal biopsy were divided into the ‘CRF group’ and the ‘fair group’. The CRF group consisted of 30 patients whose creatinine clearance (Ccr) had fallen to less than 50% of that during the initial period or they had developed end stage renal failure (ESRF). The fair group consisted of 62 patients whose Ccr had been kept at over 80% of that during the initial period, even 7 years after the diagnosis. The patients were genotyped and their clinical findings were compared. One hundred healthy Japanese subjects with normal urinalysis and renal function were analysed. The patients and controls were informed of the ethical approval of this study before entry into the study. The genotype of the hOGG1 gene was determined using the PCR‐SSCP method followed by direct sequencing analysis. The details of PCR‐SSCP methods have been previously described.1 Clinical and biochemical data were extracted from case records. Blood pressure was evaluated as the average during 1 week of the patient’s hospitalization for a first renal biopsy. Proteinuria was also evaluated as the average data obtained from 24 h collected urine samples for a week. Significant differences in allele frequency and genotype between groups were tested by χ2 test. Biochemical and clinical data were tested by ANOVA and the t‐test.

We found a high frequency of the C allele in the CRF group compared to the fair group and controls (P < 0.05, Table 1). The frequency of ESRF patients was significantly higher among the patients with the CC genotype than in those woth the CS and SS genotype (CC, CS, SS = 50%, 27%, 16%; CC vs CS, P < 0.05; CC vs SS, P < 0.01; Fig. 1).

Genotype and allele frequencies in each group

image

Frequency of ESRF patients in each group.

image

The creatinine increase rate CC, CS, SS = 0.6090 ± 0.924, 0.1998 ± 0.561, 0.0766 ± 0.2558 mg/dL per year, P < 0.05, Table 2) and proteinuria (CC, CS, SS = 1.89 ± 2.24, 1.02 ± 1.07, 1.17 ± 1.57 (g/24 h), P < 0.05) were significantly higher in the patients with the C allele than in those with the S allele.

Creatinine increase rate and proteinuria in each group

CC
CS
SS

Crn increase rate
0.6090 ± 0.924
0.1998 ± 0.561
0.0766 ± 0.2558
(mg/dL per year)

Proteinuria
1.89 ± 2.24
1.02 ± 1.07
1.17 ± 1.57
(g/24 h)

P < 0.05

These findings indicate that the polymorphism of the hOGG1 gene is associated with progression of IgA GN. hOGG1 polymorphism correlates with the amount of proteinuria and a decreasing speed of renal function. In this study, the patients with the CC genotype tended to fall into ESRF. A previous study disclosed that the ability to excise 8‐OH‐dG is greater with the S allele than with the C allele.2 These facts suggest that accumulation of oxidative DNA damage might be an important factor in the progression of IgA GN. Excision oxidative DNA damage, which is genetically decided, may play an important role in IgA GN.