Won Ki Min

Genetic variations of the paraoxonase gene in patients with coronary artery disease

OBJECTIVES Paraoxonase (PON) plays an important role in preventing low density lipoprotein (LDL) oxidation and thus may be involved in protection against atherosclerosis. Several studies have suggested that genetic variations of the PON gene are associated with plasma HDL levels and coronary artery disease (CAD). This study was conducted to elucidate the association between three polymorphisms of the PON1 and PON2 genes and Korean patients with CAD. DESIGN AND METHODS One hundred ninety-one patients with CAD and 113 age-matched normal controls were examined by polymerase chain reaction (PCR). The PCR products were analyzed for PON polymorphisms by restriction enzyme digestion. RESULTS There was linkage disequilibria between each polymorphism pair in the CAD and control groups. The Hsp92II polymorphism at codon 54 of the PON1 gene was positively associated with HDL-cholesterol levels in the control group (p = 0.02). An association between the AlwI polymorphism and HDL-cholesterol level appeared statistically significant in women of the normal group (p = 0.04). In addition, the DdeI and AlwI polymorphisms were positively associated with HDL (p = 0.02) and LDL (p = 0.03) levels in men of the CAD group, respectively. CONCLUSIONS Our study suggested a gene-gene interaction between the PON1 and PON2 polymorphisms for CAD risk. However, we could not exclude the possibility that these polymorphisms may have linkage disequilibrium with a tightly linked PON3 locus or significant atherosclerotic alleles of nearby genes. Family studies may, therefore, help to confirm the role of the PON polymorphism for CAD risk.

Association between HaeIII polymorphism of scavenger receptor class B type I gene and plasma HDL-cholesterol concentration.

Background: Evidence has recently been found for significant associations between genetic variation within the scavenger receptor class B type I gene (SR-BI), plasma lipids and anthropometric measurements in healthy Caucasians. The present case-control study was conducted to determine whether there is an association between three polymorphisms identified by the restriction endonucleases HaeIII, AluI and ApaI of SR-BI and coronary artery disease (CAD) in Korean subjects. Methods: DNA was extracted from 137 subjects with CAD and 124 age-matched controls; it was amplified using the polymerase chain reaction. Individual alleles at each of the three polymorphic sites were identified by digestion with the appropriate restriction enzyme. Results: Only a single allele was identified at the AluI and ApaI polymorphic sites. The frequency of the common (+) allele at the HaeIII polymorphic site was higher in CAD patients than in the controls (P = 0·001). The concentrations of plasma HDL-cholesterol and apolipoprotein AI also varied significantly among HaeIII genotypes in the CAD patients. The common (+) allele of the HaeIII polymorphism was associated with a lower body mass index in female controls. Conclusions: Allele frequencies of the AluI and ApaI polymorphisms in this study were different to those in a Caucasian population studied previously, suggesting a difference in the genetic background. Further comparative studies of SR-BI polymorphism in other racial or ethnic groups should therefore prove to be of value.

Effect of Increasing Serum Albumin on Serum Lipoprotein(a) Concentration in Patients Receiving CAPD

Lipoprotein(a) [Lp(a)], an independent risk factor for atherosclerotic cardiovascular disease in the general population, is known to be elevated in patients with renal disease accompanied by hypoalbuminemia such as nephrotic syndrome and end-stage renal disease. In this study, the role of hypoalbuminemia in the elevation of serum Lp(a) was investigated in 20 continuous ambulatory peritoneal dialysis (CAPD) patients with serum albumin below 3.5 g/dL. The patients were divided into two groups. In group 1 (n = 10), fasting serum Lp(a) and albumin were measured before, after repeated infusion of 20% albumin 100 mL three times per week for 2 weeks, and 4 weeks after withdrawal of albumin infusion. In group 2 (n = 10), serum albumin and Lp(a) were measured similarly without albumin infusion. C-reactive protein was monitored in both group as an indicator of acute-phase reactant. Serum Lp(a) was also measured in 20 age- and sex-matched normal controls. Apolipoprotein(a) [apo(a)] phenotype was determined in all the subjects. CAPD patients as a whole (n = 20; median, 70.2 mg/dL; interquartile range, 45.0 to 86.2 mg/dL) had higher serum Lp(a) than normal controls (n = 20; median, 9.9 mg/dL; interquartile range, 2.4 to 24.3 mg/dL) (P < 0.0001), although the distribution of apo(a) phenotype was similar. Serum albumin in group 1 increased from 2.6+/-0.5 g/dL to 3.5+/-0.6 g/dL (P < 0.0005) at the end of repeated infusion of albumin, whereas serum Lp(a) decreased from 73.7 mg/dL (range, 43.2 to 89.0 mg/dL) to 25.6 mg/dL (range, 10.7 to 71.7 mg/dL) (P < 0.01). Four weeks after withdrawal of albumin infusion, serum albumin decreased again to 2.9+/-0.5 g/dL (P < 0.001), whereas serum Lp(a) increased to 65.2 mg/dL (range, 43.3 to 106.0 mg/dL) (P < 0.05). Serum albumin in group 2 was 2.8+/-0.6 g/dL, 3.0+/-0.4 g/dL, and 2.9+/-0.7 g/dL, respectively. The change of serum Lp(a) was not significant (67.0 mg/dL [range, 46.8 to 84.8 mg/dL], 62.8 mg/dL [range, 45.1 to 81.0 mg/dL], and 63.0 mg/dL [range, 44.7 to 74.0 mg/dL]). C-reactive protein was stable during the study period in both groups. These findings support the hypothesis that hypoalbuminemia is one of the important trigger factors in the elevation of serum Lp(a) in CAPD patients.

EFFECTS OF HORMONAL REPLACEMENT THERAPY ON OXIDATIVE STRESS AND TOTAL ANTIOXIDANT CAPACITY IN POSTMENOPAUSAL HEMODIALYSIS PATIENTS

Background: Oxidative stress is known to be implicated in the pathogenesis of atherosclerotic cardiovascular disease. Many studies have demonstrated that hormone replacement therapy (HRT) has beneficial effects on oxidation injury in postmenopausal women with normal renal function. In this study, we examined the effects of HRT on plasma malondialdehyde (MDA) level and total antioxidant capacity (TAC) in postmenopausal hemodialysis women. Methods: We randomly assigned 70 postmenopausal women on maintenance hemodialysis into either a HRT group or a control group. Oral conjugated estrogen (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg) was given daily for 12 weeks in HRT group. Plasma MDA, TAC, albumin, uric acid and C-reactive protein (CRP) were measured before, 4 and 12 weeks after the start of medication in the HRT group. In the control group, the same parameters were measured without HRT. Results: There was no difference in baseline values between the two groups. In the control group (n = 32), all these parameters showed no change at 4 and 12 weeks. HRT decreased MDA from 1.32 (0.55–1.88) µM to 1.08 (0.44–1.50) µM (p<0.001) at 4 weeks and to 1.11 (0.50–1.37) µM (p<0.001) at 12 weeks (n = 33). TAC was not changed at 4 weeks, however, it decreased from 1.59 (1.27–2.00) mM to 1.45 (1.08–1.65) mM (p<0.05) at 12 weeks. The albumin, uric acid and CRP levels were not changed significantly after HRT. Conclusions: These results suggest that HRT has a favorable effect on oxidative stress in postmenopausal women with ESRD as in the general population.BACKGROUND Oxidative stress is known to be implicated in the pathogenesis of atherosclerotic cardiovascular disease. Many studies have demonstrated that hormone replacement therapy (HRT) has beneficial effects on oxidation injury in postmenopausal women with normal renal function. In this study, we examined the effects of HRT on plasma malondialdehyde (MDA) level and total antioxidant capacity (TAC) in postmenopausal hemodialysis women. METHODS We randomly assigned 70 postmenopausal women on maintenance hemodialysis into either a HRT group or a control group. Oral conjugated estrogen (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg) was given daily for 12 weeks in HRT group. Plasma MDA, TAC, albumin, uric acid and C-reactive protein (CRP) were measured before, 4 and 12 weeks after the start of medication in the HRT group. In the control group, the same parameters were measured without HRT. RESULTS There was no difference in baseline values between the two groups. In the control group (n = 32), all these parameters showed no change at 4 and 12 weeks. HRT decreased MDA from 1.32 (0.55-1.88) microM to 1.08 (0.44-1.50) microM (p < 0.001) at 4 weeks and to 1.11 (0.50-1.37) microM (p < 0.001) at 12 weeks (n = 33). TAC was not changed at 4 weeks, however, it decreased from 1.59 (1.27-2.00) mM to 1.45 (1.08-1.65) mM (p < 0.05) at 12 weeks. The albumin, uric acid and CRP levels were not changed significantly after HRT. CONCLUSIONS These results suggest that HRT has a favorable effect on oxidative stress in postmenopausal women with ESRD as in the general population.

Serum High-Sensitivity C-Reactive Protein Is Not Increased in Patients with IgA Nephropathy

Background/Aims: The development of renal injury in glomerulonephritis (GN) has been related to systemic inflammatory mediators. We investigated whether serum high-sensitivity C-reactive protein (hs-CRP) is a marker reflecting the inflammatory pathogenesis of primary GN. Methods: We compared serum hs-CRP levels in 192 patients with IgA nephropathy (IgAN), 43 patients with membranous nephropathy (MN), and 25 patients with minimal change disease (MCD) undergoing kidney biopsy and 638 matched controls. Results: There were no differences in hs-CRP levels between controls (median 0.08 mg/dl; range 0.03–1.87 mg/dl) and patients with IgAN (0.08 mg/dl; 0.03–3.13 mg/dl), MN (0.07 mg/dl; 0.03–0.99 mg/dl) or MCD (0.08 mg/dl; 0.03–1.75 mg/dl). In patients with IgAN, hs-CRP levels did not differ according to Haas’ pathological subclasses or subsequent renal outcomes. In the IgAN group, hs-CRP showed positive correlations with IgA, uric acid, systolic blood pressure, BMI and age. Hs-CRP level was significantly higher in male than in female IgAN patients. Serum IgA concentration was the strongest independent correlate with hs-CRP levels, and gender and BMI were also independently associated with hs-CRP. There were no correlations between hs-CRP and markers of disease activity. Conclusion: It is likely that hs-CRP does not closely reflect inflammatory pathogenesis in patients with IgAN, MN and MCD.

Effects of Celecoxib on High‐Sensitivity C‐Reactive Protein in Chronic Peritoneal Dialysis Patients

To evaluate the effects of celecoxib, a cyclooxygenase‐2 inhibitor, on the level of high‐sensitivity C‐reactive protein (hs‐CRP), D‐dimer, von Willebrand factor (vWF) and troponin‐T, 46 chronic peritoneal dialysis (CPD) patients with hs‐CRP equal or greater than 0.25 mg/dL were randomized to the treatment group who took 200 mg of celecoxib daily for 4 weeks or to the control group who did not take the medication. The levels of hs‐CRP, albumin, D‐dimer, vWF and troponin‐T were measured at baseline and at 4 weeks of the study. Baseline values of all the parameters were not significantly different between the two groups. In the control group, the levels of hs‐CRP, albumin, D‐dimer, vWF and troponin‐T did not change. In the treatment group, administration of celecoxib for 4 weeks significantly reduced hs‐CRP from median 0.77 (range 0.25–7.08) to 0.39 mg/dL (range 0.11–5.22, p < 0.05). The levels of albumin, D‐dimer, vWF and troponin‐T levels were not affected by the administration of celecoxib. These results showed that celecoxib had an antiinflammatory effect in usual dosage in CPD patients.