Apolipoprotein E polymorphism in 385 patients on renal replacement therapy in Sweden

OBJECTIVE: To examine apolipoprotein (apo) E polymorphism and its possible link to kidney disease in all patients receiving renal replacement therapy in our region. MATERIAL AND METHODS: The apo E genotype, plasma (P) lipids, blood pressure and albumin excretion rate were determined retrospectively in 385 patients. RESULTS: No differences in apo E genotype or the allelic frequencies of epsilon2, epsilon3 or epsilon4 were found between the patient group and a control group of 343 healthy individuals. The apo E3/E4 genotype, however, was found in only 1/24 patients with non-insulin-dependent diabetes mellitus (NIDDM), a significantly lower frequency than that seen in the rest of the patient group (p = 0.041). Similarly, the apo E4/E4 genotype was absent in patients with glomerulonephritis (GN) (p = 0.027). The relative frequency of the epsilon4 allele in patients with GN (0.116) was significantly lower than that in the rest of the patients (0.193; p < 0.05) and that in the control group (0.186; p = 0.027). Furthermore, 19/47 patients (40.4%) with autosomal dominant polycystic kidney disease (ADPKD) had the E3/E4 genotype, as compared to 77/338 (22.8%) in the rest of the patient group (p = 0.035; odds ratio 2.07; CI 1.09-3.92). An increase in the relative frequency of the epsilon4 allele was seen in the same diagnostic group: 0.29 vs 0.16 in the rest of the patient group (p = 0.0023). The mean P-cholesterol level in patients with the epsilon4 allele was 5.9 +/- 1.0 mmol/l, compared to 5.0 +/- 1.1 mmol/l in patients without the epsilon4 allele (p = 0.026). CONCLUSIONS: In this study, variations in the frequencies of the apo epsilon4 allele and the apo E3/E4 and E4/E4 genotypes were found in patients with NIDDM, GN and ADPKD. This result may be a consequence of the effects of the apo epsilon4 and epsilon2 alleles on P-cholesterol and remnant lipoprotein levels. The decreased frequency of apo E3/E4 found in patients with NIDDM may be explained by the fact that the epsilon4 allele gives renoprotection against diabetic nephropathy by lowering plasma remnant lipoprotein levels. Conversely, there may be an association between the apo E3/E4 genotype and the epsilon4 allele in patients with ADPKD, due to the effect of the epsilon4 allele in elevating P-cholesterol levels. The most plausible explanation for the absence of the apo E4/E4 genotype and the lower prevalence of the epsilon4 allele in patients with GN, which is known to result in a higher P-cholesterol compared to the epsilon2 and epsilon3 alleles, ought to be an increase in cardiovascular morbidity, which is known to be associated with a higher P-cholesterol level.     

Preliminary report on the association of apolipoprotein E polymorphisms, with postoperative peak serum creatinine concentrations in cardiac surgical patients

BACKGROUND: Renal dysfunction after cardiac surgery occurs in up to 8% of patients and is associated with major increases in morbidity, mortality, and cost. Genetic polymorphisms have been implicated as a factor in the progression of chronic renal disease, but a genetic basis for the development of acute renal impairment has not been investigated. The authors therefore tested the hypothesis that apolipoprotein E alleles are associated with different postoperative changes in serum creatinine after cardiac surgery. METHODS: The authors performed a prospective observational study with use of data from 564 coronary bypass surgical patients who were enrolled in an ongoing investigation of apolipoprotein E genotypes and organ dysfunction at a university hospital between 1989-1999. Renal function was assessed among apolipoprotein E genotype groups by comparisons of preoperative (CrPre), peak in-hospital postoperative (CrMax) and perioperative change (DCr) in serum creatinine values. RESULTS: The epsilon4 allele grouping (E2 = 2/2,2/3,2/4; E3 = 3/3; E4 = 3/4,4/4) was associated with a smaller increase in postoperative serum creatinine (perioperative change: E4, +0.17; E3, +0.26; E4, +0.27 mg/dl) and a lower peak postoperative creatinine than the epsilon2 and epsilon3 in univariate and multivariate analysis (peak in-hospital postoperative serum creatinine multivariate P = 0.015 vs. epsilon3, P = 0.038 vs. epsilon2). There was no difference in baseline creatinine among allele groups. CONCLUSIONS: Inheritance of the apolipoprotein epsilon4 allele is associated with reduced postoperative increase in serum creatinine after cardiac surgery, compared with the epsilon3 or epsilon2 allele. This is the first report of a possible genetic basis for acute renal impairment. These data may contribute to renal risk stratification for cardiac surgery and raise questions regarding apolipoprotein E and the pathophysiology of acute renal injury.     

Plasminogen activator inhibitor-1 polymorphism is associated with progressive renal dysfunction after acute rejection in renal transplant recipients

BACKGROUND: Plasma level of plasminogen activator inhibitor (PAI)-1 is genetically determined by a polymorphism in the promoter region, involving two alleles, 4G and 5G. Plasma PAI-1 concentrations are higher in subjects homozygous for the 4G allele than other genotypes (5G/5G and 4G/5G). Such genetic variation in fibrinolytic system may affect the long-term renal transplant outcome. METHODS: We determined PAI-1 4G/5G-promoter genotype polymorphism among our renal transplant recipients between 1985 and 2001. Primary event was defined as doubling of baseline serum-creatinine level. RESULTS: Over a median period of 79 months, 130 patients with 132 kidney grafts were assessed. Baseline clinical variables were comparable among three genotype groups. There was no association between primary event and PAI-1 genotype among the entire cohort. However, among subjects with prior acute rejection episodes, those homozygous for 4G had significantly higher risk of serum creatinine doubling than the other two genotypes (relative risk 2.45, 95% confidence interval 1.19-5.04). PAI-1 genotype does not predict primary events in patients without rejection (relative risk 0.57, 95% confidence interval 0.07-4.17). CONCLUSIONS: PAI-1 4G/5G-promoter polymorphism modulates the risk of renal transplant outcomes after acute rejection(s). Recipients homozygous for PAI-1 4G allele have a higher risk of progressive renal damage after acute rejection episode(s). PAI-1 promoter polymorphisms are potentially important determinants of renal response to rejection.     

Role of apolipoprotein E epsilon 4 allele on chronic allograft nephropathy after renal transplantation

Lipid abnormalities may contribute to chronic allograft nephropathy (CAN). Apolipoprotein E (ApoE) gene polymorphism regulates lipoprotein metabolism, but little is known about an association between CAN and this polymorphism. The ApoE gene (E3/E4) polymorphism was typed by PCR assay (99 E3/E3, 28 E3/E4, 1 E4/E4) on 128 consecutive renal transplant patients with functioning grafts for more than 3 years (6.7 +/- 2.8 years). Twenty-eight patients with histological CAN were compared with 100 patients who had no clinical evidence of chronic rejection (no proteinuria and sCr < 2.5 mg%). As expected, univariate analysis revealed that patients with CAN experienced a greater acute rejection rate (78% vs 21%; P=.001), a higher serum creatinine (3.6 +/- 1.7 vs 1.4 +/- 0.5 mg%; P=.0001), and an older organ donor (43 +/- 20 vs 29 +/- 13 years; P=.0001). The lipid profiles (total cholesterol and triglycerides levels) were similar in both groups with 60% in each group receiving anti-lipemic drugs. Interestingly, the ApoE epsilon 4 allele was overrepresented in the group with CAN (39% vs 17%, P=.019). Logistic regression analysis showed that the epsilon 4 allele was an independent predictor of CAN (OR: 3.4; CI 95%: 1.07 to 11; P=.040) as were donor age and acute rejection episodes. In conclusion, an interaction between risk factors and genetic factors may determine CAN in this population. This finding may help to target prophylactic interventions in these recipients.     

Cytotoxic T-lymphocyte antigen 4 gene polymorphisms and susceptibility to acute allograft rejection

BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA4) has been shown to play a critical role in the down-regulation of the immune response. We retrospectively examined the association between acute rejection and two polymorphisms in the CTLA4 gene, the dinucleotide (AT)n repeat polymorphism in exon 3 and the single nucleotide polymorphism A/G at position 49 in exon 1, in a cohort of liver and kidney transplant recipients. METHODS AND RESULTS: A total of 207 liver and 167 renal transplant recipients were analyzed. In the case of the (AT)n repeat polymorphism we found an increased incidence of acute rejection in association with allele 3 and 4 in both liver and kidney (P=0.002 and 0.05, respectively). In addition, in liver transplant recipients, allele 7 was associated with acute rejection independent of ethnicity (P<0.05). Allele 1 was less frequently observed in African American as compared with Caucasian liver and kidney transplant recipients, with a frequency of 33.8% and 69%, respectively (P<0.0001). Those patients with allele 1 had a tendency toward a lower rate of rejection at 42% versus 57.8% (P=0.058), suggesting a potential protective effect of allele 1. Analysis of the A/G single nucleotide polymorphism demonstrated no association between either allele and the incidence of acute rejection in the patients studied. CONCLUSION: These initial observations provide the necessary basis to further investigate the risk stratification of transplant recipients based on specific CTLA4 gene polymorphisms.     

Genetic variations of the apolipoprotein E gene determine the plasma triglyceride levels after heart transplantation.

OBJECTIVES: To study whether the presence of the polymorphism in the apolipoprotein E (apo E) gene influences the lipid profile in heart-transplant recipients. METHODS: A cohort of 103 recipients of heart transplant (93 men and 10 women, with a mean age of 47 +/- 13 years) under triple immunosuppressive therapy were submitted to a genetic study of the apo E gene region. Anthropometric and analytical data, including lipid profile and arterial blood pressure were collected prior to transplantation and 3, 6, 12, and 24 months after it. RESULTS: 65 subjects present the genotype E3E3, 27 the genotype E3E4, 6 the genotype E2E3, and 5 the genotype E2E4. Carriers of the E2 allele (that is, genotypes E3E2 and E4E2) had higher total plasma triglyceride (TG) levels after 3 months (3.47 +/- 1.88 mmol/liter p < 0.001) and after 1 year of transplantation (3.13 +/- 1.77 mmol/liter p < 0.05) than the other genotypes. There were no differences in the plasma levels of total cholesterol (TC), LDL-cholesterol (LDL-C), and HDL-cholesterol (HDL-C). Multiple regression analysis revealed that the apoprotein E gene polymorphism determines 5% (p = 0.0425) and age 8.7% (p < 0.009) of the variants in TG levels. CONCLUSIONS: The presence of the E2 allele in heart-transplant recipients produces a greater rise in total TG plasma levels than the other genotypes.     

Interleukin-2 gene polymorphism is associated with renal but not cardiac transplant outcome

It was recently shown that IL-2 gene single nucleotide polymorphism (SNP) at position -330 (G-->T) is related to in vitro cytokine production levels, with the T/T and T/G genotypes being associated with low production and the G/G genotype associated with high production. The objective of this study was to investigate a possible influence of this polymorphism on renal and cardiac allograft outcomes. IL-2 SNP G-T (-330) was determined by PCR-RFLP in 67 recipients of heart allografts and in 63 recipients of renal grafts from HLA-haplo-identical, related donors. A higher frequency of the T/T genotype was observed in renal transplant patients who experienced at least one acute rejection episode during the first 3 months after transplantation than in those without rejection during this period (80% vs 49%, respectively, P <.05). Accordingly, the same genotype tended to be more frequent in renal recipients with a 6-month serum creatinine level above 1.5 mg/dL (median value for the whole group of kidney recipients) than in patients with lower creatinine levels (79% vs 45%, P <.08). Regarding cardiac transplant recipients, no associations were observed concerning acute rejection or graft survival. The finding of the association of T/T but not T/G genotype with acute kidney rejection was unexpected considering that both genotypes were shown to be associated with equal (low) IL-2 in vitro production. Further studies are necessary not only to dissect the nature of IL-2 T/T genotype association with kidney rejection, but also to explain why this genotype does not apparently influence cardiac allograft outcome.     

Preliminary Report on the Association of Apolipoprotein E Polymorphisms, with Postoperative Peak Serum Creatinine Concentrations in Cardiac Surgical Patients

Background: Renal dysfunction after cardiac surgery occurs in up to 8% of patients and is associated with major increases in morbidity, mortality, and cost. Genetic polymorphisms have been implicated as a factor in the progression of chronic renal disease, but a genetic basis for the development of acute renal impairment has not been investigated. The authors therefore tested the hypothesis that apolipoprotein E alleles are associated with different postoperative changes in serum creatinine after cardiac surgery.

Methods: The authors performed a prospective observational study with use of data from 564 coronary bypass surgical patients who were enrolled in an ongoing investigation of apolipoprotein E genotypes and organ dysfunction at a university hospital between 1989-1999. Renal function was assessed among apolipoprotein E genotype groups by comparisons of preoperative (CrPre), peak in-hospital postoperative (CrMax) and perioperative change (DCr) in serum creatinine values.

Results: The [epsilon]4 allele grouping (E2 = 2/2,2/3,2/4; E3 = 3/3; E4 = 3/4,4/4) was associated with a smaller increase in postoperative serum creatinine (perioperative change: E4, +0.17; E3, +0.26; E4, +0.27 mg/dl) and a lower peak postoperative creatinine than the [epsilon]2 and [epsilon]3 in univariate and multivariate analysis (peak in-hospital postoperative serum creatinine multivariate P = 0.015 vs. [epsilon]3, P = 0.038 vs. [epsilon]2). There was no difference in baseline creatinine among allele groups.     

Human platelet antigens: HPA-1, -2, -3, -4, and -5 polymorphisms in kidney transplantation

To investigate the association between kidney transplant rejection and polymorphisms of HPA-1, -2, -3, -4, and -5, the genomic DNA of 70 renal transplant recipients and 100 healthy blood donors was analyzed by polymerase chain reaction (PCR)-SSP. The patients were classified into two groups. Group 1 included 33 HLA-identical recipients and group 2, 37 one haplo-identical recipients. Thirty-one recipients experienced an acute rejection episode (ARE): 10 in group 1 and 21 in group 2. Ten group 2 patients developed chronic allograft dysfunction (CAD). Before transplantation, five patients in group 1 were lymphocytocytotoxic antibodies (LCT) positive, among them three developed an ARE. In group 2, seven recipients were LCT positive and four had an ARE. After transplantation, 29 patients were LCT positive: 11 in group 1 and 18 in group 2, among them: 6/11 and 11/18 had an ARE. The allelic frequencies of HPA-1, -2, and -5 among patients and controls did not reveal significant differences, whereas the HPA-3a and HPA-4b alleles were significantly more frequent among patients than controls: 91.4% and 27.8% versus 76.5% and 11.5% respectively (P < .05 and P < .001). The frequency of the HPA-3b allele was increased in patients with an ARE (11.3%) and those who developed CAD (20%) compared with those not affected by these complications (6.6% and 6.4%, respectively), but the difference was not significant. The genotype distribution of HPA-1, -3, and -4 genes of GPIIb/IIIa revealed that the most frequent genotype was HPA-1a1a/3a3a/4a4a (19%) among controls and HPA-1a1a/3a3a/4a4b (31.4%) among patients. This genotype was associated with an ARE in 25.8%, namely 50% of group 1 recipients and 14.28% of group 2. The HPA-4b polymorphism of GPIIb/IIIa receptor seem to be an independent risk factor for acute allograft rejection in kidney transplantation.     

Association studies of Toll-like receptor gene polymorphisms with allograft survival in renal transplant recipients of North India

Organ transplantation itself inevitably activates the innate immune system by Toll-like receptors (TLRs), potentially leading to allograft rejection and graft failure. We evaluated the possible association of TLR2, TLR3, and TLR9 polymorphisms of donor-recipient pairs and acute rejection in renal transplant patients of North India. TLR2 (-196 to -174 del), TLR3 (c.1377C/T; rs 3775290), and TLR9 (+2848 G/A; rs 352140) were genotyped using DNA samples from 200 donor-recipient pairs of live donor kidney transplantation by applying Restriction Fragment Length Polymorphism (RFLP) methodology. The variant allele frequency of TLR2 (-196 to -174 del) was significantly different between recipients and donors (7.5% vs. 5.0%; p = 0.049; OR = 3.9; 95% CI = 1.01-15.32). However, no significant association for allograft rejection was observed in transplant recipients for TLR3 and TLR9. Interestingly, a low prevalence of AA genotype of TLR9 + 2848 G>A was observed in rejecters when compared with non-rejecters, demonstrating protective association with allograft rejection (OR = 0.30, 95% CI = 0.12-0.88, p = 0.028). An allele in patients was also observed to be associated with higher rejection-free survival (log-rank = 0.044). These TLR gene polymorphisms, upon further evaluation, may be helpful in elucidation of immunobiological mechanisms associated with renal graft rejection.     

Ctla-4 exon 1 (+49) and promoter (-318) gene polymorphisms in kidney transplantation

To investigate the association between kidney transplant rejection and the polymorphisms of CTLA-4 gene exon 1(+49) and promoter (-318), genomic DNA of 70 renal transplant recipients and 110 healthy blood donors were genotyped by PCR-RFLP and PCR-SSP, respectively. The patients were classified in two groups: G1 included 33 HLA-identical recipients and G2, 37 one haplo-identical recipients. Thirty-one recipients experienced an acute rejection episode: 10 in G1 and 21 in G2. Ten G2 patients developed chronic allograft dysfunction (CAD). Allelic frequencies and genotype distribution were similar among patients and controls. CTLA-4 exon 1 genotype A/A and CTLA-4 promoter genotype C/C were significantly higher among G2 patients with CAD than without CAD (P < .01). The distribution of CTLA-4 exon 1-promoter genes did not reach significance between graft recipients and controls. The genotype frequency of (G/G-C/C) was increased among controls (42.72%) compared with graft recipients (G1 and G2; 35.71%). CTLA-4 polymorphisms gene were associated with susceptibility to chronic allograft dysfunction.     

Apolipoprotein E genotype and cognitive dysfunction after noncardiac surgery

BACKGROUND: Apolipoprotein E is important in recovery after neuronal damage. The epsilon4 allele of the apolipoprotein E gene has been shown as a risk factor for Alzheimer disease, poor outcome after cerebral injury, and accelerated cognitive decline with normal aging. The authors hypothesized that patients with the epsilon4 allele would have an increased risk of postoperative cognitive dysfunction (POCD) after noncardiac surgery. METHODS: In a multicenter study, a total of 976 patients aged 40 yr and older undergoing noncardiac surgery were tested preoperatively and 1 week and 3 months after surgery with a neuropsychological test battery comprising seven subtests. POCD was defined as a decline in test performance of more than 2 SD from the expected. Apolipoprotein E genotypes were determined by blood sample analysis at a central laboratory. Multivariate logistic regression analysis with POCD as the dependent variable assessed presence of the epsilon4 allele (yes/no) and other possible risk factors. RESULTS: The epsilon4 allele was found in 272 patients. One week after surgery, the incidence of POCD was 11.7% in patients with the epsilon4 allele and 9.9% in patients without the epsilon4 allele (P = 0.41). Three months later, POCD was found in 10.3% of patients with the epsilon4 allele and in 8.4% of patients without the epsilon4 allele (P = 0.40). Multivariate logistic regression analysis did not identify the epsilon4 allele as a risk factor at 1 week (P = 0.33) or 3 months (P = 0.57). CONCLUSIONS: The authors were unable to show a significant association between apolipoprotein E genotype and POCD, but statistical power was limited because of a lower incidence of POCD than expected.     

Genetic association of interleukin-4, interleukin-10, and transforming growth factor-beta gene polymorphism with allograft function in renal transplant patients

Despite advances in immunosuppressive therapy in the past decade, allograft rejection remains the primary cause for kidney graft failure. Cytokines are known to be important mediators in renal allograft outcome. The aim of the present study was to ascertain whether interleukin (IL)-4, IL-10, and transforming growth factor (TGF)-beta cytokine gene polymorphisms contributed to kidney graft outcome. We evaluated single nucleotide polymorphism in IL-4 (-1098G/T, -590C/T, -33C/T), IL-10 (-1082A/G, -819C/T, -592A/C), and TGF-beta (codon 10 and 25) in 100 renal transplant recipients and 139 normal healthy control using polymerase chain reactions based on sequence-specific primers. Recipients were clinically characterized as rejection episode (RE) versus stable graft function (SGF). The results showed the frequencies of IL-4 -33 T allele in the RE, SGF, and control group to be 7%, 73%, and 28%, respectively. IL-10 -592 A allele frequency was 39% in RE, 26% in SGF, and 28% in the control group. TGF-beta codon 10 T allele was 39% in RE, 35% in SGF, and 53% in control group. In conclusion, this study suggested that some cytokine gene alleles reflected SGF among kidney transplant recipients.     

Presence of apolipoprotein E epsilon4 allele in cerebral palsy

The apolipoprotein E gene, which is located on chromosome 19, has three alleles (epsilon2, epsilon3, and epsilon4). Several recent publications associate the presence of the apolipoprotein E epsilon4 allele with the occurrence of neurologic diseases, and consider it a risk factor for the development of central nervous system affections. A group of 40 patients with cerebral palsy was studied and compared to a control group of 40 subjects, and higher occurrence of the allele epsilon4 in the group of subjects with cerebral palsy was observed. A significantly higher risk of developing cerebral palsy was demonstrated among those subjects with the apolipoprotein E epsilon4 allele.     

细胞因子基因型多态性与肾移植排斥反应的关系

目的：探讨细胞因子基因型多态性对肾脏移植后急性排斥反应发生率的影响。方法：采用序列特异引物聚合物酶链反应（PCR－SSP）法对115例肾移植受者和24名健康对照者的细胞因子肿瘤坏死因子（TNF）－α,转化生长因子（TGF）－β1,白细胞介素（IL）－6和IL－10基因型进行测定,探讨其细胞因子基因型对肾脏移植后急性排斥反应发生率的影响。结果：在115例肾移植受者及24名健康对照者中,TNF－α和IL－10低产生型基因型者分别为88.7%(102.115),87.5%(21/24)和80％(92/115),75%(18／24）,占明显优势。而TGF－β1和IL－6的硎 是以高产生型占明显优势,分别为79.1%(91/115),100%(115/115)和66.7%(16/24),100%(24/24)。115例肾移植受者中,在移植后6个月内共有26例发生了急性排斥。其中TNF－α高产生基因型和IL－10的中,高产基因型受者的急性排斥发生率分别为53．8％（7／13）和43．5％（10／23）,显著高于相应的低产生基因型受者的18．6％(19/102,x^2=8.17)和17．4％（16／92,x^2=7.16),差异有非常显著意义（P值均＜0＝0．01）。结论：肾移植受者和正常健康人群的TNF－α和IL－10基因型是以低产生型为主;TGF－β1和IL－6的基因型是以高产生型为主;TNF－β1和IL－10细胞因子基因型多态性对肾移植术后急性排斥反应的发生率有显著的影响。     

Association between apolipoprotein E polymorphism and macroalbuminuria in patients with non-insulin dependent diabetes mellitus.

OBJECTIVES: Apolipoprotein E (apo E) is known to play an important role in lipoprotein metabolism through its ability to bind to the receptors as a ligand. Three different apo E alleles (epsilon2, epsilon3 and epsilon4) produce six apo E genotypes (epsilon2/2, epsilon2/3, epsilon2/4, epsilon3/3, epsilon3/4 and epsilon4/4). The objective of this study was to investigate an association between apo E gene polymorphism and macroalbuminuria in 167 Korean patients with non-insulin dependent diabetes mellitus (NIDDM). METHODS: The patients in the macroalbuminuria group (n = 74) represent those in whom 24 h urinary albumin excretion was above 300 mg. The patients in the normoalbuminuria group (n = 93) represent those in whom 24 h urinary albumin excretion was below 30 mg and serum creatinine levels were less than 1.2 mg/dl. The duration of diabetes in all patients was at least 8 years. RESULTS: There were no significant differences in terms of age, sex, body mass index, HbA1c, total cholesterol, triglyceride, HDL-cholesterol and LDL-cholesterol between the two groups. In the macroalbuminuria group, the distribution of apo E genotypes revealed epsilon2/2 2 (2.7%), epsilon2/3 14 (18.9%), epsilon2/4 0 (0%), epsilon3/3 47 (63.5%), epsilon3/4 11 (14.9%) and epsilon4/4 0 (0%). In the normoalbuminuria group, the distribution of apo E genotypes revealed epsilon2/2 0 (0%), epsilon2/3 7 (7.5%), epsilon2/4 1 (1.1%), epsilon3/3 72 (77.4%), epsilon3/4 12 (12.9%) and epsilon4/4 1 (1.1%). There was no significant difference in the distribution of apo E genotypes between the two groups. However, there was a significant difference in the allele frequencies, epsilon2 frequency was significantly higher in macroalbuminuria group compared to normoalbuminuria group (12.2% vs 4.3%, P<0.05). Also, we compared apo E carrier frequencies between the two groups. Epsilon2 carrier frequency was significantly higher in macroalbuminuria group compared to normoalbuminuria group (21.6% vs 7.6%, P<0.05). In each group, there was no significant difference in the degree of lipid abnormalities between apo epsilon2 carrier (epsilon2/2, epsilon2/3 genotypes), epsilon3 carrier (epsilon3/3 genotype) and epsilon4 carrier (epsilon3/4, epsilon4/4 genotype). CONCLUSION: Apo epsilon2 allele and epsilon2 carrier frequencies were significantly higher in macroalbuminuria group. These results suggest that epsilon2 allele may be associated with the development of clinical albuminuria in Korean patients with NIDDM.     

Higher frequency of apolipoprotein E2 allele in type 2 diabetic patients with nephropathy in Taiwan

BACKGROUND: Diabetes is one of the major causes of end stage renal failure in Taiwan. Previous studies have indicated that lipid abnormalities might contribute to the development and progression of diabetic nephropathy (DN). Apolipoprotein E (apo E) regulates the metabolism of lipoproteins. Three different apo E alleles (epsilon2, epsilon3 and epsilon4) produce apo E isoproteins, apo E2, apo E3 and apo E4. Thus, the apo E gene polymorphism may be associated with DN. METHODS: To investigate the distribution of apo E genotype in type 2 diabetic Taiwanese, we examined 314 patients with type 2 diabetes (100 without nephropathy and 214 with nephropathy) and 150 age-matched normal controls. The diagnosis of nephropathy was made when daily protein loss exceeded 500 mg. The apo E gene polymorphism was analyzed by polymerase chain reaction. RESULTS: Our study found that the frequency of apo E2 allele was significantly higher in the diabetics with nephropathy- non-dialysis group (7.7%) and diabetics with nephropathy- dialysis group (7.7%) than in normal controls (1.7%) (p < 0.001) and diabetics without nephropathy (2.0%) (p < 0.01). The E3 and E4 allele frequencies were not significantly different among groups. CONCLUSION: These findings imply that apo E polymorphism is apparently related to the development of DN in type 2 diabetes in Taiwan.     

Factor V R506Q mutation (activated protein C resistance) is an additional risk factor for early renal graft loss associated with acute vascular rejection

BACKGROUND: The factor V R506Q mutation (FV R506Q, FV:Q506, or FV Leiden) resulting in activated protein C (APC) resistance is the most common inherited risk factor for venous thrombosis, including in renal transplant recipients. We investigated a possible association between the FV mutation and early renal graft loss, and the prevalence of macro- and microvascular thrombosis, endothelialitis, and fibrinoid vascular necrosis by FV genotype. METHOD: One hundred and nine renal allograft recipients were genotyped for FV mutation. A vascular rejection subgroup of patients (n=29) had experienced at least one episode of vascular rejection, or graft thrombosis. A second group of patients (n=80) had experienced no acute rejection and retained a well-functioning graft. RESULTS: The prevalence of APC resistance was numerically but not statistically significantly higher in the vascular rejection group (17.2%) compared with the group without rejection episodes (7.5%) (P=0.16). There was a significant association between the presence or absence of FV mutation and graft survival, with a 55.6% 1-year graft survival rate versus a 76.4% rate, respectively (P=0.02). The prevalence of vascular rejection, as evidenced by endothelialitis or fibrinoid vascular necrosis, was significantly associated with APC resistance but macro- or microvascular thrombosis were not. CONCLUSION: Renal transplant recipients who are carriers of the FV:Q506 allele have an increased risk of early graft loss. Vascular rejection changes including endothelialitis and fibrinoid vascular necrosis were more common in this group, and therefore an association between the hypercoagulable state, which entails an up-regulation of the mitogenic and proinflammatory enzyme thrombin, and the immunological challenge to the endothelium may be the cause of inferior prognosis in these patients.     

Polymorphisms in cytotoxic T lymphocyte associated antigen-4 influence the rate of acute rejection after renal transplantation in 167 Chinese recipients

Gene polymorphisms of cytotoxic T lymphocyte associated antigen 4 (CTLA4) play an influential role in the graft rejection and long-term clinical outcome of organ transplantation. We investigated the associations of five CTLA4 single nucleotide polymorphisms (SNPs) (rs733618T/C, rs4553808A/G, rs5742909C/T, rs231775G/A, rs3087243G/A) on the early acute rejection (AR) of Chinese deceased donor renal transplantation recipients. Genotyping of the CTLA4 SNPs was performed in 167 deceased donor renal transplantation recipients. Each patient underwent a 6-month follow-up observation for AR. The incidence of AR during the 6 months post-transplantation was 26.9% (45 out of 167 patients). Patients experiencing AR were found to have a higher frequency of the rs733618TT genotype and T allele (p=0.000 and p=0.002, respectively). While the haplotype CACAG was merely observed in non-AR group (corrected p=0.000), the frequency of haplotype TACGG was significantly higher in AR group than in non-AR group even after 50,000 permutation tests (corrected p=0.018). In conclusion, these polymorphisms statistically significantly associated with acute renal allograft rejection may be considered as a risk factor of AR in Chinese renal transplantation recipients except for haplotype CACAG as a protective one.