No association of the TGF-beta1 gene polymorphisms with the renal progression in autosomal dominant polycystic kidney disease (ADPKD) patients

BACKGROUND: Two genetic loci, PKD I and PKD2, have been identified as being responsible for ADPKD, and PKD1 is known to be associated with a poor prognosis. However, the presence of an intrafamilial study clinical diversity suggests that there are disease-modifying loci. Because the mechanism ofthe renal failure in ADPKD includes a cystic growth and tubulointerstitial atrophy and fibrosis, we studied the associations between 2 polymorphisms in the TGF-beta1 gene, which are known to be associated with chronic tubulointerstitial inflammation, and ADPKD progression in Korean patients. PATIENTS AND METHODS: One hundred and twenty-five individuals who had ADPKD and 47 normal control subjects were genotyped by PCR-RFLP, the T869C (Leu10Pro) variant of TGF-beta gene leader sequence was discriminated with MspA1I and the G915C (Arg25Pro) variants with Bg1I. Statistical significances were determined using the Chi-square test. RESULTS: The distribution of the alleles for the TGF beta1 Leu10Pro polymorphism in ADPKD was: T 54%, C 46%, which was similar to the Korean (56: 44, p = 0.887) and Western controls (65: 35). In addition, no differences were found between the ESRD and the non-ESRD groups (p = 0.888) or the early hypertension and the normotension groups (p = 0.249). The distribution of alleles for the TGF beta1 Arg25Pro polymorphism showed only the GG type which was different from the Western population controls (G:C = 90:10, p = 0.000). CONCLUSIONS: Our results suggest that the polymorphism at Arg25Pro of TGF-beta1 in the Korean population has an allele distribution different from that ofthe Western population and that the polymorphism at Leu10Pro of TGF-beta1 has no association with the renal progression in Korean ADPKD patients.     

The influence of the endothelin-converting enzyme-1 gene polymorphism on the progression of autosomal dominant polycystic kidney disease

BACKGROUND; A significant phenotypical variability is observed in autosomal dominant polycystic kidney disease (ADPKD), the most common renal hereditary disease. Endothelin-1 (ET-1) has been suggested to be an important disease-promoting factor of the kidney. Endothelin-converting enzyme-1 (ECE-1) is the main protease responsible for ET-1 generation by cleavage of its functionally inactive precursor. We examined the influence of the ECE-1b C-338A polymorphism on the progression of ADPKD toward end-stage renal disease (ESRD). The A allele was suggested to be associated with higher plasma level of ET-1. METHODS: 200 ADPKD patients (107 males, 93 females) who had reached ESRD were analyzed. Patients were divided into three groups: (1) 47 patients (23 males, 24 females) with ESRD later than in 63 yr (slow progressors); (2) 71 patients (38 males, 33 females) with ESRD before 45 yr (rapid progressors); and (3) 82 patients (46 males, 36 females) with ESRD between 45-63 yr. Moreover, we analyzed 160 genetically unrelated healthy Czech subjects as the control group (82 males, 78 females, mean age 51.4 +/- 8.2 yr). DNA samples from collected blood were genotyped for ECE-1b C-338A polymorphism using described polymerase chain reaction (PCR) followed by restriction enzyme digestion. We compared the frequencies of different genotypes between the groups of slow and rapid progressors and the ages of ESRD with regard to different genotypes. RESULTS: The ECE-1b C-338A genotype distribution showed no differences among the groups of slow progressors, rapid progressors, ADPKD group with ESRD between 45-63 yr and control group. Comparing the ages of ESRD of all patients, we did not find significant differences in the ages with regard to different genotypes: CC (51.5 +/- 10.1 yr), AC (51.6 +/- 11.4 yr), AA (48.2 +/- 5.9 yr). There was a tendency to lower age of ESRD in AA homozygotes in comparison with other genotypes (t-test, p = 0.12). We found no influence of gender. CONCLUSION: We excluded the effect of ECE-1b C-338A polymorphism on the progression of ADPKD. We could observe a mild tendency toward faster decline of renal function in AA homozygous individuals.     

No effect of angiotensin-converting enzyme gene polymorphism on disease progression and left ventricular hypertrophy in autosomal dominant polycystic kidney disease

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) shows a variable clinical course suggesting that genetic modifiers might play a role. There are conflicting results about the effect of angiotensin-converting enzyme (ACE) gene polymorphism on the progression of renal failure in ADPKD. Also, the association between ACE gene polymorphism and the occurrence of left ventricular hypertrophy (LVH) has not been investigated in patients with ADPKD. METHODS: ACE genotype analysis was performed in 409 Caucasian patients (137 male, 272 female) with ADPKD. Echocardiographic examination was done in 164 of these patients. RESULTS: There were no significant differences between different ACE genotypes regarding renal function, renal volume, urinary protein excretion, blood pressure, the rate of hypertension, the age at diagnosis of hypertension, the rate of LVH and the incidence of end-stage renal disease (ESRD). CONCLUSION: ACE gene polymorphism does not have a significant effect on the development of ESRD and the prevalence of LVH in patients with ADPKD.     

Influence of ACE (I/D) and G460W polymorphism of alpha-adducin in autosomal dominant polycystic kidney disease.

BACKGROUND: The deleterious effect of the DD genotype of ACE in autosomal dominant polycystic kidney disease (ADPKD) remains controversial. Small sample size, population admixture and lack of consideration of parameters modulating the effects of ACE genotype, such as gender or alpha-adducin (ADD) genotype, might explain the discrepancy. METHODS: We investigated the effect of ACE (I/D) polymorphism on the age at end-stage renal disease (ESRD) in a homogeneous population of 191 ADPKD patients, according to gender and genotype for the G460W polymorphism of ADD. Cumulative renal survival was assessed in 276 patients from the same families. RESULTS: Though no effect was detected in the whole population, analysis of the male subset (n = 97) showed that patients harbouring the DD genotype of ACE had a 5-year lower mean age at ESRD than DI + II patients [47.8 +/- 1.8 (n = 31) vs 52.8 +/- 1.1 (n = 66), respectively] (P = 0.02). Furthermore, cumulative renal survival was lower in the corresponding pedigrees [47 +/- 1 years, 95% confidence interval (CI) 45-49, vs 51 +/- 1 years, 95% CI 48-54]. The G460W polymorphism of ADD had no effect on the age at ESRD and cumulative renal survival, either alone or in combination with the ACE (I/D) polymorphism. CONCLUSIONS: In this large series of ADPKD patients, we found no effect of the ACE (I/D) polymorphism on the age at ESRD, either alone or in combination with the G460W polymorphism of ADD. However, a deleterious effect of the DD genotype of ACE on renal disease progression was observed in ADPKD males.     

Endothelial nitric oxide synthase gene intron 4 polymorphism in patients with end-stage renal disease.

BACKGROUND: Nitric oxide (NO) synthesized by endothelial cell NO synthase (ecNOS) is a potent regulator of intrarenal haemodynamics. A polymorphism in intron 4 of the ecNOS gene is a candidate gene in cardiovascular and renal diseases. We investigated a potential involvement of this polymorphism in chronic renal failure. METHODS: We performed a case-control study involving 706 patients with end-stage renal disease (ESRD) and 321 healthy controls. All subjects were genotyped for the ecNOS4 polymorphism by the polymerase chain reaction followed by agarose gel electrophoresis. RESULTS: The analysis revealed that the frequencies of the ecNOS4 genotypes were significantly different in ESRD patients, both diabetic and non-diabetic, than in controls. In all dialysis patients for aa, ab and bb genotypes the frequencies were, respectively, 6.5, 35 and 58.5% in the patient group, and 1, 25 and 74% in control subjects. The a allele carriers (aa + ab) were more frequent among ESRD patients than in controls (OR 1.95; 95% CI 1.13-3.4; P = 0.0031). No significant association was found when hypertensive ESRD patients were compared with normotensive patients. The distribution of genotypes was similar in both subgroups (P = 0.21). CONCLUSION: There was a significantly higher frequency of the ecNOS4a allele carriers among ESRD patients, both diabetic and non-diabetic, than in control subjects. This suggests that the ecNOS gene polymorphism may be associated with an increased risk of chronic renal failure.     

Genetic polymorphisms of the renin-angiotensin system in end-stage renal disease.

BACKGROUND: End-stage renal disease (ESRD) is a complex phenotype resulting from underlying kidney diseases of different etiologies as well as from environmental and genetic factors. The responsible genes influencing the development and rate of progression to ESRD have yet to be defined. We examined an association of the three renin-angiotensin system (RAS) gene polymorphisms with renal disease and progression to ESRD in dialyzed patients. METHODS: Genotyping was performed in 745 ESRD patients and 520 control subjects for the angiotensin-converting enzyme (ACE) I/D, angiotensinogen (AGT) M235T and angiotensin II type 1 receptor (AT1R) A1166C gene polymorphisms using polymerase chain reaction and gel analysis. RESULTS: Allele and genotype frequencies of the ACE polymorphism did not differ significantly between ESRD patients and controls. The patient group showed an increased frequency of the T allele of the AGT polymorphism (P = 0.02) and the C allele and CC genotype of the AT1R polymorphism (P<0.01). There was an association of the AT1R gene polymorphism with the progression of renal disease to end-stage failure. The time from diagnosis to the onset of ESRD was significantly shorter in patients carrying the C allele than in subjects with the homozygous AA genotype (4.7 years vs 12.6 years, P<0.001). The observed effect was not associated with hypertension in studied subjects. CONCLUSION: The results of our study demonstrate the association between the AT1R A/C polymorphism and renal disease progression. The CC/AC genotype of this polymorphism might serve as a predictor for early ESRD and might be useful in planning therapeutic strategies for individual patients.     

Influence of ACE I/D gene polymorphism in the progression of renal failure in autosomal dominant polycystic kidney disease: a meta-analysis.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a renal disease characterized by an important variability in clinical course, which cannot be fully explained by the genetic heterogeneity of the disease. Although the role for the angiotensin I-converting enzyme (ACE) insertion/deletion (I/D) polymorphism as a modifier factor in ADPKD renal deterioration has been suggested, direct evidence from genetic association studies remain inconclusive. To provide a more robust estimate of the putative effect of the ACE I/D polymorphism on the renal progression in ADPKD, we performed a meta-analysis pooling data from all relevant studies in which the role of the ACE I/D variant in ADPKD clinical features was evaluated. METHODS: We applied a random-effects model to combine odds ratio and 95% confidence intervals. Q-statistic was used to evaluate the homogeneity, and both Egger's and Begg-Mazumdar tests were used to assess publication bias. RESULTS: Altogether, three distinct meta-analyses were generated using data from 13 studies. Despite the absence of publication bias and the presence of homogeneity among study results, the DD genotype failed to show an influence on risk of end-stage renal disease (ESRD), mean age at ESRD or risk of hypertension in ADPKD patients when compared with I-allele carriers (DD vs ID+II). Likewise, meta-analyses carried out separately for Caucasian and Asian studies showed no indication of an association between the DD genotype and a faster renal deterioration in ADPKD. CONCLUSION: These findings do not support the hypothesis that the enhanced ACE activity associated with the D allele might promote a significantly worse prognosis in patients with ADPKD.     

The Influence of the Endothelin-Converting Enzyme-1 Gene Polymorphism on the Progression of Autosomal Dominant Polycystic Kidney Disease

Background. A significant phenotypical variability is observed in autosomal dominant polycystic kidney disease (ADPKD), the most common renal hereditary disease. Endothelin-1 (ET-1) has been suggested to be an important disease-promoting factor of the kidney. Endothelin-converting enzyme-1 (ECE-1) is the main protease responsible for ET-1 generation by cleavage of its functionally inactive precursor. We examined the influence of the ECE-1b C-338A polymorphism on the progression of ADPKD toward end-stage renal disease (ESRD). The A allele was suggested to be associated with higher plasma level of ET-1. Methods. 200 ADPKD patients (107 males, 93 females) who had reached ESRD were analyzed. Patients were divided into three groups: (1) 47 patients (23 males, 24 females) with ESRD later than in 63 yr (slow progressors); (2) 71 patients (38 males, 33 females) with ESRD before 45 yr (rapid progressors); and (3) 82 patients (46 males, 36 females) with ESRD between 45–63 yr. Moreover, we analyzed 160 genetically unrelated healthy Czech subjects as the control group (82 males, 78 females, mean age 51.4 ± 8.2 yr). DNA samples from collected blood were genotyped for ECE-1b C-338A polymorphism using described polymerase chain reaction (PCR) followed by restriction enzyme digestion. We compared the frequencies of different genotypes between the groups of slow and rapid progressors and the ages of ESRD with regard to different genotypes. Results. The ECE-1b C-338A genotype distribution showed no differences among the groups of slow progressors, rapid progressors, ADPKD group with ESRD between 45–63 yr and control group. Comparing the ages of ESRD of all patients, we did not find significant differences in the ages with regard to different genotypes: CC (51.5 ± 10.1 yr), AC (51.6 ± 11.4 yr), AA (48.2 ± 5.9 yr). There was a tendency to lower age of ESRD in AA homozygotes in comparison with other genotypes (t-test, p = 0.12). We found no influence of gender. Conclusion. We excluded the effect of ECE-1b C-338A polymorphism on the progression of ADPKD. We could observe a mild tendency toward faster decline of renal function in AA homozygous individuals.     

Association of endothelial nitric oxide synthase gene intron 4 polymorphism with end-stage renal disease

BACKGROUND: Nitric oxide (NO) released from endothelial cells is related to the maintenance of physiological vascular tone. The impairment of endothelial NO generation brought about by gene polymorphism is considered one of the deterioration factors in progressive renal disease. In the endothelial nitric oxide synthase (eNOS) intron 4 polymorphism, the presence of the aa genotype has been associated with cardiovascular and renal disease. The aim of this study was to investigate the presence of eNOS gene intron 4 polymorphism in patients with end-stage renal disease (ESRD). METHODS: A total of 114 patients and 94 controls were studied. DNA specimens were extracted from blood and amplified by polymerase chain reaction. The alleles were separated by agarose gel electrophoresis. Genotype distribution and allele frequencies were compared between groups using the chi-squared test. RESULTS: Statistical analysis revealed that the frequency of the eNOS4 genotype aa was significantly different in ESRD patients and in controls (P=0.016, OR=2.07, CI 95%: 1.14-3.74). There was also a statistically significant difference between ESRD patients and controls regarding allele carriers (P=0.004; OR=2.26; CI 95%: 1.29-3.96). When the frequencies of allele carriers in the diabetic nephropathy group and in the control group were compared, a significant difference was found (P=0.034, OR=2.28; CI 95%: 1.04-5.00). CONCLUSION: This study showed a strong correlation between eNOS4a polymorphism and end-stage renal disease.     

Progressive loss of renal function is an age-dependent heritable trait in type 1 autosomal dominant polycystic kidney disease

Significant intrafamilial phenotypic variability is well documented in autosomal dominant polycystic kidney disease (ADPKD) and suggests a modifier effect. In this study, variance components analysis was performed to estimate the contribution of genetic factors for within-family renal disease variability in 406 patients from 66 type 1 ADPKD families. Overall, 39% of the study patients had ESRD at their last follow-up, and their renal survival did not differ by gender (P = 0.35, log-rank test). Because their frequency plot of creatinine clearance (Ccr) assumed a bimodal distribution with a marked kurtosis that was not improved by transformations, the study cohort was decomposed into two separate groups (non-ESRD [n = 247] and ESRD [n = 159]) in which the Ccr plots were normally distributed. The heritability (h(2)) of Ccr and age at ESRD (age(ESRD)) and the genetic correlations between these measures and their covariates were estimated. In patients without ESRD, a significant heritability was found for Ccr (h(2) = 0.42; P = 0.0015) after adjusting for age (P = 0.0001), systolic BP (P = 0.0006), and treatment with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (P = 0.00001). Birth year, gender, BMI, diastolic and mean BP, and pack-years of cigarette smoking did not significantly influence the heritability of this trait. In patients with ESRD, age(ESRD) provides a better measure than Ccr, which was very narrowly distributed. A significant heritability was found for age(ESRD) (h(2) = 0.78; P = 0.00009) in these latter patients. None of the above covariates influenced the heritability of this trait. It is concluded that a significant modifier gene effect influences the progression of renal disease in type 1 ADPKD.     

(AT) repeat in the 3' untranslated region of the CTLA-4 gene and susceptibility to acute allograft rejection in Tunisian renal transplantation

Allograft rejection is an immune response relying on the proliferation and the differentiation of T cells. CTLA-4 is a co-stimulatory molecule, expressed on activated T lymphocytes, which has been shown to play a crucial role in the down-regulation of T-cell activation. Herein, we have examined the impart of a genetic marker in the CTLA-4 gene on renal transplant outcomes. A cohort of 144 renal recipients and 100 healthy subjects were genotyped by the fragments analysis method using an automated sequencer. Patients were classified into two groups: Group I included 31 HLA-identical haplotype allograft recipients and Group II, 113 showing one or more HLA haplotype mismatches. Forty patients (27.78%) developed at least one acute rejection episode (ARE): 9 in Group I and 31 in Group II. Before transplantation, 20 patients were lymphocytotoxic antibodies (LCT) positive: 4 Group I, 2 of whom developed an ARE, and sixty in Group II, including 8 with an ARE. The occurrence of an ARE was associated with the presence of LCT before transplantation among the entire cohort of patients (P = .032) and among Group II (P = .037). The allelic frequencies of (AT)n polymorphism did not reveal significant differences between patients and controls. The most prevalent alleles were the 88 bp (51% in controls and 44.44% in patients) and the 106 bp (8% and 10.76%, respectively). We noticed an increase of the 120 bp allele frequency among patients who had undergone an ARE compared with those who did not display this complication (8.75% vs 3.85%). Likewise, among LCT-negative Group I, recipients the incidence of the 120 bp allele was higher in ARE than non-ARE patients. Although the differences were not statistically significant, we propose that the 120 bp allele of the CTLA-4 gene (AT)n microsatellite a predisposes to acute rejection episodes in renal transplantation.     

Association of the tissue kallikrein gene promoter with ESRD and hypertension

BACKGROUND: Kallikreins have long been implicated in human essential hypertension and associated complications. In particular, low urinary kallikrein excretion has been associated with hypertension and renal disease in African Americans. In an effort to identify the source of differential kallikrein excretion, we investigated the promoter of KLK1, the tissue kallikrein gene. The KLK1 promoter is uniquely polymorphic with a poly-G length polymorphism coupled with multiple single base substitutions. In this report, we genetically evaluated the association of KLK1 gene promoter alleles with end-stage renal disease (ESRD) in African Americans. METHODS: A total of 15 haplotypes were identified in the KLK1 promoter region through detailed DNA sequence analysis. This polymorphic region was then genetically evaluated for association with ESRD in African Americans with diabetic and non-diabetic etiologies of ESRD. RESULTS: The complex polymorphic nature of the promoter presents challenges to determining the alleles. We have redefined the region as six separate loci: five substitution loci and one length locus. The length locus was defined as G repeats starting at position -130 and ending at -121 on the gene. Among four relevant substitution loci for this study, one at position -131, just outside the G repeats, is an A-to-G substitution. The other three variant positions are -129, -128, and -127, all G-to-C substitutions within the G repeats. This region was genotyped in African American subjects with and without ESRD using semiautomated sequencing. Four different G repeat alleles ranging from 11.8% for 12 Gs to 52.3% for 10 Gs were observed in 86 control subjects. The C substitution of Gs ranges from 2.9% at position -127 to 8.2% at -129. When affected probands from each of 76 hypertensive ESRD families were genotyped, an association for the 12 G allele, the longest of the length locus alleles, was detected (allele specific P = 0.004 and locus total P = 0.02). When all ESRD affected individuals with hypertension from each family (107 patients in total) were used in the analysis, an even stronger association was observed for this allele (allele specific P = 0.003, locus total P = 0.01). This allele was more frequent in the hypertensive (non-diabetic) patients (0.20 in probands and 0.19 in all ESRD cases) than in the controls (0.12). No evidence of association in diabetic ESRD patients was observed (P = 0.93). CONCLUSIONS: The KLK1 promoter is uniquely polymorphic. The observed genetic association suggests an etiologic effect of the KLK1 promoter on hypertension and/or hypertension associated ESRD.     

Association of an IL-1A 3'UTR polymorphism with end-stage renal disease and IL-1 alpha expression

BACKGROUND: We evaluated polymorphisms in the interleukin-1 alpha 3'-untranslated region (IL-1A 3'[UTR]) for association with type 2 diabetes-associated (DM) and nondiabetic-associated (non-DM) end-stage renal disease (ESRD) in two ethnic groups. METHODS: IL-1A 3'UTR polymorphisms were identified by alignment of overlapping human expressed sequence tags (ESTs). Sequence ambiguities were experimentally confirmed and variants genotyped to test for association with ESRD in 75 unrelated Caucasians with DM ESRD, 95 unrelated Caucasian controls and, in a parallel study, 92 unrelated African Americans with type 2 DM ESRD, 95 unrelated African Americans with non-DM ESRD, and 86 unrelated African American controls. IL-1A 3' UTR genotype and lipopolysaccharide (LPS)-stimulated IL-1 alpha protein levels were measured in healthy Caucasians (N = 112) and African Americans (N = 101) to evaluate association between genotype and protein level. RESULTS: A polymorphism in the 3' UTR of the human IL-1A gene was associated with ESRD and IL-1 alpha protein expression. The polymorphism consists of two single nucleotide polymorphisms (SNPs) and an insertion/deletion generating four different haplotypes: TN7TTCAA, AN7TTCAA, TN7TTCAG and an allele deleted for four internal bases, TN7(delTTCA)A. The 4 bp deletion allele, TN7(delTTCA)A, was significantly less common among Caucasian DM ESRD and African American non-DM ESRD patients (recessive model; P = 0.0364 and P = 0.0293, respectively). In vitro, this polymorphism is associated with the amount of IL-1 alpha protein synthesized in LPS-stimulated lymphocytes from healthy subjects (P = 0.0013, additive model), with the TN7(delTTCA)A haplotype associated with higher levels of stimulated IL-1 alpha. CONCLUSION: The association of the TN7(delTTCA)A haplotype with higher levels of IL-1 alpha expression and reduced risk for ESRD is consistent with involvement of cytokines in risk for developing nephropathy.     

Angiotensin-converting enzyme activity and the ACE Alu polymorphism in autosomal dominant polycystic kidney disease.

BACKGROUND: Previous studies concerning Alu I/D polymorphism in the ACE gene and ADPKD severity have used the Alu genotypes as a representative of the true biological variable, namely ACE activity. However, wide individual and ethnic differences in the proportion of variance in ACE activity explained by the I/D genotype may have confounded these studies. This investigation examines the association between ADPKD severity and ACE in terms of plasma enzyme activity and I/D genotypes in individuals from three different countries. METHODS: Blood samples were collected from 307 ADPKD patients (116 Australian, 124 Bulgarian and 67 Polish) for determination of ACE activity levels and I/D genotypes. Chronic renal failure (CRF) was present in 117 patients and end-stage renal failure (ESRF) in 68 patients. RESULTS: ACE activity was related to the I/D genotype, showing a dosage effect of the D allele (P=0.006). The proportion of variance due to the Alu polymorphism was 14%. No difference in ACE activity and I/D genotype distribution was found between patients with CRF versus normal renal function (P=0.494; P=0.576) or between those with ESRF versus those without ESRF (P=0.872; P=0.825). No effect of the I/D genotype on age at development and progression to renal failure (CRF; ESRF) was detected in the overall group, and in subgroups based on ethnic origin, linkage status and sex. CONCLUSION: ACE is not likely to play a role as a determinant of ADPKD phenotype severity.     

Interleukin 1 receptor antagonist and tumor necrosis factor-alpha gene polymorphism in patients with end-stage renal failure

End-stage-renal disease (ESRD) is a final result of various etiologies. Prognostic indicators leading to ESRD in chronic kidney diseases have been studied extensively, of which, genetic factors remain a subject of great concern. Interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) are potent proinflammatory cytokines that are involved in several chronic kidney diseases. Studies on cytokine gene polymorphism have revealed important information about the role of genetic factors in disease susceptibility and severity. Gene polymorphism of interleukin-1 receptor antagonist (IL-1ra) and TNF-alpha were determined in 297 ESRD patients and in 145 normal healthy controls. IL-1ra gene polymorphism was characterized as a variable number of tandem repeats of a 86 bp sequence within intron 2. Five alleles were identified and were designated as IL1RN*1, IL1RN*2, IL1RN*3, IL1RN*4, and IL1RN*5, corresponding to 4,2,5,3, and 6 repeats, respectively. A polymorphism in the promoter region of the TNF-alpha gene was also studied. This polymorphism involved a guanidine to adenosine transition at position -308 and was designated as TNF1 (- 308 G) and TNF2 (-308 A). The genotypes and allele frequencies were compared between patients and control group. The distributions of genotypes of IL-1ra and TNF-alpha did not differ significantly between ESRD patients and normal controls. Analysis of allele frequencies revealed a trend toward an increase in IL1RN*2 frequency (7.5% versus 3.8 %, p=0.064) and noncarriage of TNF2 in the patient group (7.2% versus 11.0%, p=0.076) when compared with the control group. When both alleles were considered together, the patient group had a significantly higher frequency of carriage of IL1RN*2 in combination with noncarriage of TNF2 (p=0.0468). We conclude that carriage of IL-1RN*2 and noncarriage of TNF2 allele appear to be poor prognostic factors in patients suffering from various chronic renal diseases that eventually enter end-stage renal failure.     

Association of Human Leukocyte Antigen Haplotypes With End-Stage Renal Disease in Vietnamese Patients Prior to First Transplantation

IntroductionThe prevalence of chronic kidney failure is significantly increasing in Vietnam, causing a burden for health care. This study assessed the relationship of HLA-A, -B, and –DRB1 alleles with end-stage renal disease (ESRD).MethodA retrospective, cross-sectional study and a comparative study using secondary data analysis were conducted on 196 ESRD patients and 187 controls from 2009 to 2017. The patient and donor profiles were collected from medical records, including age, sex, etiology of renal failure, and HLA phenotypes. HLA-A*, -B*, and -DRB1* typing were done by polymerase chain reaction-sequence specific primers.ResultThe most frequent HLA alleles in Vietnamese patients with ESRD were HLA-A*02, -A*11, -B*15, -B*46, -DRB1*04, -DRB1*09, and -DRB1*12. The haplotypes HLA-A*0233 (odds ratio [OR] = 0.40, 95% CI: 0.15–0.98) had a negative association for ESRD. The haplotypes HLA-B*1515 (OR = 4.14, 95% CI: 1.52–11.26) and HLA-DRB1*1212 (OR = 2.01, 95% CI: 1.06–3.81) had a positive association for ESRD. The haplotypes HLA-B*1515 (OR = 4.69, 95% CI: 1.69–13.03) and -DRB1*1212 (OR = 2.15, 95% CI: 1.10–4.21) had a positive association for ESRD related to glomerulonephritis. The HLA-B*1557 (OR = 17.34, 95% CI: 2.70–11.49) had a positive association for ESRD related to hypertension.ConclusionThe haplotypes of HLA class I and II had significant relationships with ESRD. The results of our study should be confirmed in further investigations.     

Comparison between siblings and twins supports a role for modifier genes in ADPKD

BACKGROUND: Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by intrafamilial variability in renal disease progression, which could result from a combination of environmental and genetic factors. Although a role for modifier genes has been evidenced in mouse models, direct evidence in ADPKD patients is lacking. The analysis of variability in affected siblings and monozygotic (MZ) twins would help evaluate the relative contribution of environment and genetic factors on renal disease progression in ADPKD. METHODS: The difference in the age at end-stage renal disease (ESRD) and the intraclass correlation coefficient (ICC) were quantified in a large series of ADPKD siblings from western Europe and compared with the values obtained in a series of MZ ADPKD twins from the same geographic area. RESULTS: Fifty-six sibships (including 129 patients) and nine pairs of MZ twins were included. The difference in the age at ESRD was significantly higher in siblings (6.9 +/- 6.0 years, range 2 months to 23 years) than in MZ twins (2.1 +/- 1.9 years, range 1 month to 6 years; P = 0.02). Furthermore, the intraclass correlation coefficient was significantly lower in siblings than in MZ twins (0.49 vs. 0.92, respectively; P = 0.003). The intrafamilial difference in the age at ESRD was not influenced by gender. CONCLUSION: These data substantiate the existence of a large intrafamilial variability in renal disease progression in ADPKD siblings. The fact that the variability in siblings is in a significant excess of that found in MZ twins strongly suggests that modifier genes account for a significant part of this variability.     

The E-selectin gene polymorphism and carotid atherosclerosis in end-stage renal disease.

BACKGROUND: E-selectin is a cell surface glycoprotein that mediates the adhesion of leucocytes to vessels endothelium, an important early step in the atherosclerotic process. End-stage renal disease (ESRD) is a highly atherogenic disease but it is unknown whether genetic polymorphism(s) in the E-selectin gene plays a role in the severity of arterial damage in this condition. Method. In this study, we tested whether the Leu554Phe variant in the E-selectin gene is linked to carotid atherosclerosis in 134 well-characterized ESRD patients. The frequency of this polymorphism was also measured in a population sample of the same geographical area. RESULTS: A total of 84% patients had the CC genotype, 13% had the CT genotype, 3% had the TT genotype and this distribution did not differ from that in the control population. Intima-media thickness (IMT) (P = 0.01) and cross-sectional area (P = 0.02) were significantly higher in patients with the T-allele than in those without this allele. Furthermore, the degree of carotid stenosis was significantly higher (P = 0.02) in patients with T-allele than in CC patients. On multivariate analyses including the traditional and non-traditional risk factors, the Leu554Phe polymorphism was confirmed as an independent correlate of IMT (P = 0.02), cross-sectional area (P = 0.03) and carotid stenosis (P = 0.02). CONCLUSION: In ESRD, the Leu554Phe polymorphism of E-selectin gene is associated with the severity of carotid atherosclerosis, suggesting that genetically-determined alterations in the E-selectin molecule may render ESRD patients with this gene variant particularly susceptible to the detrimental effects of inflammation on the arterial wall.