Megsin 2093T-2180C haplotype at the 3' untranslated region is associated with poor renal survival in Korean IgA nephropathy patients

AIMS: Megsin is a mesangial cell-predominant gene which belongs to the serpin superfamily. The expression of megsin was upregulated and coincided with mesangial proliferation and extracellular matrix expansion in IgA nephropathy (IgAN). In the present study, we evaluated the influence of the C2093T and C2180T polymorphism within the 3' untranslated region (3'UTR) of megsin gene and its haplotypes on the development and progression of Korean IgAN patients. METHODS: Korean IgAN patients (n = 260) with a minimal follow-up of 4 years were recruited. Healthy subjects with normal renal function, normal urinalysis and normotension (n = 315) were included as controls. The polymorphisms were determined by the 5' nuclease allelic discrimination assay, and the haplotypes were constructed using the Phase program. RESULTS: The C2093T and C2180T genotype and allele frequencies were not different significantly between IgAN patients and controls. In C2093T polymorphism, patients with CC genotype showed a better renal survival than those with CT or TT genotypes by Kaplan-Meier analysis (p = 0.027). The megsin C2093T polymorphism remained an independent risk factor for progression (Cox regression model, HR for TT genotype: 3.52, 95% CI 1.69 - 7.34; HR for CT genotype: 2.15, 95% CI 1.30 - 3.57). In C2180T polymorphism, patients with TT genotype showed a better outcome than those with CC or CT genotypes (p = 0.025). The C2180T polymorphism was also an independent risk factor for progression (HR for CC genotype: 4.05, 95% CI 1.93 - 8.51; HR for CT genotype: 2.35, 95% CI 1.40 - 3.94). The two alleles showed linkage disequilibrium in phased haplotype. The patients with 2093T-2180C haplotype showed a poor renal survival compared to those with 2093C-2180T haplotype (p = 0.028). The haplotype remained an independent risk factor for progression (HR for 2093T-2180C haplotype: 2.01, 95% CI 1.44 - 2.81). CONCLUSIONS: Our results suggest that the 2093T-2180C haplotype at the 3'UTR of megsin gene is associated with rapid disease progression in Korean IgAN patients. This is the reverse of the results from the Chinese IgAN patients. Further studies are strongly needed to elucidate the reasons of disparity.     

Family-based association study showing that immunoglobulin A nephropathy is associated with the polymorphisms 2093C and 2180T in the 3' untranslated region of the Megsin gene

Immunoglobulin A nephropathy (IgAN) is considered to be a multifactorial disease with genetic and environmental factors contributing to its pathogenesis. The genes involved in susceptibility and progression of the disease have not yet been clearly elucidated. Megsin (SERPINB7) is an important candidate gene, predominantly expressed in glomerular mesangium and upregulated in IgAN. To investigate the potential role of this and other genes in IgAN, patients with biopsy-proven IgAN were recruited, as were family members, for a family-based association study. The genotypes of the polymorphisms C2093T and C2180T within the 3' untranslated region of the gene were determined by polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. The results were analyzed by transmission disequilibrium test (TDT) and haplotype relative risk (HRR). TDT analyses revealed that Megsin 2093C and 2180T alleles were significantly more transmitted from heterozygous parents to patients than expected (C2093T: 127 trios, P = 0.034, C2180T: 100 trios, P = 0.002). Extended TDT showed increased cotransmission of the 2093C and 2180T alleles (232 families, P < 0.001). HRR revealed that the 2093C and 2180T alleles were more often transmitted to patients (P = 0.014, <0.001, respectively). Genetic variation in Megsin confers susceptibility to IgAN.     

Association of Megsin 2093C/T, 2180C/T and C25663G gene polymorphism with the risk of IgA nephropathy

The association between megsin 2093C/T, 2180C/T and C25663G gene polymorphisms and IgA nephropathy (IgAN) risk remains unclear. We aimed to evaluate the association between megsin 2093C/T, 2180C/T and C25663G gene polymorphisms and IgAN risk by performing a meta-analysis. Eligible studies were searched according to predefined criteria by using electronic databases. Six articles were identified for the analysis of the association between megsin 2093C/T, 2180C/T and C25663G gene polymorphisms and IgAN risk. 2093C/T C allele was associated with IgAN risk in overall populations and Asians (overall populations: p?=?0.014, Asians: p?=?0.037). 2093C/T CC/TT genotype was not associated with IgAN risk in overall populations, Caucasians and Asians. 2180C/T C allele was correlated with IgAN risk in Caucasians (p?=?0.024). 2180C/T CC/TT genotype was not associated with IgAN risk in overall populations, Caucasians and Asians. C25663G gene polymorphism was not associated with IgAN onset in Asians. In conclusion, megsin 2093C/T C allele may be genetic marker for IgAN susceptibility in overall populations and Asians. 2180C/T C allele may be risk factor for IgAN onset in Caucasians. However, more studies should be performed in the future.     

Angiotensinogen gene variation and renoprotective efficacy of renin-angiotensin system blockade in IgA nephropathy

BACKGROUND: Blockade of the renin-angiotensin system (RAS) is well documented to be renoprotective; however, not all patients with glomerulonephritis respond well to this therapy. The interindividual variation in response to the RAS blockade may be in part genetically determined, whereas the results have been controversial. METHODS: We investigated whether the therapeutic efficacy of angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blocker on renal prognosis is modified by the angiotensinogen gene (AGT) polymorphism in immunoglobulin A nephropathy (IgAN). In total, 259 patients with histologically proven IgAN were analyzed for clinical manifestations, renal survival, and their associations with AGT A(-20)C and M235T. RESULTS: The renal prognosis of 110 patients, who received ACE inhibitors/angiotensin receptor blocker during their clinical course, was significantly better than those without ACE inhibitors/angiotensin receptor blockers despite higher blood pressures and heavier proteinuria. The Cox proportional hazards regression model showed an increased hazard ratio (HR) for urinary protein (more than 1.0 g/day) of 3.346 (P = 0.0001), hypertension of 1.949 (P = 0.01), deteriorated renal function of 3.040 (P < 0.0001), no ACE inhibitor/angiotensin receptor blocker administration of 2.725 (P = 0.0004), and the T235 and C(-20) haplotype of 1.608 (P = 0.0322). Only in patients carrying at least one M235 and A(-20) haplotype did the administration of ACE inhibitors/angiotensin receptor blockers have no significant effect on the prognosis of renal function (Kaplan-Meier, log rank test, chi2 = 0.700; P = 0.4028), whereas it was significant in patients who had other haplotypes of AGT (chi2 = 11.805; P = 0.0006). CONCLUSION: This study provides evidence that the M235T and A(-20)C genotype of AGT can influence the therapeutic efficacy of a RAS blockade on the renal survival in IgAN.     

Association between transforming growth factor beta1 gene polymorphisms and IgA nephropathy

BACKGROUND: Transforming growth factor beta1 (TGF-beta1) plays an important role in the modulation of cellular growth and differentiation in a wide variety of cell types and in the production/degradation of the extracellular matrix (ECM). We investigated whether G-800A, C-509T and Leu10-->Pro polymorphisms in the TGF-beta1 gene could be involved in the development and progression of immunoglobulin A nephropathy (IgAN). METHODS: DNA samples were obtained from 101 patients with biopsy proven IgA mesangial nephropathy and 118 healthy controls. The genotypes of G-800A, C-509T and Leu10-->Pro polymorphisms in the TGF-beta1 gene were determined by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) with MaeIII, Eco 81I and Pst I, respectively. RESULTS: No significant differences were observed in the genotype distribution of the three TGF-beta1 polymorphisms between patients and controls. The TAC haplotype (T=Leu10, A-800 and C-509 alleles, respectively) was significantly associated with IgAN (p=0.043; odds ratio (OR) =2.334, 95 % confidence interval (95%CI) 1.01-5.41). CONCLUSION: Our study suggests that the haplotype reconstruction of TGF-beta1 gene polymorphisms could be more informative than the investigation of single nucleotide polymorphisms for defining the associated risk of developing IgAN. Further research is needed on larger cohorts to confirm TGF-beta1 involvement and test other TGF-beta1 variants with possible additive or synergistic effects.     

G protein beta3 subunit C825T polymorphism in primary IgA nephropathy

BACKGROUND: The T allele of the G protein beta3 subunit (GNB3) C825T polymorphism has been associated with increased signal transduction, increased activity of the kidney Na+/H+ exchanger, and also with late-onset essential hypertension. Hypertension is a strong independent risk factor for progression in IgA nephropathy (IgAN). METHODS: We have studied this polymorphism in a regularly followed cohort of 299 biopsy-proven incident cases of IgAN, collected from 1989 to 1999 [208 males (70%)] and compared the genotypes and alleles distributions to 303 local Caucasian controls matched for the male predominance (214 males). The technique used was a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) with BseDI as restriction enzyme and specific primers, followed by gel electrophoresis. RESULTS: The TT, CT, and CC genotype frequencies were 13.7%, 45.8%, and 40.5% in IgAN, respectively, versus 7.6%, 47.2%, and 45.2% in controls, respectively (chi(2)= 6.16; P= 0.05). The excess of TT patients versus non-TT was significant in IgAN versus controls (chi(2)= 5.94; P= 0.015). The T allele frequency was 0.366 in IgAN versus 0.312 in controls (chi(2)= 3.97; P= 0.05). This data indicated that this polymorphism had a significant but mild influence on the occurrence/initiation of IgAN (RR = 1.81; 95% CI 1.07-3.07). In contrast, we could not demonstrate any significant and sustained difference in the clinical presentation and evolution of the homozygous TT patients compared to non-TT patients (CC + CT) despite a mean and median follow-up about 10 years. The progression to arterial hypertension or to chronic renal failure or to end-stage renal failure (ESRF) was not significantly different. In addition, multivariate Cox regression analysis excluded a significant independent role of C825T polymorphism on progression. CONCLUSION: The C825T GNB3 polymorphism had a mild influence on occurrence/initiation of IgAN, but played no significant role in the progression of the disease.     

Polymorphisms of the tumour necrosis factor alpha gene at position -308 and TNFd microsatellite in primary IgA nephropathy.

BACKGROUND: The development of glomerular inflammation in immunoglobulin A nephropathy (IgAN) has been associated with various cytokines, including tumour necrosis factor alpha (TNFalpha). A biallelic polymorphism in the promoter region of the TNFalpha gene (TNFA), at position -308, has been described (TNFA-1 and TNFA-2) and is associated with increased TNFalpha production for the TNFA-2 allele. Another microsatellite polymorphism has been described for TNFd, which is functional and associated with increased production of TNFalpha for the d3 allele. METHODS: We have studied these two polymorphisms in 242 Caucasian patients with biopsy-proven IgAN (169 male, 73 female), who were followed from 1990 to 1999, and in 210 appropriate local Caucasian controls (133 male, 77 female) for comparison of genotypes and allelic distribution. RESULTS: The respective frequencies of A1/A1, A1/A2 and A2/A2 TNFA genotypes were 76.4, 22.3 and 1.3% in IgAN vs 78.1, 19.5 and 2.4% in controls (P=NS). For TNFd, the frequencies of the respective genotypes d3/d3, d3/non-d3 and non-d3/non-d3 were significantly different (chi(2)=12.30, P=0.002, Pc=0.013) with an increased frequency of the low-producer genotype non-d3/non-d3 in IgAN patients (24 vs 12%). The combination of TNFA and TNFd polymorphisms demonstrated that compared with controls, patients with non-A2 and non-d3 alleles (low producers) were more common (18 vs 9%; P=0.006). In the genotype/clinical phenotype correlations, we could not demonstrate significant differences between the different subgroups of patients. However, high-producer TNFalpha patients (A2 and d3 alleles) had more chronic renal failure than others (36.6 vs 22.9%) at last follow-up and their survival without chronic renal failure (Kaplan-Meier) was lower. Nevertheless, TNFalpha polymorphisms were not an independent risk factor for the progression of the disease. CONCLUSIONS: TNFA and TNFd polymorphisms seem to influence the occurrence or initiation of the disease, but do not play a significant role, if any, in the progression of IgA nephritis.     

HLA DQ region gene polymorphism associated with primary IgA nephropathy

IgA nephropathy (IgAN) has been associated with HLA-DR4. We have recently described two non-allelic Taq I DQ beta gene-associated fragments sized 2.0 kb (T2) and 6.0 kb (T6), which strongly associate with DR4. T2 represents a polymorphism of the DQ beta gene and has been redesignated DQw8 (10th International HLA Workshop). The origin of the T6 fragment has not been determined, but probably represents a polymorphism of either the DQ beta or DX beta gene. When present together T2 and T6 define a subgroup of DR4 subjects at high risk of developing autoimmune disease. We have, therefore, studied DQ beta gene polymorphisms in IgAN. The DR antigen distribution was similar in IgAN and normal controls. The T2+/T6+ phenotype was present in 49% patients with IgAN compared to 15% of controls [P less than 0.0001, chi 2 = 32.8, Cramer's V = 0.41; relative risk = 5.5 (range, 2.8-11.0)]. Seventy-two percent of DR4+ IgAN patients and 29% of DR4+ controls were T2+/T6+ (P = 0.007, chi 2 = 17.0). These findings confirm the hypothesis that disease susceptibility genes are important in IgAN, and suggest that the putative gene(s) are located within or near to the DQ subregion. Moreover, similar DQ beta gene associations have been found in IDDM and pemphigus vulgaris, pointing to a common immunogenetic mechanism predisposing to several autoimmune diseases.     

Polymorphism of angiotensin converting enzyme, angiotensinogen, and angiotensin II type 1 receptor genes and end-stage renal failure in IgA nephropathy: IGARAS--a study of 274 Men

The impact of renin-angiotensin system (RAS) gene polymorphism on the prognosis of IgA nephropathy (IgAN) is still debated. A longitudinal study of renal prognosis in patients with IgAN was conducted to search retrospectively for a genotype-phenotype association between RAS polymorphisms and end-stage renal failure (ESRF). A classification based on serum creatinine (S(cr)) and 24-h proteinuria (24-P) measured at the time of renal biopsy was used to estimate the risk of ESRF in IgAN: stage 1 (S(cr) 150 micromol/L and 24-P < 1 g or S(cr) < or = 150 micromol/L and 24-P > or = 1 g), stage 3 (S(cr) > 150 micromol/L and 24-P > or = 1 g). Deletion/insertion polymorphism (D/I) of the angiotensin I converting enzyme gene, M235T polymorphism (T/M) of the angiotensinogen gene and A1166C polymorphism (C/A) of the angiotensin II type 1 receptor gene were determined in 274 Caucasian men with biopsy-proven IgAN (n = 86, 112, and 76 in stages 1, 2, and 3, respectively). Mean global follow-up was 6 +/- 5 yr after renal biopsy. For stages 1, 2, and 3, ESRF developed in 7 (8. 1%), 39 (34.8%), and 49 (64.4%) cases (P: < 0.0001), 11.7 +/- 4, 5.4 +/- 4, and 2 +/- 2 yr, respectively, after renal biopsy (P: < 0.001). The distributions of the three genotypes into the three stages were similar. Different distributions were observed when patients were grouped by stage and genotype: ID+DD: 72% in stage 1 versus 84.6% in stages 2 + 3 (P: = 0.02; kappa = 0.14); MT+TT: 66.2% in stages 1 + 2 versus 78.9% in stage 3 (P: = 0.04; kappa = 0.09); and AA+AC: 89.9% in stages 1 + 2 versus 97.4% in stage 3 (P: = 0.04; kappa = -0.1). However, with the use of the Cox proportional hazard model, none of the three genotypes was found to have predictive value for renal survival. Compared with S(cr) and 24-P, genotypes DD, TT, and AA are unlikely to serve as clinically useful predictors of ESRF in IgAN.     

Variants of C1GALT1 gene are associated with the genetic susceptibility to IgA nephropathy

IgA nephropathy (IgAN) is a polygenic disorder and the precise role of genetic factors remains elusive. Increasing evidences have implicated the aberrant galactosylation of IgA1 molecules in the pathogenesis of IgAN. The galactosyltransferase, core 1 beta3-Gal-T, and its chaperone, Cosmc, play important roles in beta1,3 glycosylation of IgA1 molecule. A case-control association study was performed to investigate the association between single-nucleotide polymorphisms (SNPs) of C1GALT1 and C1GALT1C1 genes and the susceptibility to IgAN. A total of 1164 subjects were enrolled, including 670 IgAN patients and 494 geographically matched healthy controls. Five SNPs, -734C/T, -465A/G, -330G/T, -292C/-, and 1365G/A in C1GALT1 were selected as tagging SNPs. The D allele and DD genotype of -292C/- in IgAN patients were significantly lower than in the controls (P<0.01). The frequency of haplotype YATIG (Y=C or T) was significantly lower in patients than in controls (0.0719 vs 0.1168, P=2.775 x 10(-4), odds ratio (OR)=0.70). The haplotype YAGDA (0.1236 vs 0.0791, P=3.815 x 10(-3), OR=1.77) and YATDG (0.0840 vs 0.0298, P=1.258 x 10(-5), OR=3.03) were significantly higher in patients than in controls. The present study suggested that the polymorphisms of C1GALT1 gene were associated with the genetic susceptibility to IgAN in Chinese population.     

Association of interleukin-10 gene G-1082A polymorphism with the progression of primary glomerulonephritis

BACKGROUND: Interleukin-10 (IL-10) is a cytokine with immunosuppressive properties. We evaluated the influence of G-1082A polymorphism in the IL-10 gene promoter, which has been associated with modified IL-10 production, on the two most common forms of primary glomerulonephritis: IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS). METHODS: We studied Caucasian patients (N= 191) with biopsy-proven glomerulonephritis (IgAN: N= 123, FSGS: N= 68) followed-up for 6.5 +/- 5.5 years. Patients were classified according to the slope of reciprocal serum creatinine (>/= or <-0.1 dL(*)mg(-1) (*)year(-1)) into group A (slow progressors, IgAN: N= 75, FSGS: N= 47) and group B (fast progressors, IgAN: N= 48, FSGS: N= 21). One hundred healthy volunteers were analyzed as control patients. G-1082A polymorphism was determined by polymerase chain reaction (PCR) amplification. RESULTS: The allele frequencies were similar in patients and control group (NS). Initial renal function, proteinuria, and blood pressure did not differ significantly between patients with different genotypes. G-1082A polymorphism was associated with the progression of both IgAN and FSGS: GA/AA genotypes were more frequent in group B (fast progressors) than in group A (slow progressors; P= 0.012 for IgAN, P < 0.05 for FSGS). Patients with the GA/AA genotypes showed a worse outcome in the Kaplan-Meier analysis of renal survival (P < 0.05 for both IgAN and FSGS). The IL-10 polymorphism remained an independent risk factor for progression in multivariate analysis (Cox regression model, P < 0.05 for IgAN and FSGS). CONCLUSION: Our results suggest that IL-10 gene G-1082A polymorphism is an important marker of progression in patients with IgAN and FSGS.     

Interleukin-13 genetic polymorphisms in Singapore Chinese children correlate with long-term outcome of minimal-change disease.

BACKGROUND: Minimal-change nephrotic syndrome (MCNS) has been associated with atopy. As interleukin-13 (IL-13) has been implicated in the pathogenesis of MCNS, we postulated that IL-13 genetic polymorphisms could influence either susceptibility or clinical course of the disease. METHODS: Seventy-two Singapore Chinese children with MCNS and 78 normal controls were screened for single nucleotide polymorphisms (SNPs) in the IL-13 gene by direct sequencing. Allele and genotype frequencies of these SNPs were determined and their relationship with different clinical courses was analysed. RESULTS: Six SNPs were identified in the 5' promoter, exon 4 and 3' untranslated region (3'UTR). The three SNPs in the 3'UTR--4738 (G/A), 4793 (C/A) and 4926 (C/T)--were in tight linkage disequilibrium (Delta > or = 0.99). There was no difference in allele or genotype frequencies between MCNS children and normal controls. However, there was a significantly lower frequency of allele 4738G in those MCNS children who were still relapsing after 5 years of follow-up (G = 0.52), compared with those in complete remission (G = 0.72; P<0.05) and normal controls (G = 0.69; P<0.05). Haplotype analysis showed a significantly higher frequency of the GCC haplotype in controls and MCNS patients in complete remission (chi2 = 6.35; P<0.02), while the frequency of AAT haplotype was higher in those MCNS children still relapsing after 5 years of follow-up (chi2 = 5.38; P<0.02). Moreover, peripheral blood mononuclear cell IL-13 mRNA expression in patients with haplotype AAT was significantly higher than in those with haplotype GCC. CONCLUSIONS: These results suggest that genetic polymorphisms in the 3'UTR of the IL-13 gene correlate with long-term outcome of MCNS, rather than disease susceptibility, in Singapore Chinese children.     

Systemic and vascular inflammation is elevated in early IgA and type 1 diabetic nephropathies and relates to vascular disease risk factors and renal function.

BACKGROUND: Inflammation is implicated in cardiovascular disease (CVD) and mortality in end-stage renal failure (ESRF). Its importance in early renal disease is yet to be defined. METHODS: Serum levels of systemic and vascular inflammatory markers in early IgA nephropathy (IgAN) and control subjects were measured and related to renal function and vascular risk factors. A parallel study in type 1 diabetes mellitus subjects with (T1DM Nx) and without nephropathy (T1DM No Nx) was performed. RESULTS: Fifty-one IgAN patients aged 46+/-2 years (mean+/-SEM), calculated creatinine clearance (CrCl) 88+/-5 ml/min, were compared with 51 matched control subjects. Forty-six T1DM Nx patients aged 40+/-2 years, CrCl 84+/-5 ml/min, and 73 T1DM No Nx patients aged 38+/-2 years were also compared. High sensitivity C-reactive protein (hsCRP) was elevated in IgAN, T1DM Nx and T1DM No Nx patients compared with controls [4.2+/-0.6 (P < 0.001), 4.1+/-0.6 (P < 0.001), 2.6+/-0.4 (P < 0.05) vs 1.6+/-0.3 mg/l]. Levels in T1DM Nx patients were higher than in T1DM No Nx patients (P < 0.05). Inflammation and vascular dysfunction as measured by pulse pressure (PP) were related. HsCRP correlated with PP in IgAN and T1DM Nx (r = 0.47, P = 0.001; r = 0.40, P < 0.05). PP was the strongest independent predictor of hsCRP in IgAN (T = 2.45, P < 0.001), while body mass index (T = 7.83, P < 0.001) was the strongest predictor in T1DM Nx. Endothelial cell adhesion molecules were increased in T1DM Nx > IgAN > T1DM No Nx vs controls: soluble vascular adhesion molecule-1 (sVCAM-1) 760+/-30 (P < 0.001) > 663+/-34 (P = 0.001) > 601+/-21 (P < 0.05) vs 536+/-15 ng/ml; soluble intracellular adhesion molecule-1 (sICAM-1) 320+/-8 (P < 0.001) > 313+/-13 (P < 0.001) > 307+/-8 (P < 0.001) vs 244+/-6 ng/ml. sVCAM-1 levels were higher in T1DM Nx than in T1DM No Nx, P < 0.001. In IgAN and T1DM Nx, hsCRP correlated with sICAM-1 (r = 0.33, P = 0.017; r = 0.37; P = 0.017). sVCAM-1 was related to renal function in IgAN and T1DM Nx: serum cystatin C (r = 0.63, P < 0.001: r = 0.425, P = 0.002), and urine protein:creatinine ratio in IgAN (r = 0.48; P = 0.001). CONCLUSIONS: Systemic and vascular markers of inflammation are increased in early renal disease and relate to renal dysfunction and cardiovascular risk factors. Inflammation may be a common process in various renal diseases and may link and accelerate renal dysfunction and CVD.     

Association of hypertension genotypes and decline in renal function after kidney transplantation

BACKGROUND: Polymorphisms of genes such as angiotensin-converting enzyme (ACE), angiotensinogen (AGT), and angiotensin receptor type I (AGTR1) have been associated with hypertension. Hypertension, in turn, has been associated with decreased renal allograft survival. Therefore, this study investigated whether single nucleotide polymorphisms (SNPs) in these genes are associated with decline in renal function posttransplantation. METHODS: We enrolled patients from a prospective cohort of renal transplant recipients of deceased donor kidneys being conducted at 9 centers in the Delaware Valley Region. Medical records were assessed every 6 months and estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease equation. Genotypes of 10, 2, and 5 SNPs in the AGTR1, AGT, and ACE gene were analyzed, respectively. RESULTS: The G and the T alleles of the respective AGTR1 SNPs rs275704 and rs5182 were both associated with 50% decline in eGFR (HR for rs275704: CG=1.22, 95% confidence interval [CI] 0.67-2.25 and GG=2.55, 95% CI 1.22-5.32, overall P=0.03; HR for rs5182: CT=1.26, 95% CI 0.72-2.19 and TT=3.09, 95% CI 1.50-6.37, overall P=0.007) in the adjusted analysis. Similarly, haplotype analysis showed that AGTR1 SNPs were associated with 50% decline in eGFR (global P=0.010). The GG genotype of SNP rs275704 occurred more frequently in African Americans than in non-African Americans (44% vs. 7%, chi2=36.03, P<0.0001). In contrast, the TT genotype of SNP rs5182 occurred more frequently in non-African Americans than in African-Americans (24% vs. 2%, chi2=21.40, P<0.0001). Polymorphisms in the ACE and AGT genes were not associated with renal allograft outcomes. CONCLUSIONS: SNPs in AGTR1 gene are associated with decline in renal function posttransplantation.     

Susceptibility to type 1 diabetes is associated with ApoCIII gene haplotypes

Type 1 diabetes is a disease of beta-cell destruction leading to insulin deficiency. Genes for type 1 diabetes have been identified; however, much of the genetic risk remains unexplained. Genetic variation within the apolipoprotein CIII (apoCIII) gene alters apoCIII levels, which are increased in type 1 diabetes and induce beta-cell apoptosis. We therefore hypothesize haplotypes within the apoCIII gene are associated with type 1 diabetes. DNA from 584 type 1 diabetic patients and 591 control subjects were genotyped for six single nucleotide polymorphisms (SNPs) in the apoCIII gene (C-641A, C-482T, T-455C, C1100T, C3175G, and T3206G). Two alleles of a haplotype block (promoter SNPs + C3175G) were associated with type 1 diabetes. The A-T-C-C allele frequency was higher in type 1 diabetes (0.19 vs. 0.16, P = 0.05), and the C-C-T-C allele was reduced in type 1 diabetes (0.60 vs. 0.65, P = 0.04). The odds ratio (OR) for A-T-C-C allele increased with 0, 1, and 2 copies (OR of 1.00, 1.24, and 1.60, respectively; P = 0.05) and decreased for the C-C-T-C allele (1.00, 0.97, and 0.73, respectively; P = 0.03). This haplotype block contains an insulin response element. Screening for this haplotype may identify at-risk individuals, and this pathway may offer a target for prevention of type 1 diabetes.     

存在肾小动脉微血管病变且非高血压IgA肾病患者的临床病理特点和预后分析

目的总结和分析非高血压的IgA肾病(IgA nephropathy,IgAN)合并肾小动脉微血管病变(microangiopathy,MA)患者的临床病理特点和预后。方法抽取北京大学第一医院IgAN前瞻性队列人群中非高血压成人患者,重新进行病理阅片,根据肾小动脉病变,分为MA组、动脉硬化病变(AS)组和无血管病变组,分析其临床病理及预后特点。复合肾脏终点事件包括终末期肾病或估算肾小球滤过率(eGFR)下降≥30%。采用Cox回归模型分析预后的危险因素。结果共420例IgAN患者被纳入本研究,其中37(8.8%)例患者合并MA,134(31.9%)例合并AS,其余249例无血管病变。相对于AS组或无血管病变组,合并MA的患者尿蛋白量更严重[1.47(1.08,2.84)g/d比1.31(0.68,2.56)g/d、1.04(0.55,2.00)g/d,P=0.002],肾功能更差[eGFR:(75.3±26.5)ml·min-1·(1.73 m2)-1比(85.7±27.0)ml·min-1·(1.73 m2)-1、(98.6±24.8)ml·min-1·(1.73 m2)-1,P<0.001],并有更高的节段性肾小球硬化和(或)球囊粘连(S1)、肾小管萎缩/间质纤维化(T1/2)、细胞/细胞纤维新月体病变(C1/2)比例(均P<0.05)。随访期间,合并MA的患者发生终点事件比例更高[54.1%比33.6%、32.9%,χ2=6.491,P=0.039]。Cox多因素分析模型显示,MA是IgAN发生进展的独立危险因素(HR=1.872,95%CI 1.044~3.357,P=0.035),而其他类型血管病变不影响预后。结论非高血压IgAN患者合并MA不少见,这提示高血压并非导致IgAN血管病变的唯一危险因素。     

IgA synthesis by lymphocytes from patients with IgA nephropathy and their relatives

To investigate the hypothesis that a predisposition to IgA nephropathy (IgAN) is linked to the major histocompatibility complex (MHC) and associated with poorly regulated IgA synthesis, we performed HLA typing and lymphocyte cultures on patients with IgAN and their relatives. Nineteen of 22 patients had elevated culture supernatant IgA concentrations (620 vs. 154 ng/2 X 10(6) cells, P = 0.007). Supernatant IgG and IgM were normal. No HLA antigen occurred with increased frequency in patients. There was an increased incidence of homozygous null C4 alleles in patients (P less than 0.01). In families, six of 11 mothers, six of 12 fathers, and seven of 15 siblings had elevated supernatant IgA concentrations. There was no segregation of abnormal IgA production with any HLA antigen or parental haplotype. The data confirm elevated in vitro IgA production by lymphocytes from patients with IgAN, but do not support a linkage with the MHC. The increased incidence of homozygous null C4 alleles may result from functional differences in C4 A and B gene products. The familial clustering of elevated IgA production without an obvious inheritance pattern suggest that shared environmental factors may be important in the development of IgAN.