GNB3 C825T等位基因多态性与原发性IgA肾病相关性研究

目的：研究G蛋白β3亚基（GNB3）C825T等位基因多态性与原发性IgA肾病（IgAN）的发生与病情进展。方法：病例组为216例原发性IgAN患者,对照组为200例健康志愿者。采用聚合酶链式反应-限制性片段长度多态性（PCR-RFLP）技术检测各组GNB3 825位点基因型。病例组分为高血压组与非高血压组;同时按基因型的不同将病例组分为TT组、CT组与CC组。结果：（1）病例组与对照组TT、CT、CC基因型频率分别为21.76%、54.63%、23.61%与18.00%、47.00%、35.00%,两组TT、TC、TT＋TC基因型与CC基因型分布频率存在统计学差异（P〈0.05）;病例组T等位基因分布频率高于对照组（49.07%vs 41.50%,P〈0.05）。（2）216例IgAN中,高血压组与非高血压组TT、CT、CC基因型频率分别为32.88%、49.31%、17.81%与16.09%、57.34%、26.57%（P〈0.05）。高血压组T等位基因频率较非高血压组明显增加（57.53%vs 44.76%,P〈0.05）。（3）病例组不同基因型携带者病理分级轻重无统计学差异（P〉0.05）。（4）病例组中不同基因型携带者在性别、年龄、体重指数、尿蛋白排泄量（〉1 g/d）、血肌酐水平、血胆固醇水平及三酰甘油水平无统计学差异（P〉0.05）,而高尿酸血症的发生存在统计学差异（P〈0.05）,TT组高尿酸血症患者较CT组及CC组高。结论：（1）病例组TT基因型和T等位基因频率较对照组明显增加,结果显示GNB3 825T等位基因可能与IgA肾病的发病有关,提示该基因可能与IgA肾病的遗传易感性相关。（2）GNB3 825T等位基因能影响IgA肾病患者高血压、高尿酸血症的发生。GNB3C825T等位基因多态性与IgA肾病发病及病情进展的相关机制有待进一步研究。     

Sildenafil response is influenced by the G protein beta 3 subunit GNB3 C825T polymorphism: a pilot study

PURPOSE: Sildenafil is the oral phosphodiesterase-5 inhibitor that revolutionized treatment for erectile dysfunction. We investigated a potential association of the G protein beta 3 subunit (GNB3) C825T polymorphism, a determinant of intracellular signal transduction, with the drug response to sildenafil in patients with erectile dysfunction. MATERIALS AND METHODS: In 113 men with erectile dysfunction and 111 healthy male controls genotype status of the GNB3 C825T polymorphism was determined by polymerase chain reaction and restriction analysis. Patients with erectile dysfunction received sildenafil at a dose of 25 to 100 mg. according to the individual erectile response. Drug response was measured by interviewing the patient according to the erection scale of 0 to 5. RESULTS: The GNB3 genotype distribution of patients with erectile dysfunction exactly matched that of healthy controls. Analysis of the response to sildenafil revealed a significant association of C825T allele status with the erectile response to sildenafil. In the group with TT genotype we observed a 90.9% response but only a 50.9% and 48.9% response in patients with the CC and TC genotype, respectively. The odds ratio for a positive erectile response was 10.0 (95% CI 1.2 to 81.1) for patients with the TT versus the TC/CC genotype (p = 0.01). CONCLUSIONS: The response to sildenafil is significantly associated with GNB3 C825T genotype status in patients with erectile dysfunction.     

Association between the clara cell secretory protein (CC16) G38A polymorphism and the progression of IgA nephropathy

AIMS: Clara cell secretory protein (CC16) is a protein with anti-inflammatory and immunomodulatory properties. Moreover, both CC16 gene knockout and antisense-transgenic mouse models developed glomerulonephritis resembling IgA nephropathy (IgAN). In the present study, we evaluated the influence of the G38A polymorphism in the CC16 gene exon 1 on the development and progression of IgAN. METHODS: Korean patients with biopsy-proven IgAN (n=267) with a minimal follow-up of 4 years (mean +/- SD 103.8 +/- 52.6 months) were recruited. Healthy normal subjects (n=315) were included as controls. The G38A polymorphism was determined using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: GG, GA and AA genotype frequencies were 36.3, 50.2 and 13.5% in IgAN patients, respectively, and 34.3, 50.2 and 15.5% in controls (chi2 = 0.596, p = 0.742). The G allele frequency was 0.614 in IgAN patients and 0.594 in controls (chi2 = 0.429, p = 0.512). Moreover, the GG genotype frequencies were 40.4% in patients showing stable disease course and 26.6% in those with progressive disease (chi2 = 4.029, p = 0.045). Patients with the GG genotype showed a better outcome by Kaplan-Meier analysis in terms of renal survival (p = 0.043). The CC16 polymorphism remained an independent risk factor for progression after multivariate analysis (Cox regression model, HR for CC16 AA genotype: 2.34, 95% CI 1.19-4.64, p = 0.014). CONCLUSION: Our results suggest that CC 16 gene G38A polymorphism is not associated with the development of IgAN, but that it is an important marker of progression in IgAN.     

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.     

Association study of the G-protein β3 subunit C825T polymorphism with disease progression in patients with bladder cancer

The T-allele in the GNB3 C825T polymorphism has been associated with increased cell migration, a prerequisite for metastasis. In this study we investigated a potential association of the C825T-allele status and disease progression in patients with transitional cell carcinoma of the bladder (TCC). Genotyping of the GNB3 C825T polymorphism was performed in 389 patients with transitional cell carcinoma of the bladder and in 104 control subjects and clinical follow-up was worked up in 339 patients. Genotype distribution in 389 patients with bladder cancer was comparable to genotype distribution of the control group. There was no association of GNB3 C825T genotype with tumor stage or grade, but follow-up analysis in the subgroup of non-smokers revealed a shorter time to metastasis in 825T-allele carriers compared to individuals homozygous CC. The genotype of the GNB3 C825T polymorphism appears to influence the biological behavior of tumor disease in non-smoking TCC patients. This work was supported by a grant of the Deutsche Forschungsgemeinschaft     

Genotyp des GNB3-C825T-Polymorphismus

Background

G protein-mediated signal transduction plays a key role in pathways of metastasis. A C/T polymorphism (dbSNP rs5443) at position 825 of the GNB3 gene has been described. Previous studies demonstrated an association between the GNB3 C825T genotype and different cancer entities.

Patients and methods

In this report genotyping for this marker was performed in 235 prostate cancer patients and 111 healthy control subjects. Clinical follow-up data were available for a subset of 197 patients.

Results

Neither significant evidence for differences in genotype distributions between the prostate cancer cases and controls (odds ratio CT/TT=0.94, 95% CI 0.58?C1.51, p=.82) nor evidence for genotype differences in e.g. progression-free survival in the subset of patients was observable (hazard ratio CT/TT=0.77, 95% CI 0.44?C1.37, p=.38). Similar results were obtained in the subgroup of patients with primary tumor stage ?? pT2 N0 M0 undergoing radical prostatectomy.

Conclusion

Our data do not support an association between prostate cancer and the genotype of the GNB3 C825T polymorphism. This finding might either indicate a much smaller genetic effect undetectable with the given sample size or a possible hormone dependence of the disease superimposed on the potential effect of the GNB3 C825T genotype.     

Increased frequency of G-protein beta 3-subunit 825 T allele in dialyzed patients with type 2 diabetes

BACKGROUND: A polymorphism (C825T) in exon 10 of the gene encoding the beta 3 subunit of heterotrimeric G proteins (GN beta 3) has recently been described, and the T allele was found to be associated with late-onset hypertension. Because hypertension is a known risk factor for the development of clinically manifest progressive renal disease, we examined the C825T polymorphism in older hemodialysis patients suffering from nondiabetic renal disease or type 2 diabetes with presumed diabetic nephropathy, respectively, and in older healthy controls. METHODS: Genotyping was performed by polymerase chain reaction, followed by restriction enzyme analysis. RESULTS: The study showed that the frequency of the T allele in the nondiabetic patients on dialysis (0.232) was significantly (P < 0.03) lower than in older healthy controls (0.293). In contrast, the frequency was significantly (P < 0.02) higher in older patients with type 2 diabetes on dialysis. No significant change in T-allele frequency was noted in older patients with type 2 diabetes without microangiopathy (0.286). The odds ratios for patients with type 2 diabetes on dialysis versus nondiabetic patients on dialysis were 3.24 (1.3 to 7.9, P < 0.00079) for TT/CC and 1.82 (1.07 to 3.09, P < 0.02) for CT/CC. The respective odds ratios for patients with type 2 diabetes on dialysis versus controls were 2.05 (1.07 to 3.9, P < 0.028) for CT/CC and 1.216 (0.79 to 1.87; P < 0.37) for CT/CC. CONCLUSION: The data do not support a role of the hypertension-associated T allele in the genesis of dialysis-dependent end-stage renal failure in general, but are compatible with a specific role of the T allele in the development or progression of diabetic nephropathy.     

Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with osteoporotic vertebral fractures, but is a weak predictor of BMD

Osteoporosis is a common disease with a strong genetic component. Linkage studies have suggested linkage between BMD and loci on chromosome 1. The MTHFR gene is located on chromosome 1. MTHFR catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methylenetetrahydrofolate, which is used for homocysteine methylation to methionine. The rare genotype (TT) of the C677T polymorphism has previously been demonstrated to be associated with increased plasma homocysteine levels in individuals with inadequate plasma folate levels. Recently, the TT genotype has been found to be associated with reduced bone mass. We therefore examined if the C677T polymorphism in the MTHFR gene is associated with changes in bone mass and risk of osteoporotic fractures in 388 osteoporotic patients and 336 normal individuals. The distributions of the genotypes CC, CT and TT in women with osteoporotic vertebral fractures and normal controls were 43.5%, 42.2% and 14.3% and 52.0%, 42.0% and 8.0%, respectively, ²=5.62, P=0.06. Since studies of the functionality of this polymorphism have revealed that only the TT genotype is associated with biochemical changes, we also compared the prevalence of the TT genotype versus the CT- and CC genotypes in patients and controls and found that the TT genotype is significantly more common in women with vertebral fractures (14.3%) compared with normal controls (8.0%), ²=4.31, P<0.05. Logistic regression analysis demonstrated that vertebral fractures were significantly associated with BMD (lumbar spine) and height but only marginally with the MTHFR genotype (P=0.06). Multiple linear regression analysis revealed that weight, age and the MTHFR polymorphism were predictors of lumbar spine BMD in women. However, age- and gender-corrected BMD of the lumbar spine and the hip was not significantly different between MTHFR genotypes. Furthermore, individuals with the TT genotype did not have BMD significantly lower than the combined group of individuals with the CT- or CC genotypes. In conclusion, we have demonstrated that the rare TT genotype of the C677T polymorphism in the MTHFR gene is associated with increased risk of osteoporotic fractures in women and a weak predictor of lumbar spine BMD.     

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.     

DNA损伤修复基因XRCC1 Arg194Trp基因多态性与中国人群结直肠癌易感性的Meta分析

【摘要】 目的 探讨DNA损伤修复基因XRCC1 Arg194Trp基因多态性与中国人群结直肠癌易感性的关系。方法 按照制定的检索策略,通过计算机和手工检索相关数据库,收集有关XRCC1 Arg194Trp基因多态性与中国人群结直肠癌易感性的病例对照研究,按照纳入标准筛选文献、并从纳入文献中提取相关数据,以病例组和对照组基因型分布的比值比(OR)为效应指标,应用Stata12.0软件进行异质性检验,对各研究原始数据进行Meta合并,并行敏感性分析和发表偏倚的评估。结果〓本Meta分析共纳入11项病例对照研究,累积病例2710例,对照3567例。根据各研究间的异质性,采用不同的模型进行合并效应量。在等位基因比较(T vs C) [OR(95%CI)=1.18(1.01-1.39),P=0.036],纯合子比较模型(TT vs CC) [OR (95%CI)=1.39(1.02-1.90),P=0.038],显性模型(CT/TT vs CC) [OR(95%CI)=2.24(1.78-2.82),P<0.001] 以及隐性模型 (TT vs CT/CC) [OR(95%CI)=1.23(1.02-1.49),P=0.030]均存在显著的统计学差异。发表偏倚评估均未见明显偏倚。结论〓在中国人群中,携带突变等位基因T或突变纯合子TT的人群罹患CRC的风险有所升高,而在显性遗传模型中,携带有CT/TT基因型的人群其CRC的易感性明显升高。     

CC-chemokine receptor five gene polymorphism in primary IgA nephropathy: the 32 bp deletion allele is associated with late progression to end-stage renal failure with dialysis

The chemokine (CK) receptor 5 (CCR5) is necessary for two adjacent cysteines (CC)-CKs such as Regulated upon Activation Normal T cell Expressed and Secreted, a/o Macrophage Inflammatory Protein 1alpha/beta to mediate their inflammatory properties. The CCR5 gene polymorphism with 32-basepair deletion (d32) leads to receptor inactivation/dysfunction in homo/heterozygous individuals. We have evaluated its role in both initiation and/or progression of primary immunoglobulin A (IgA) nephropathy (IGAN) in a case-control study involving a prospective cohort of 318 IGAN patients and a matched group of 294 controls. Genotyping was performed by a two-specific primers single polymerase chain reaction technique: normal allele (nl) vs d32 allele. The d32 allele frequency was not different in patients (11.0%) vs controls (8.3%), indicating no significant influence on IGAN initiation. Genotype to clinical phenotype correlation demonstrated that progression to renal/patient death was associated with the d32 allele: 18.2% (12 out of 66 with d32) vs 8.3% (21 out of 252); chi(2)=6.73; P=0.017. The Kaplan-Meier survival without renal/patient death was worse in d32-positive patients (log-rank test; P=0.002). The Cox regression analyses confirmed that the nl/nl genotype was a significant and independent protective factor for progression to end-stage renal failure (ESRF)/dialysis: beta/standard error (s.e.)=-3.1; chi(2)=9.5; relative risk=0.31 (95% confidence interval 0.15-0.65); P=0.002. The d32-CCR5 polymorphism played a significant role in the progression of primary IGAN, with the nl/nl genotype being an independent protective factor for late progression towards ESRF/dialysis. These data raise question about the usefulness of systematic CCR5 genotyping in IGAN patients.     

No association between a genetic variant of the p22(phox) component of NAD(P)H oxidase and the incidence and progression of IgA nephropathy.

BACKGROUND: The course of glomerulonephritis varies even within the same histological entity, which suggest that genetic factors determine the progression of inflammatory renal diseases. We studied a potential relationship between the C242T gene polymorphism of p22(phox), a subunit of the NAD(P)H oxidase, and frequency as well as progression of immunoglobulin A (IgA) nephropathy. Patients with lupus nephritis were also investigated. The distribution of the C242T gene variation of p22(phox) has not been previously studied in patients with renal disease. METHODS: Patients with IgA nephropathy were from a homogenous ethnic group of patients living in Northern Germany (n=127). Patients with active lupus nephritis WHO classes III/IV (n=46) were also studied. All diagnoses were confirmed by renal biopsy. Healthy blood donors (n=151) exhibited a genotype distribution similar to previously reported values for Caucasians (CC, 41.2%; CT, 45%; TT, 13.8%). However, C242T genotype distribution was not significantly different (chi(2) test) in patients with IgA nephropathy (CC, 44.9%; CT, 48%; TT, 7.1%) or in active lupus nephritis (CC, 54.3%; CT, 34.7%; TT, 11%). Grouping of IgA nephropathy patients as those with mild renal impairment at the time of biopsy (serum creatinine <1.3 mg/dl) and those with more severe renal failure (serum creatinine >1.3 mg/dl) also failed to show a relationship with p22(phox) polymorphism. Log-rank analysis for up to 15 years in selected cases of IgA nephropathy did not show a significant difference in renal survival rate among the three genotypes. CONCLUSIONS: It appears that the C242T polymorphism is not associated with IgA nephropathy or active lupus nephritis and may not affect the progressive deterioration of renal function in patients with IgA nephropathy. However, whether the C242T polymorphism plays a role in other renal diseases remains to be studied.     

TNFA2 and d2 alleles of the tumor necrosis factor alpha gene polymorphism are associated with onset/occurrence of idiopathic membranous nephropathy

Idiopathic membranous nephropathy (IMN) has a strong association with the major histocompatibility complex HLA B8DR3(17)DQ2 haplotype. The tumor necrosis factor (TNF)A gene is located within the major histocompatibility complex region on chromosome 6. We have studied the influence of two functional polymorphisms; the -308 (promoter region) and the TNFd microsatellites on initiation and/or progression of IMN. This was a case-control study comparing data from 100 Caucasians patients (67 male subjects; 67%) with IMN to 232 Caucasians local controls (171 male subjects; 74%). We have analyzed genotypes and alleles distributions and the role of these polymorphisms in disease progression towards end-stage renal failure or patient death. For -308 TNFA polymorphism, distribution of genotypes was significantly different between IMN and controls (chi(2)=16.25; P=0.0003): the A2 allele frequency was 28.0% in IMN vs 15.3% in controls (chi(2)=14.57; P=0.0001). For TNFd polymorphism, alleles distribution (from d1 to d7) was also significantly different between IMN and controls (chi(2)=56.74; P<0.0001) with both diminished d3 allele frequency (chi(2)=27.30; P<0.0001; Pc=0.001) and increased d2 allele frequency (chi(2)=29.95; P<0.0001; Pc=0.001) in IMN. We could not isolate any significant and independent influence of these different genotypes on IMN disease progression. The TNFA2 and TNFd2 alleles were strongly associated with occurrence/initiation of IMN and should be considered as susceptibility genes for this disease.     

Transmission of G-protein beta3 subunit C825T alleles to offspring affected with end-stage renal disease.

BACKGROUND: Results of epidemiological studies have suggested that a hereditary predisposition to the development of chronic renal failure exists, and that such predisposition might be independent from underlying etiology of kidney disease. On the other hand, high blood pressure contributes substantially to a faster rate of progression of renal damage, regardless of underlying etiology of kidney disease. In this study we tested whether GNB3 C825T polymorphism, previously reported to be associated with hypertension, contributes to predisposition to end-stage renal disease (ESRD). METHODS: GNB3 polymorphism was genotyped in 247 family trios: offspring affected with ESRD and both parents, and transmission/disequilibrium test was used to establish the allele-phenotype association. Among the examined offspring, 47 patients had ESRD in the course of type 1 diabetes and diabetic nephropathy, 120 had primary glomerulonephritis and 80 had interstitial nephritis. We observed no significant differences between the GNB3 C and T allele transmission from heterozygous parents to affected offspring. RESULTS: In the overall group of examined patients, the C:T allele transmission (%) was 48:52, while in patients with diabetic nephropathy, chronic glomerulonephritis and chronic interstitial nephritis the transmission was (%) 50:50, 48:52 and 48:52, respectively. CONCLUSION: The results of our study suggest that GNB3 C825T polymorphism does not contribute substantially to the increased risk of the development of ESRD.     

G protein polymorphisms do not predict weight loss and improvement of hypertension in severely obese patients

Both the gene encoding the α subunit of G stimulatory proteins (GNAS1) and the β3 subunit gene (GNB3) of G proteins are associated with obesity and/or hypertension. Moreover, the TT/TC825 polymorphism of GNB3 predicts greater weight loss than the CC825 polymorphism in obese patients (mean body mass index, 35 kg/m²) undergoing a structured nonpharmacologic weight loss program. Gastric banding enforces a low-calorie diet by diminishing the need for volitional adherence. It is unknown whether these polymorphisms predict the variable weight loss in patients after bariatric surgery. Three hundred and four severely obese patients (mean +- SEM age, 42 +- 1 years; 245 women and 59 men; mean +- SEM body mass index, 43.9 +- 0.3 kg/m²) followed prospectively for at least 3 years after surgery were genotyped for theGNB3C825T, G814A,andGNAS1T393 polymorphisms. All analyses were performed blinded to the phenotypic characteristics of the study group. Frequencies of polymorphisms were comparable to those previously published. No polymorphism studied predicted 3-year weight loss or was associated with high blood pressure in severely obese patients after gastric banding. Multivariate analysis of potentially confounding factors such as reoperation rate or use of sibutramine or orlistat revealed similar results (P > 0.1). Regardless of the mechanism(s) involved for these discordant findings, GNB3 C825T, G814A, and GNAS1 T393C polymorphisms do not seem to be reliable predictors of long-term weight loss. Presented at the Forty-Fifth Annual Meeting of The Society for Surgery of the Alimentary Tract, New Orleans, Louisiana, May 15–19, 2004 (oral presentation).     

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.     

CIGALTl基因多态性与维吾尔族IgA肾病易感性的关联性分析

目的探讨β1,3-转移酶（C1GALTl）基因单核苷酸位点（SNP）rs9639031、rs5882115多态性与新疆维吾尔族IgA肾病（IgA ephropathy,IgAN）遗传易感性的关系。方法选取经肾活检明确诊断为IgAN的90例维吾尔族患者为实验组,以同期在同一医院体检的90例维吾尔族健康体检者作为对照组,2组的性别和年龄等相匹配。采集纳入研究对象的外周血,提取DNA,应用PCR法扩增C1GALT1因上2个SNP分别为rs9639031、rs5882115位点对应的基因片段;采用直接测序法检测2个SNP位点的基因型,分析rs9639031、rs5882115基因型及基因频率在2组间分布的差异,进一步分析C1GAT态性与IgAN发病的关系。结果（1）C1GALT1因SNPrs5882115中各基因型、等位基因频率在IgAN组与对照组的分布有显著性差异（基因型P=0．014,等位基因P=0．005）。IgAN组DI、Ⅱ型频率（32．2％、2．2％）较对照组（14．4％、1．1％）高,对照组DE）型频率（84．4％）较IgAN组（65．6％）高。单因素Logist回归分析显示,rs5882115多态性对IgAN患病风险可能有影响（P=0．005）,携带DI基因型的患病风险为携带DD基因型的2．874倍（OR=2．874,95％CI=1．3756．007）,而携带I等位基因的患病风险亦较携带D等位基因高（OR=2．469,95％CI=1．290～４.728）。（2）C1GALT1基因rs9639031中,IgAN组CC、CT、TT基因型及c、T等位基因频率分别为40．0％、42．2％、17．8％、61．1％、38．9％,对照组分别为32．2％、46．7oA、21．1％、55．6％、44．4％,但差异无统计学意义（P〉0．05）。结论C1GALTl基因上的SNP位点rs5882115多态性可能与维吾尔族IgAN发病风险有一定关系,但未发现C1GALT1基因上的SNP位点rs9639031多态性与维吾尔族IgAN发病风险的关联性。     

The influence of G-protein beta3-subunit gene and endothelial nitric oxide synthase gene in exon 7 polymorphisms on progression of autosomal dominant polycystic kidney disease

BACKGROUND: A significant phenotypical variability is observed in autosomal dominant polycystic kidney disease (ADPKD). The variability cannot be fully explained by the genetic heterogeneity of the disease. We examined the influence of G-protein beta3-subunit C825T polymorphism and endothelial nitric oxide synthase Glu298Asp polymorphism on the progression of ADPKD towards end stage renal failure (ESRF). METHODS: 306 ADPKD patients (pts) were analyzed; 261 pts (136 males, 125 females) with ESRF, with subgroup of 73 pts (44 males, 29 females) with ESRF before 45 years (rapid progressors), 46 pts (20 males, 26 females) with ESRF later than in 63 years (slow progressors) and 45 ADPKD pts (17 males, 28 females) in mean age 51 years with serum creatinine under 110 micromol/L (slow progressors) and 100 genetically unrelated healthy Czech subjects. DNA samples from collected blood were genotyped for G-protein beta3-subunit C825T genotype in exon 10 and for endothelial nitric oxide synthase Glu298Asp genotype in exon 7. RESULTS: The G-protein beta3-subunit C825T genotype exhibited no significant differences among the groups of slow progressors (6.6% (6/91) TT, 54.9% (50/91) CT, 38.8% (35/91) CC), rapid progressors (9.6% (7/73) TT, 46.6% (34/73) CT, 43.8% (32/73) CC), ADPKD group with ESRF between 40-63 years (9.2% (13/142) TT, 50% (71/142) CT, 40.8% (58/142) CC) and control group (12% TT, 44% CT, 44% CC). When comparing the ages of ESRF of all patients with ESRF, we did not find significant differences in the ages: males TT--51.7+/-8.8 years, CT--51.9+/-10.3 years, CC--49.7+/-10.2 years and females TT--56+/-9.9 years, CT--53.2+/-8.5 years, CC--53.9+/-8.7 years. The endothelial nitric oxide synthase Glu298Asp and Asp29Asp genotypes were significantly more frequent in rapid progressors (9.6% (7/73) Asp/Asp, 39.7% (29/73) Asp/Glu, 50.7% (37/73) Glu/Glu) and in ADPKD group with ESRF between 40-63 years (11.3% (16/142) Asp/Asp, 41.5% (59/142) Asp/Glu, 47.2% (67/142) Glu/Glu) in comparison with slow progressors (8.8% (8/91) Asp/Asp, 24.2% (22/91) Asp/Glu, 67.0% (61/91) Glu/Glu) and with control group (8% Asp/Asp, 32% Asp/Glu, 60% Glu/Glu) (Chi-square test, p<0.05). Comparing the ages of ESRF of all patients with ESRF, we did not find significant differences in the ages in males with Asp/Asp--54.9+/-10.4 years, Asp/Glu--50.2+/-9.4 years, Glu/Glu--51.0+/-10.4 years. We found out in homozygous Asp/Asp females significantly earlier onset of ESRF (49.2+/-5.6 years) in comparison with heterozygous females (53.3+/-7.2 years) and with Glu/Glu homozygous females (54.8+/-9.7 years) (t-test, p<0.05). CONCLUSION: We excluded the significance of G-protein beta3-subunit C825T polymorphism on the progression of ADPKD. We established the negative prognostic value of the carriers of Asp variant of eNOS polymorphism. Finding of new modifiers could have in future clinical consequences for ADPKD patients.     

Association between MTHFR C677T polymorphism and diabetic nephropathy in the Chinese population: An updated meta‐analysis and review

To clarify the effects of MTHFR C677T polymorphism on the risk of diabetic nephropathy (DN) in the Chinese population, an updated meta‐analysis was performed. Related studies were identified from PubMed, Springer Link, Ovid and Chinese Databases up to 24 February 2015. A total of 15 studies including 1227 DN cases, 586 healthy controls and 1277 diabetes mellitus (DM) controls were involved in this meta‐analysis. Overall, a significantly elevated risk of DN was associated with all variants of MTHFR C677T when compared with the healthy group (T vs C, odds ratio (OR) = 2.22, 95% confidence interval (CI) = 1.88–2.61; TT vs CC, OR = 4.22, 95% CI = 3.02–5.90; TT + CT vs CC, OR = 2.62, 95% CI = 2.07–3.31; TT vs CC + CT, OR = 2.81, 95% CI = 2.08–3.81) or DM (T vs C, OR = 1.78, 95% CI = 1.59–2.00; TT vs CC, OR = 2.95, 95% CI = 2.33–3.73; TT + CT vs CC, OR = 1.93, 95% CI = 1.63–2.29; TT vs CC + CT, OR = 2.31, 95% CI = 1.87–2.84). In subgroup analyses stratified by ethnicity and geographic areas, it revealed the significant results in Chinese Han, in North and South China. The risk conferred by MTHFR C677T polymorphism is higher in North China than in South China. This meta‐analysis showed that the MTHFR C677T variants may influence DN risk in Chinese, and further studies with gene–gene and gene–environment interactions are required for definite conclusions.