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.     

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.     

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.     

Association of MEGSIN 2093C-2180T haplotype at the 3' untranslated region with disease severity and progression of IgA nephropathy.

BACKGROUND: MEGSIN is a gene predominantly expressed in the renal mesangium, and is upregulated in IgA nephropathy (IgAN). Our previous study has shown that the 2093C and 2180T alleles at the 3' untranslated region (3'UTR) of the gene are associated with susceptibility to IgAN, but the relationships of these genetic variants with the clinical manifestations and renal histological lesions of IgAN have not been examined previously. METHODS: 302 IgAN patients followed up for 52.8+/-22.5 months were investigated. Haplotypes at the 3'UTR were constructed using the 2093C/T and 2180C/T alleles. The genotype-phenotype relationship was studied by correlations of haplotypes and the clinical data and renal histopathological changes. RESULTS: The 2093C-2180T haplotype was present more often in patients with disease that progressed more rapidly (chi2((C-T/others)) = 8.429, P = 0.004), and was also correlated with hypertension (chi2((C-T/others)) = 6.459, P = 0.012), severe proteinuria (>or=2 g/d) (chi2((C-T/others)) = 6.332, P = 0.013), and Lee's class IV and V histological changes (chi2((C-T/others)) = 9.640, P = 0.008). CONCLUSION: In this Chinese population, the 2093C-2180T haplotype at the 3'UTR of MEGSIN gene is associated with more severe forms of IgAN, and more rapid disease progression. This provides further evidence for the involvement of genetic variations of MEGSIN in the pathogenesis of IgAN.     

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.     

荆门地区CD14-159C/T多态性和幽门螺杆菌在胃癌中交联作用研究

目的探讨荆门地区人群CD14-159C/T多态性与胃癌关联性及其与幽门螺杆菌交互作用。 方法采用多聚酶链反应-限制性片段长度多态性（PCR-RFLP）方法,分析127例胃癌患者和127名健康者的CD14-159C/T基因型。非条件Logistic分析各基因型与发病中易感性关系以及与幽门螺杆菌的交互作用。 结果携带C（CC/CT）基因个体患病风险较非C基因携带者（TT）风险明显增加（OR=1.35,95% CI=1.22~2.56,P=0.000;校正OR=1.61,95% CI=1.21~3.01,P=0.000）。条件Logistic分析表明,携带CC/CT基因型幽门螺杆菌个体胃癌罹患风险是携带TT基因非幽门螺杆菌个体的3.39倍（OR=3.39,95% CI=2.66~5.36,P=0.000）（RERI=1.94,95% CI=1.41~2.77;API=0.59,95% CI=0.33~0.84;S=1.46,95% CI=1.37~2.66）。 结论CD14-159C/T多态性增加荆门地区个体胃癌的罹患风险,且与幽门螺杆菌在胃癌发病中存在协同效应。     

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。     

IL‐16 polymorphism and risk of renal cell carcinoma: Association in a Chinese population

Objectives: Interleukin‐16 (IL‐16) plays a fundamental role in inflammatory diseases, as well as in the development and progression of tumors. A T‐to‐C polymorphism at the ‐295 position in the promoter region of the IL‐16 gene has been described. This variation might lead to altered IL‐16 expression, and might modulate an individual's susceptibility to cancer. The objective of the present study was to determine if IL‐16 polymorphism is associated with risk of renal cell carcinoma (RCC). Methods: A case–control study including 335 RCC cases and 340 cancer‐free controls was carried out. All subjects were genetically unrelated ethnic Han Chinese recruited from a single institution between July 2006 and July 2009. The IL‐16 ‐295 T>C polymorphism was determined by using the polymerase chain reaction‐restriction fragment length polymorphism method. Serum samples were available for 70 RCC cases and 96 controls to detect IL‐16 concentration. Results: Compared with the IL‐16 ‐295 TT genotype, the CC genotype had a significantly decreased RCC risk (adjusted odds ratio [OR] = 0.34, 95% confidence interval [CI] = 0.18–0.66). Furthermore, a significant decreased risk of RCC was found in the combined variant genotypes CT + CC compared with the TT genotype (adjusted OR = 0.68, 95% CI = 0.50–0.93). In addition, the serum IL‐16 levels in RCC patients were significantly lower than those in controls (P < 0.001). Furthermore, patients carrying CC genotype or CT genotype had higher serum IL‐16 levels than TT carriers. Conclusion: IL‐16 ‐295 T>C polymorphism is significantly associated with a higher risk of developing RCC in Chinese population.     

男性FASL-844基因多态性与特发性无精子症及严重少精子症发病风险的研究

目的:研究FASL-844位点基因多态性在中国南方汉族男性人群中的分布,探讨其与特发性无精子症及严重少精子症发病风险的关系。方法:采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法,分析184例特发性无精子症及严重少精子症患者与236例正常生育男性FASL-844位点的基因型及等位基因频率,分析该基因多态性与特发性无精子症及严重少精子症之间的关系。结果:不育组与正常生育组FASL-844CT和TT基因型分布差异有显著性(P=0.024;P=0.008)。携带FASL-844TT基因型个体罹患特发性无精子症或严重少精子症的风险是CC基因型个体的2.76倍(95%CI:1.20~6.35);将携带CC和CT基因型的个体合并,携带TT基因型的个体罹患特发性无精子症或严重少精子症的风险是(CC+CT)基因型个体的2.90倍(95%CI:1.28~6.58)。结论:FASL-844基因多态性可能是中国南方汉族男性特发性无精子症及严重少精子症的遗传易感因素之一。     

Investigation of the human ANP gene in type 1 diabetic nephropathy: case-control and follow-up studies

The atrial natriuretic peptide gene (PND) is a candidate gene for diabetic nephropathy. We systematically analyzed five nonsynonymous PND polymorphisms and tested the association of genotype and haplotype distributions with diabetic nephropathy in a cross-sectional study and a 6-year follow-up study (489 and 301 type 1 diabetic patients, respectively). For this purpose, a new maximum-likelihood method dealing with haplotype-based association analysis for survival data was developed. None of the genotypes or haplotypes were associated with the disease in the case-control study. In the follow-up study, C708T and T2238C showed a weak association with disease progression, but T2238C was strongly associated with progression in poorly controlled subjects (mean HbA(1c) during follow-up was more than the median value [8.5%]; log-rank [TC or CC versus TT], P = 0.007; adjusted hazard ratio, TC or CC versus TT, 2.28, 95% CI 1.10-4.74; P = 0.027). The raw effect of the 2238C allele (hazard risk ratio 1.93, 95% CI 1.15-3.24; P = 0.012) was further confirmed by the haplotype analysis, suggesting that the 2238C allele of PND may affect the course of nephropathy in inadequately controlled type 1 diabetic patients.     

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。     

肌球蛋白重链9基因单核苷酸多态性与内蒙古自治区汉族IgA肾病临床、病理及预后的关系

目的 探讨肌球蛋白重链(MYH)9基因单核苷酸多态性与内蒙古自治区汉族IgA肾病患者临床特征、病理及预后的关系.方法 以经肾组织活检确诊的IgA肾病患者148例为研究对象,对其中56例患者进行了1～97月的随访.取外周血提取DNA,采用PCR限制性片段长度多态性分析(RFLP)法检测MYH9基因Rs3752462、Rs4821480位点单核苷酸多态性.研究各位点基因型与IgA肾病患者临床特征的相关性.分析不同基因型与疾病进展和预后的关系.结果 (1)Rs3752462位点符合Hardy-Weinberg平衡,Rs4821480位点不符合Hardy-Weinberg平衡.(2)IgA肾病患者MYH9基因Rs3752462位点TT基因型患者的收缩压低于CC+CT基因型(P＜0.05).Rs4821480位点GG基因型与TT+GT基因型两组患者收缩压、舒张压、年龄差异有统计学意义(P＜0.05).Scr、肌酐清除率、血白蛋白、血红蛋白、镜下血尿、蛋白尿程度等临床指标及病理HASS分级、肾病理改变在Rs4821480位点、Rs3752462位点3种基因型组间差异无统计学意义.(3) Kaplan-Meier生存分析提示Rs3752462位点CC基因型、Rs4821480位点TT基因型患者肾活检到肾功能减退时间显著较短(P＜0.05).结论 MYH9基因Rs3752462位点C等位基因是引起IgA肾病患者高血压损害的独立危险因素.MYH9基因Rs4821480位点3种基因型多态性与患者预后相关.携带Rs3752462位点C等位基因、Rs4821480位点T等位基因可能影响患者的预后.     

Methylenetetrahydrofolate reductase polymorphism in childhood primary focal segmental glomerulosclerosis

AIM: The purpose of this study was to evaluate the association between the methylenetetrahydrofolate reductase (MTHFR) C/T polymorphism and the prevalence and course of focal segmental glomerulosclerosis (FSGS) in our pediatric population. METHODS: Genotypes for MTHFR were determined in 15 primary FSGS patients (male/female, 6/9) and 238 control subjects (male/female, 110/128) by the polymerase chain reaction and restriction fragment length polymorphism method. RESULTS: For the whole group, the genotype frequencies (CC/CT/TT) of MTHFR in FSGS and control subjects were almost comparable. The TT genotype was associated with early onset of the disease as compared with the CC genotype. Furthermore, all the patients with the TT genotype had steroid-resistant FSGS and developed into end-stage renal failure, while those carrying either CC or CT genotype did not. CONCLUSION: We speculate that the TT genotype may be associated with early development and progression of childhood FSGS. Confirmatory studies using larger and ethnically distinct populations are needed to reveal the role of homocysteine in FSGS with consideration of medical interventions.     

Relationship of p22phox C242T polymorphism with nephropathy in type 2 diabetic patients

BACKGROUND: In this case-control study, we investigated the possible involvement of the p22phox C242T polymorphism in the development and progression of diabetic nephropathy (DN) in 535 Caucasian Brazilians with type 2 diabetes. We also evaluated the effects of the interaction of the C242T polymorphism with smoking and hypercholesterolemia on the susceptibility to nephropathy. METHODS: Genotype analysis was performed using polymerase chain reaction (PCR) followed by digestion with restriction enzyme. Logistic regression analysis was used to control for independent risk factors associated with nephropathy. RESULTS: The genotype frequencies in patients with overt DN (CC/CT/TT: 0.36/0.47/0.17) were not significantly different from those of diabetic individuals with normoalbuminuria (0.47/0.41/0.12) or microalbuminuria (0.42/0.48/0.10) (p=0.214). Likewise, there were no differences in the T allele frequency among patients with normoalbuminuria, microalbuminuria or overt DN (0.33, 0.34 and 0.40, respectively; p=0.111). However, the T allele was found to be more frequent among smokers with overt nephropathy (macroalbuminuria and/or in dialysis) than those who had normoalbuminuria (43 vs. 32%, p=0.045). The multiple logistic regression analysis confirmed that the CT+TT genotypes were independently associated with a higher risk of having overt nephropathy among smokers [odds ratio (OR)=6.76, 95% confidence interval (95% CI) 1.83-25.02]. CONCLUSIONS: Our study shows a gene-environment interaction associated with the increased risk of DN progression in Caucasian Brazilian smokers with type 2 diabetes. Further studies should be performed to clarify whether it exists, and to what extent there is a relationship between the p22phox C242T polymorphism and DN.     

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.     

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。     

VEGF -460 genotype plays an important role in progression to chronic kidney disease stage 5.

BACKGROUND: Changes in renal vasculature, with vascular and interstitial fibrosis, are hallmarks of progression to chronic kidney disease (CKD) stage 5. Vascular endothelial growth factor (VEGF) is a potent angiogenic and vascular permeability factor. Transforming growth factor-beta1 (TGF-beta1) plays a critical role in promoting extracellular matrix (ECM) deposition and fibrosis. This study investigates whether genetic polymorphisms of VEGF or TGF-beta1 are associated with (i) progressive decline in renal function in patients with glomerular disorders (cohort 1) and (ii) predisposition to CKD stage 5 in a separate group of renal transplant recipients with various primary diseases (cohort 2). METHODS: Two patient groups were studied. Cohort 1 comprised 91 patients with biopsy-proven glomerular disease who were followed-up for 5 years before categorization as either non-progressors (with stable serum creatinine or < or =30% increase over 5 years, n = 39) or progressors (requiring dialysis, transplantation or whose serum creatinine increased by >30% over 5 years, n = 52). Cohort 2 comprised 107 patients with various primary renal diseases, who had reached CKD stage 5 and undergone renal transplantation at the time of study. All patients were genotyped for the VEGF polymorphisms at positions -460 (C/T) and +405 (G/C). Linkage disequilibrium (LD) was established using EHplus. SNPHAP was used to estimate haplotype frequency and to infer haplotypes to all patients. Cohort 1 patients were genotyped for the TGF-beta1 polymorphisms at positions -800, -509, codons 10 and 25. Genotyping was performed by polymerase chain reaction-restriction length polymorphism (PCR-RFLP). RESULTS: In cohort 1, there was a significant increase in frequency of the -460 VEGF CC genotype 30.8 vs 5.1%, P = 0.008; odds ratio (OR), CC vs TT 10.67, 95% confidence interval (CI), 1.94-58.72 and C allele 56.7 vs 37.2%, P = 0.009; OR 2.22, 95% CI, 1.21-4.04, in the progressor patients when compared with the non-progressors. In cohort 2, there was a significant increase in the VEGF -460 CC genotype when compared with healthy volunteers 37 vs 20.8%, P = 0.011; OR CC vs TT 1.59, 95% CI, 0.72-3.51. The -460 and +405 polymorphisms were in LD P < 0.00007. There were significant differences in diplotype (haplotype pair) frequencies in cohort 1 and 2, P = 0.018, which confirmed the importance of the -460C allele. There were no associations between the VEGF +405 or TGF-beta1 polymorphisms and progressive renal disease. CONCLUSION: In this study, we have demonstrated an association between the VEGF -460 polymorphism and progression to CKD stage 5. The function of this polymorphism remains unclear although previous evidence suggests that promoter constructs containing this single nucleotide polymorphism (SNP) have been associated with increased activity. Clearly there is a role for TGF-beta1 in chronic kidney disease. However, this study found no associations with four TGF-beta1 polymorphisms in this cohort.