Ichiei Narita

Association between Single-Nucleotide Polymorphisms in Selectin Genes and Immunoglobulin A Nephropathy

Although intensive efforts have been undertaken to elucidate the genetic background of immunoglobulin A nephropathy (IgAN), genetic factors associated with the pathogenesis of this disease are still not well understood. We designed a case-control association study that was based on linkage disequilibrium among single-nucleotide polymorphisms (SNPs) in the selectin gene cluster on chromosome 1q24-25, and we found two SNPs in the E-selectin gene (SELE8 and SELE13) and six SNPs in the L-selectin gene (SELL1, SELL4, SELL5, SELL6, SELL10, and SELL11) that were significantly associated with IgAN in Japanese patients. All eight SNPs were in almost complete linkage disequilibrium. SELE8 and SELL10 caused amino acid substitutions from His to Tyr and from Pro to Ser (chi2=9.02, P=.0026, odds ratio = 2.73 [95% confidence interval [CI] 1.38--5.38] for His-to-Tyr substitutions; chi2=17.4, P=.000031, odds ratio = 3.61 [95% CI 1.91--6.83] for Pro-to-Ser substitutions), and SELL1 could affect promoter activity of the L-selectin gene (chi2=19.5, P=.000010, odds ratio = 3.77 [95% CI 2.02--7.05]). The TGT haplotype at these three loci was associated significantly with IgAN (chi2=18.67, P=.000016, odds ratio = 1.88 [95% CI 1.41--2.51]). Our results suggest that these eight SNPs in selectin genes may be useful for screening populations susceptible to the IgAN phenotype that involves interstitial infiltration.

Macrophage Metalloelastase as a Major Factor for Glomerular Injury in Anti-Glomerular Basement Membrane Nephritis

Rat anti-glomerular basement membrane (GBM) nephritis is a model of crescentic glomerulonephritis induced by injection of anti-GBM antiserum. To elucidate the mechanism of glomerular injury, we analyzed the gene expression patterns in the kidneys of anti-GBM nephritis rats using DNA arrays, and found that macrophage metalloelastase/matrix metalloproteinase (MMP)-12 was one of the highly expressed genes in the kidneys on days 3 and 7 after the injection of anti-GBM antiserum. Enhancement of MMP-12 mRNA expression was confirmed by Northern blot analysis, and in situ hybridization revealed that MMP-12 mRNA was expressed in ED-1-positive macrophages and multinuclear giant cells in the glomeruli with crescent. Moreover, these cells were positive with anti-rat rMMP-12 Ab on the section of the kidneys of anti-GBM nephritis rats on day 7. To clarify the role of MMP-12, we conducted a neutralization experiment using anti-rat rMMP-12 Ab, which had an ability to inhibit rMMP-12 activity of degrading natural substrate such as bovine elastin or human fibronectin in vitro. Anti-rat rMMP-12 Ab or control Ig was injected in each of six rats on days 0, 2, 4, and 6 after the injection of anti-GBM antiserum. Consequently, crescent formation and macrophage infiltration in the glomeruli were significantly reduced in the rats treated with anti-rat rMMP-12 Ab, and the amount of urine protein was also decreased. These results disclosed that MMP-12 played an important role in glomerular injury in a crescentic glomerulonephritis model, and inhibition of MMP-12 may lead to a new therapeutic strategy for this disease.

Interaction Between ACE and ADD1 Gene Polymorphisms in the Progression of IgA Nephropathy in Japanese Patients

Abstract—An interaction effect between the angiotensin-converting enzyme insertion/deletion (ACE I/D) and &agr;-adducin (ADD1) Gly460Trp polymorphisms (G460W) on blood pressure regulation has recently been suggested, although its significance in the prognosis of renal function in IgA nephropathy (IgAN) has not been fully investigated. Therefore, we evaluated the clinical manifestations and renal prognosis in 276 Japanese patients with histologically proven IgAN with respect to their ACE I/D and ADD1 G460W polymorphisms. The prognosis of renal function was analyzed by Kaplan-Meier survival curves and multivariate Cox proportional-hazards regression models. Baseline data, including blood pressures, proteinuria, renal function, and incidence of hypertension, were similar for the different genotypes of ACE and ADD1. The individual genotypes taken alone were not associated with the progression of renal dysfunction. However, renal survival of patients with the 460WW polymorphism of ADD1 was significantly worse within the group with the II genotype of ACE (Kaplan-Meier, log rank test; &khgr;2=6.062, P =0.0138) but not for those with other ACE genotypes. In the Cox proportional-hazards regression model with adjustment for clinical risk factors, including hypertension, proteinuria, and no administration of an angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, the 460WW variant of ADD1 was a highly significant and independent risk factor only for patients with the ACE II genotype, with a hazard ratio of 3.65 (P =0.0016), but not for those with other ACE genotypes (hazard ratio=0.65, P =0.2902). These findings suggest an interaction between ACE and ADD1 polymorphisms not only on blood pressure regulation but also on the progression of renal dysfunction in patients with IgAN.

Single-nucleotide polymorphisms in the class II region of the major histocompatibility complex in Japanese patients with immunoglobulin A nephropathy

AbstractImmunoglobulin A nephropathy (IgAN) is a form of chronic glomerulonephritis of unknown etiology and pathogenesis. Immunogenetic studies have not conclusively indicated that human leukocyte antigen (HLA) is involved. As a first step in investigating a possible relationship between HLA class II genes and IgAN, we analyzed the extent of linkage disequilibrium (LD) in this region of chromosome 6p21.3 in a Japanese test population and found extended LD blocks within the class II locus. We designed a case-control association study of single-nucleotide polymorphisms (SNPs) in each of those LD blocks, and determined that SNPs located in the HLA-DRA gene were significantly associated with an increased risk of IgAN (P = 0.000001, odds ratio = 1.91 [95% confidence interval 1.46–2.49]); SNPs in other LD blocks were not. Our data imply that some haplotype of the HLA-DRA locus has an important role in the development of IgAN in Japanese patients.

Gender specific association of aldosterone synthase gene polymorphism with renal survival in patients with IgA nephropathy.

Immunoglobulin A nephropathy (IgAN), which is the most prevalent form of primary glomerulonephritis and one of the major causes of end stage renal disease (ESRD), has a variable clinical course.1–3 Poor prognostic factors for the progression of renal dysfunction in IgAN have been identified as high blood pressure, heavy proteinuria, and a severe histopathological appearance of the renal biopsy.4,5 In addition to these prognostic factors, it has been proposed that several genetic backgrounds are associated with a susceptibility to ESRD in patients with IgAN.6,7nnThe renin-angiotensin-aldosterone system is an important regulator of blood pressure and plays a central role in the development and progression of end organ damage. Polymorphisms in genes that encode components of this system have been reported to be associated with physiological risk factors for progressive renal dysfunction in IgAN. The most consistent of these is the angiotensinogen ( AGT ) gene, which is associated with essential hypertension and with an increased risk of cardiovascular diseases and renal failure.8–10 A deletion polymorphism in the angiotensin converting enzyme ( ACE ) gene influences the circulating ACE levels, and although it has little effect on blood pressure, it has been associated with an increased risk of cardiovascular diseases in some but not all studies.11–13nnAldosterone is one of the main effectors of the renin-angiotensin system14 and has classically been thought to act as a regulator for the absorption of Na and water, as well as the excretion of K in normal physiology, and as a mediator of oedema in numerous disease states. However, it is now well recognised that the actions of aldosterone are not limited to effects on ion transport in epithelial tissue, and its important role in cardiovascular disease involves non-epithelial tissues.15,16 Recently, it has been shown that …

Peroxisome proliferator-activated receptor γ C161T polymorphisms and survival of Japanese patients with immunoglobulin A nephropathy

Peroxisome proliferator‐activated receptor γ (PPARγ) plays an important role in lipid metabolism, insulin sensitivity, atherogenesis, and immune regulation. A genetic polymorphism (C161T) at exon 6 of PPARγ gene (PPARG) was reported to be associated with the onset of coronary artery disease. However, there has been no report of an association with renal disease. Genomic DNAs were isolated from 225 Japanese patients with histologically confirmed immunoglobulin A nephropathy (IgAN). The PPARG C161T genotype was determined by polymerase chain reaction‐restriction fragment length polymorphism. The association of the polymorphism with renal prognosis in IgAN patients was analyzed using the Kaplan–Meier method and Cox proportional hazard regression model. The PPARG polymorphism was not associated with the renal survival rate. However, when patients were stratified into those either with or without hypertension at the time of diagnosis, the renal survival of the CT/TT genotypes was significantly better in those without hypertension than those with the CC genotype. We report that the PPARG C161T polymorphism is associated with the survival of IgAN patients without hypertension. The T allele of the polymorphism might have a protective effect on the progression of IgAN.

Association of the MCP-1 gene polymorphism A-2518G with carpal-tunnel syndrome in hemodialysis patients.

Abstract Carpal-tunnel syndrome (CTS) in long-term hemodialysis patients is caused by the deposition of amyloid as well as by the local inflammatory process. The recruitment of monocytes/macrophages in the tenosynovium, promoted by chemokines such as monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1a (M1P-I α), is thought to play an important role in CTS development. The genetic polymorphism of these chemokines has been identified and their clinical function has been partly revealed. We attempted to analyze the relationship between these polymorphisms and their susceptibility to CTS. The subjects of this study were 366 patients who underwent hemodialysis. Ninety-five patients received surgery for CTS. No significant difference was observed in the genotype distributions of MCP-1 or MIP-lα between patients who received CTS surgery and those that did not. However, with the use of a logistic regression model, the MCP-1 GG genotype was identified as a risk factor for the development of CTS, in addition to the duration and the age of initiation of dialysis, as confirmed by a Cox proportional hazards model. In conclusion, homozygosity for G at -2518 in the MCP-1 gene might be a candidate for the genetic marker of CTS development in Japanese hemodialysis patients.