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Recurrent pregnancy loss (RPL) is a major reproductive health issue with multifactorial causes, affecting 2.6% of all pregnancies worldwide. Nearly half of the RPL cases lack clinically identifiable causes (e.g., antiphospholipid syndrome, uterine anomalies, and parental chromosomal abnormalities), referred to as unexplained RPL (uRPL). Here, we perform a genome-wide association study focusing on uRPL in 1,728 cases and 24,315 female controls of Japanese ancestry. We detect significant associations in the major histocompatibility complex (MHC) region at 6p21 (lead variant=rs9263738; P = 1.4 × 10−10; odds ratio [OR] = 1.51 [95% CI: 1.33–1.72]; risk allele frequency = 0.871). The MHC associations are fine-mapped to the classical HLA alleles, HLA-C*12:02, HLA-B*52:01, and HLA-DRB1*15:02 (P = 1.1 × 10−10, 1.5 × 10−10, and 1.2 × 10−9, respectively), which constitute a population-specific common long-range haplotype with a protective effect (P = 2.8 × 10−10; OR = 0.65 [95% CI: 0.57–0.75]; haplotype frequency=0.108). Genome-wide copy-number variation (CNV) calling demonstrates rare predicted loss-of-function (pLoF) variants of the cadherin-11 gene (CDH11) conferring the risk of uRPL (P = 1.3 × 10−4; OR = 3.29 [95% CI: 1.78–5.76]). Our study highlights the importance of reproductive immunology and rare variants in the uRPL etiology. Here, the authors perform a genome-wide association study for recurrent pregnancy loss without apparent clinical causes and identify a protective HLA haplotype. They also show that rare predicted loss-of-function variants in CDH11 are associated with risk of recurrent pregnancy loss. [ABSTRACT FROM AUTHOR]

Objectives: The current study aimed to examine the incidence of perioperative infections and graft viability in ABO-compatible and ABO-incompatible renal transplant recipients. Methods: We included 643 living donor renal transplant recipients registered in the Michinoku Renal Transplant Network from 1998 to 2021. Patients were divided into the ABO-compatible and ABO-incompatible kidney transplantation groups. We compared the characteristics of the two groups and evaluated the incidence of postoperative viral infections (cytomegalovirus and BK virus), graft loss-free survival, and overall survival between the two groups. Results: Of 643 patients, 485 (75%) and 158 (25%) were ABO-compatible and ABO-incompatible renal transplant recipients, respectively. Postoperative viral infections, rituximab use, and plasma exchange were significantly more common in ABO-incompatible than in ABO-compatible transplant recipients. However, there were no significant differences in terms of other background characteristics. The ABO-incompatible group was more likely to develop viral infections than the ABO-compatible group. Graft loss-free survival and overall survival did not significantly differ between the two groups. According to the multivariate Cox regression analysis, ABO compatibility was not significantly associated with graft loss-free survival and overall survival. Conclusion: Although the incidence of postoperative viral infections in ABO-incompatible renal transplant recipients increased, there was no significant difference in terms of rejection events, graft loss-free survival, and overall survival. [ABSTRACT FROM AUTHOR]

The prognosis for patients who achieve a pathologic complete response in bladder cancer is excellent, but the association between their prognosis and the tumor microenvironment is unclear. We investigated the tumor immune microenvironment of those with pathological complete response after platinum-based neoadjuvant chemotherapy for cT2-4aN0M0 bladder cancer using multiplex fluorescence immunohistochemistry. Our retrospective study included 12 patients with pathological complete response who underwent radical cystectomy following neoadjuvant chemotherapy for cT2-4aN0M0 muscle-invasive bladder cancer. We assessed the density of several immune cell types in pretreatment and posttreatment tissues via multiplex fluorescence immunohistochemical analysis. The median age was 67 years; 10 patients were male. Nine (75%) and 3 (25%) patients were cT2 and cT3, respectively. The 5-year progression-free and overall survivals were 90% and 100%, respectively. The densities of regulatory T cells (Treg; CD3+CD4+FoxP3+ cell) were significantly decreased and almost disappeared in the tumor microenvironment of posttreatment tissue compared with pretreatment tissue. Other immune cells, such as effector T cells or M2 macrophages, were not significantly changed between posttreatment and pretreatment tissues. In pathological complete response, Tregs in the tumor immune microenvironment were significantly decreased after platinum-based chemotherapy for muscle-invasive bladder cancer. The temporary arresting of immune response in the tumor microenvironment may reflect a favorable prognosis due to the decrease of Tregs with tumor shrinkage and improve the host tumor immune response. [ABSTRACT FROM AUTHOR]

Background: The Modified International Metastatic Renal Cell Carcinoma Dataset Consortium model (mIMDC) is a preoperative prognostic model for pT3cN0M0 renal cell carcinoma (RCC). This study aimed to validate the mIMDC and to construct a new model in a localized and locally advanced RCC (LLRCC). Methods: A database was established (the Michinoku Japan Urological Cancer Study Group database) consisting of 79 patients who were clinically diagnosed with LLRCC (cT3b/c/4NanyM0) and underwent radical nephrectomy from December 2007 to May 2018. Using univariable and multivariable analyses, we retrospectively analyzed disease-free survival (DFS) and overall survival (OS) in this database, constructed a new prognostic model according to these results, and estimated the model fit using c-index on the new and mIMDC models. Results: Independent poorer prognostic factors for both DFS and OS include the following: ≥ 1 Eastern Cooperative Oncology Group performance status, 2.0 mg/dL C-reactive protein, and > upper normal limit of white blood cell count. The median DFS in the favorable (no factor), intermediate (one factor), and poor-risk group (two or three factors) was 76.1, 14.3, and 4.0 months, respectively (P < 0.001). The 3-year OS in the favorable, intermediate, and poor-risk group were 92%, 44%, and 0%, respectively (P < 0.001). The c-indices of the new and mIMDC models were 0.67 and 0.60 for DFS (P = 0.060) and 0.74 and 0.63 for OS (P = 0.012), respectively. Conclusion: The new preoperative prognostic model in LLRCC can be used in patient care and clinical trials. [ABSTRACT FROM AUTHOR]

Integrating genomic data of multiple cancers allows de novo cancer grouping and elucidating the shared genetic basis across cancers. Here, we conduct the pan-cancer and cross-population genome-wide association study (GWAS) meta-analysis and replication studies on 13 cancers including 250,015 East Asians (Biobank Japan) and 377,441 Europeans (UK Biobank). We identify ten cancer risk variants including five pleiotropic associations (e.g., rs2076295 at DSP on 6p24 associated with lung cancer and rs2525548 at TRIM4 on 7q22 nominally associated with six cancers). Quantifying shared heritability among the cancers detects positive genetic correlations between breast and prostate cancer across populations. Common genetic components increase the statistical power, and the large-scale meta-analysis of 277,896 breast/prostate cancer cases and 901,858 controls identifies 91 newly genome-wide significant loci. Enrichment analysis of pathways and cell types reveals shared genetic backgrounds across said cancers. Focusing on genetically correlated cancers can contribute to enhancing our insights into carcinogenesis. Investigating genetically correlated cancers can enhance our understanding of carcinogenesis. Here, the authors perform Pan-cancer and cross-population GWAS meta-analysis to identify novel cancer risk loci and highlight shared heritability between breast and prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Anti-PD-1 antibodies are widely used for cancer treatment including advanced renal cell carcinoma (RCC). However, their therapeutic and adverse effects vary among patients. This study aimed to identify genetic markers that predict outcome after nivolumab anti-PD-1 antibody treatment for advanced RCC. Methods: This study was registered on the website of the University Hospital Medical Information Network (protocol ID, UMIN000037739). Patient enrollment was conducted at 23 institutions in Japan between August 19, 2019, and September 30, 2020. Patient follow-up ended on March 31, 2021. Patients were treated with nivolumab for advanced clear cell RCC. A genome-wide association study was performed in the development set, while genotyping of target regions in the validation set was undertaken. Single nucleotide polymorphisms (SNPs) in genes of interest CD274, PDCD1LG2 and PDCD1 were genotyped in the combined set. The primary endpoint was the association of SNPs with objective response following nivolumab treatment. As secondary endpoints, the associations of SNPs with radiographic progression-free survival (rPFS) and treatment-related grade ≥ 3 adverse events (AEs) were evaluated. Results: A genome-wide association study followed by a validation study identified that SNPs in FARP1 (rs643896 and rs685736) were associated with objective response and rPFS but not AEs following nivolumab treatment. Furthermore, SNPs in PDCD1LG2 (rs822339 and rs1411262) were associated with objective response, rPFS, and AEs following nivolumab treatment. Genetic risk category determined according to the number of risk alleles in SNPs (rs643896 in FARP1 and rs4527932 in PDCD1LG2) excellently predicted objective response and rPFS in nivolumab treatment. Conclusion: This study revealed that SNPs in FARP1 and PDCD1LG2 were correlated with outcome in nivolumab treatment. The use of these SNPs may be beneficial in selecting appropriate treatment for individual patients and may contribute to personalized medicine. [ABSTRACT FROM AUTHOR]

Background: We examined the relationship between the tumour microenvironment and the clinical efficacy of neoadjuvant chemotherapy in patients with cT2-4aN0M0 bladder cancer using multiplex fluorescence immunohistochemistry.Methods: The study retrospectively evaluated 51 patients who underwent radical cystectomy following neoadjuvant chemotherapy for cT2-4aN0M0 muscle-invasive bladder cancer. Patients were divided into responders (Results: The median age was 69 years; 39 patients were male. Twelve (23.5%), 17 (33.3%), 10 (19.7%) and 12 (23.5%) patients were pT0, pT1, pT2 and ≥pT3, respectively. Responders had a significantly higher 5-year cancer-specific survival rate (96.6%) than non-responders (48.4%; p = 0.0018). CD8+ T cell (p = 0.0056) and CD204+ cell (p = 0.0394) densities were significantly higher in the intratumoural area in non-responders than in responders. Patients with higher CD204+ cell densities in cancerous areas had worse prognosis.Conclusions: This comprehensive analysis of the immune microenvironment of a muscle-invasive bladder cancer specimen revealed that preexisting tumour-infiltrating proliferating CD8+ T cells and CD204+ cells are indicators of the response to neoadjuvant chemotherapy and that CD204+ cells can be considered an unfavourable prognostic factor in these patients. [ABSTRACT FROM AUTHOR]

Background: This retrospective multicenter study aimed to evaluate the survival benefit of upfront cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (RCC) patients stratified by International Metastatic RCC Database Consortium (IMDC) risk criteria. Methods: We reviewed the medical records in the Michinoku Database between 2008 and 2019. Patients who received upfront CN, systemic therapy without CN (no CN) and CN after drug therapy (deferred CN) were analyzed. To exclude selection bias due to patient characteristics, baseline clinical data were adjusted by inverse probability of treatment weighting (IPTW). Overall survival (OS) was compared between upfront CN and non-upfront CN (no CN plus deferred CN). Associations between time-varying covariates including systemic therapies and OS stratified by IMDC risk criteria were analyzed by IPTW-adjusted Cox regression method. Results: Of 259 patients who fulfilled the selection criteria, 107 were classified in upfront CN and 152 in non-upfront CN group. After IPTW-adjusted analysis, upfront CN showed survival benefit compared to non-upfront CN in patients with IMDC intermediate risk (median OS: 52.5 versus 31.3 months, p < 0.01) and in patients with IMDC poor risk (27.2 versus 11.4 months, p < 0.01). In IPTW-adjusted Cox regression analysis of time-varying covariates, upfront CN was independently associated with OS benefit in patients with IMDC intermediate risk (hazard ratio 0.52, 95% confidence interval 0.29–0.93, p = 0.03) and in patients with IMDC poor risk (0.26, 0.11–0.59, p < 0.01). Conclusions: Upfront CN may confer survival benefit in RCC patients with IMDC intermediate and poor risk. [ABSTRACT FROM AUTHOR]

This letter, published in the journal Clinical & Experimental Nephrology, discusses the case of a 60-year-old man who underwent bilateral nephrectomy for renal cell carcinoma (RCC). The authors measured the levels of erythropoietin (EPO) before and after the surgery to examine the impact of nephrectomy on EPO production. They found that EPO levels declined sharply after the surgery and gradually increased over time, but were not sufficient to correct the patient's anemia. The authors discuss the potential use of erythropoiesis stimulating agents (ESA) and hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) to address anemia in patients who have undergone nephrectomy. However, they note that the effects of HIF-PHI on malignant cells are not yet fully understood. [Extracted from the article]

Background: The aims of this study were to investigate prognosis and validate prognostic models [Memorial Sloan-Kettering Cancer Center (MSKCC), International Metastatic Renal Cell Carcinoma Data Consortium (IMDC), and Japanese metastatic renal cancer (JMRC) models] in the targeted therapy era in Japanese patients with metastatic renal cell carcinoma. Methods: We retrospectively analyzed 692 patients who were diagnosed with mRCC from January 2008 to August 2018 in the Michinoku Japan Urological Cancer Study Group database. Nivolumab as sequential therapy was widely used. Other immune checkpoint inhibitors were excluded from this study. Results: The median overall survival (95% confident interval) in all, MSKCC favorable, intermediate, and poor risk patients was 41.0 months (33.9–46.8), not reached (63.5 to not estimable), 46.8 months (37.1–52.9), and 10.4 months (8.9–14.4), respectively. The median overall survival (95% confident interval) in IMDC favorable, intermediate, and poor risk patients was not reached (61.6 to not estimable), 47.4 months (41.4–56.5), and 11.5 (9.9–16.3), respectively. The c-index of the MSKCC, IMDC, and JMRC models calculated at mRCC diagnosis was 0.680, 0.689, and 0.700, respectively. No statistical differences were found in the c-index among the models. Conclusion: While the real-world overall survival in Japanese patients with mRCC in the targeted therapy era improved compared to that previously reported in the cytokine era, there was no clear difference in the survival of poor risk patients between these eras. There were no differences in the superiority among the models. [ABSTRACT FROM AUTHOR]

The large majority of variants identified by GWAS are non-coding, motivating detailed characterization of the function of non-coding variants. Experimental methods to assess variants' effect on gene expressions in native chromatin context via direct perturbation are low-throughput. Existing high-throughput computational predictors thus have lacked large gold standard sets of regulatory variants for training and validation. Here, we leverage a set of 14,807 putative causal eQTLs in humans obtained through statistical fine-mapping, and we use 6121 features to directly train a predictor of whether a variant modifies nearby gene expression. We call the resulting prediction the expression modifier score (EMS). We validate EMS by comparing its ability to prioritize functional variants with other major scores. We then use EMS as a prior for statistical fine-mapping of eQTLs to identify an additional 20,913 putatively causal eQTLs, and we incorporate EMS into co-localization analysis to identify 310 additional candidate genes across UK Biobank phenotypes. Finding causal variants and genes from GWAS loci results remains a challenge. Here, the authors train a model to predict if a variant affects nearby gene expression, and apply the method to identify new possible causal eQTLs and mechanisms of GWAS loci. [ABSTRACT FROM AUTHOR]

Background: Prognostic outcomes and safety following treatment with pembrolizumab in patients with advanced urothelial carcinoma (UC) have not been fully elucidated in clinical practice. The aim of this study was to evaluate the oncological efficacy and safety of pembrolizumab after failure of platinum-based chemotherapy in Japanese patients with advanced UC in a routine clinical setting. Methods: This retrospective study included 41 consecutive Japanese patients with advanced UC treated with pembrolizumab as second-line or greater therapy at Iwate Medical University Hospital from January 2018 to April 2019. Results: The mean follow-up period was 6.2 months. The objective response rate, median progression-free survival, and median overall survival were 15%, 2.5 months, and 11.9 months, respectively. Univariate analysis identified poor performance status (> 1), liver metastasis, two or more metastatic organs, low hemoglobin levels, two or more prior regimens, high baseline C-reactive protein levels, higher relative C-reactive protein level change after 6 weeks, and higher relative neutrophil-to-lymphocyte ratio change after 6 weeks as significant predictors of overall survival. Among these factors, poor performance status (> 1), two or more metastatic organs, and higher relative neutrophil-to-lymphocyte ratio change after 6 weeks were identified as independent predictors of overall survival in multivariate analysis. Conclusions: The introduction of pembrolizumab can result in favorable cancer control outcomes in Japanese patients with advanced UC, and the prognosis of these patients can be stratified according to three potential parameters, including poor performance status, high number of metastatic organs, and higher relative neutrophil-to-lymphocyte ratio change. [ABSTRACT FROM AUTHOR]

Background: Nivolumab has demonstrated antitumor activity and manageable safety in the single-arm, phase II CheckMate 275 study in patients with unresectable locally advanced or metastatic platinum-resistant urothelial carcinoma. We report updated results of the global population and a subanalysis of Japanese patients from this study. Methods: Patients received nivolumab 3 mg/kg intravenously every 2 weeks until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) confirmed by blinded independent review committee (BIRC) per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included progression-free survival (PFS) by BIRC and overall survival (OS). Safety was also reported. The minimum follow-up was 21 months. Results: Overall, 270 patients were treated with nivolumab globally; 23 patients were Japanese. In the global and Japanese populations, respectively, ORR per BIRC was 20.4% and 21.7%; median PFS was 1.9 (95% confidence interval [CI] 1.9–2.3) and 3.8 months (95% CI 1.9–7.2); and median OS was 8.6 (95% CI 6.1–11.3) and 21.0 months (95% CI 7.2–not reached). The most common any grade treatment-related adverse events were fatigue (18.1%) and diarrhea (12.2%) in the global population; the most common in the Japanese population were diarrhea (26.1%) and pyrexia (13.0%). Grade 3 or 4 treatment-related adverse events occurred in 61 (22.6%) and seven (30.4%) of the global and Japanese patients, respectively. Conclusions: Nivolumab continues to show antitumor activity and survival in the global population of CheckMate 275. Meaningful clinical benefit was also observed in Japanese patients. No new safety signals were identified. [ABSTRACT FROM AUTHOR]

Background: We aimed to assess the short-term oncological outcomes of robot-assisted laparoscopic radical prostatectomy to determine the predictive factors associated with biochemical recurrence in high-risk prostate cancer patients. Methods: A total of 331 patients with localized prostate cancer underwent robot-assisted laparoscopic radical prostatectomy. Of them, 113 patients were diagnosed with high-risk prostate cancer according to the D'Amico risk group classification. We evaluated the association between pre- or postoperative predictive factors and biochemical recurrence using Cox regression analysis. Results: The 2-year biochemical recurrence-free survival rate was 65.0% in the high-risk group. On univariate analyses, PSA level > 20 ng/mL, Gleason pattern 5 component on biopsy, pathological stage T3 or higher, perineural invasion, and positive surgical margin were predictive factors for biochemical recurrence. On multivariate analysis, PSA level > 20 ng/mL, Gleason pattern 5 component on biopsy, perineural invasion, and positive surgical margin were identified as independent predictive factors. The 2-year biochemical recurrence-free survival rate was 36.5% for patients with PSA level > 20 ng/mL and/or Gleason pattern 5 component on biopsy. Conclusions: PSA level > 20 ng/mL and/or presence of the Gleason pattern 5 component on biopsy are predictive factors for early biochemical recurrence after robot-assisted laparoscopic radical prostatectomy in high-risk prostate cancer patients. We considered that these patients require a combined modality therapy to improve their prognosis. [ABSTRACT FROM AUTHOR]

Purpose: A phase I study using two peptide vaccines derived from M phase phosphoprotein 1 (MPHOSPH1) and DEP domain containing 1 (DEPDC1) demonstrated promising results for the treatment of advanced bladder cancer. Therefore, we further tested the ability of these peptides to prevent recurrence after transurethral resection of the bladder tumor in patients with non-muscle invasive bladder cancer (NMIBC).Materials and methods: 127 patients were enrolled in a multicenter, non-randomized phase II clinical trial. The primary endpoint was recurrence-free survival (RFS) rate, and secondary endpoints were safety and immunological response. HLA-A24-restricted peptides were subcutaneously administered in addition to intravesical BCG therapy. The exploratory endpoint evaluated differences of RFS rate between HLA-A*2402-positive (A24(+)) and -negative (A24(−)) groups.Results: A 2-year RFS rate in all patients was 74.0%. The RFS rate in the A24(+) group (n = 75) and in the A24(−) group (n = 52) were 76.0 and 71.2%, respectively. This vaccine therapy was well-tolerated and feasible. MPHOSPH1 and DEPDC1 peptide-specific cytotoxic T lymphocyte responses were observed in 75.8 and 77.5% of the A24(+) group, respectively. Patients having both peptide-specific CTL responses showed significantly better RFS than patients without CTL response (P = 0.014). In the A24(+) group, patients who had positive reaction at the injection sites (RAI) had significantly lower rates of recurrence than RAI-negative patients (P = 0.0019).Conclusions: Cancer peptide vaccines in combination with intravesical BCG therapy demonstrated good immunogenicity and safety, and may provide benefit for preventing recurrence of NMIBC. [ABSTRACT FROM AUTHOR]

An electrical or water supply and a blood purification machine are required for renal replacement therapy. There is a possibility that acute kidney injury can occur in large numbers and on a wide scale in the case of a massive earthquake, and there is the potential risk that the current supply will be unable to cope with acute kidney injury cases. However, non-machinery dialysis requires exclusive circuits and has the characteristic of not requiring the full-scale dialysis machines. We performed perfusion experiments that used non-machinery dialysis and recent blood purification machines in 30-min intervals, and the effectiveness of non-machinery dialysis was evaluated by the assessing the removal efficiency of potassium, which causes lethal arrhythmia during acute kidney injury. The non-machinery dialysis potassium removal rate was at the same level as continuous blood purification machines with a dialysate flow rate of 5 L/h after 15 min and continuous blood purification machines with a dialysate flow rate of 3 L/h after 30 min. Non-machinery dialysis required an exclusive dialysate circuit, the frequent need to replace bags, and new dialysate exchanged once every 30 min. However, it can be seen as an effective renal replacement therapy for crush-related acute kidney injury patients, even in locations or facilities not having the full-scale dialysis machines. [ABSTRACT FROM AUTHOR]

Purpose: Through genome-wide expression profile analysis, hypoxia-inducible protein 2 (HIG2) has previously been identified as an oncoprotein involved in development/progression of renal cell carcinoma (RCC). We subsequently identified a highly immunogenic HLA-A*0201/0206-restricted epitope peptide (HIG2-9-4) corresponding to a part of HIG2 and applied it as a therapeutic vaccine. We conducted a phase I clinical trial using the HIG2-9-4 peptide for patients with advanced RCC. Materials and Methods: Nine patients having HLA-A*0201 or HLA-A*0206 with metastatic or unresectable RCC after failure of the cytokine and/or tyrosine kinase inhibitor therapies were enrolled in this study. The patients received subcutaneous administration of the peptide as an emulsion form with Montanide ISA-51 VG once a week in a dose-escalation manner (doses of 0.5, 1.0, or 3.0 mg/body, 3 patients for each dose). The primary endpoint was safety, and the secondary endpoints were immunological and clinical responses. Results: Vaccinations with HIG2-9-4 peptide could be well tolerated without any serious systemic adverse events. Peptide-specific cytotoxic T lymphocyte (CTL) responses were detected in eight of the nine patients. Doses of 1.0 or 3.0 mg/body seemed to induce a CTL response better than did a dose of 0.5 mg/body, although the number of patients was too small to draw a firm conclusion. The disease control rate (stable disease for ≥4 months) was 77.8 %, and the median progression-free survival time was 10.3 months. Conclusions: HIG2-9-4 peptide vaccine treatment was tolerable and effectively induced peptide-specific CTLs in RCC patients. This novel peptide vaccine therapy for RCC is promising. [ABSTRACT FROM AUTHOR]

Tamsulosin hydrochloride is one of the most potent drugs for treatment of benign prostatic hyperplasia (BPH), however, the efficacy of tamsulosin hydrochloride varies among individuals. In this study, we measured the maximum serum concentration (Cmax) of tamsulosin hydrochloride in 182 of BPH patients and found remarkable individual variability. To investigate the genetic factors that regulate pharmacokinetics of tamsulosin hydrochloride, we conducted a genome-wide association study in these 182 BPH patients. As a result, rs16902947 on chromosome 5p13.2, rs7779057 on 7q22.3, rs35681285 on 7p21.2 and rs2122469 on 8p21.3 indicated possible associations with Cmax of tamsulosin hydrochloride (P=1.29 × 10−7, 2.15 × 10−7, 4.35 × 10−7 and 7.03 × 10−7, respectively), although these single-nucleotide polymorphisms (SNPs) did not reach the genome-wide significance threshold after Bonferroni correction. As these associated SNPs showed additive effects on serum tamsulosin hydrochloride concentration, we defined the 'Cmax prediction index' based on genotypes of these SNPs. This index clearly associated with Cmax values (P=4.5 × 10−6), indicating the possible roles of these four variants in tamsulosin hydrochloride pharmacokinetics. Our findings would partially explain the variability of the response to the tamsulosin hydrochloride treatment. [ABSTRACT FROM AUTHOR]

Immunoglobulin A (IgA) nephropathy is the most common form of primary glomerulonephritis worldwide. The pathogenesis of IgA nephropathy is unknown, but it is certain that some genetic factors are involved in susceptibility to the disease. Employing a large-scale, case-control association study using gene-based single-nucleotide polymorphism (SNP) markers, we previously reported four candidate genes. We report here an additional significant association between IgA nephropathy and an SNP located in the gene encoding immunoglobulin µ-binding protein 2 (IGHMBP2) at chromosome 11q13.2-q13.4. The association (?2 =17.1,p=0.00003; odds ratio of 1.85 with 95% confidence interval of 1.39-2.50 in a dominant association model) was found using DNA from 465 affected individuals and 634 controls. The SNP (G34448A) caused an amino acid substitution from glutamine to lysine (E928K). As the gene product is involved in immunoglobulin-class switching and patients with the A allele revealed higher serum levels of IgA (p=0.048), the amino acid change might influence a class switch to increase serum IgA levels, resulting in a higher risk of IgA nephropathy. [ABSTRACT FROM AUTHOR]

Immunoglobulin A nephropathy (IgAN) is a primary glomerulonephritis of common incidence world-wide whose etiology and pathogenesis remain unresolved, although genetic factors are assumed to be involved in the development and progression of this disease. To identify genetic variations that might confer susceptibility to IgAN, we performed a case-control association study involving 389 Japanese IgAN patients and 465 controls. Genome-wide analysis of approximately 80,000 single-nucleotide polymorphisms (SNPs) identified a significant association between IgAN and six SNPs located in the PIGR (polymeric immuoglob-ulin receptor) gene at chromosome 1q31-q41. One of them, PIGR-17, caused an amino-acid substitution from alanine to valine at codon 580 (χ[SUB2]=13.05, P=0.0003, odds ratio [OR] =1.59, 95% confidence interval [95% CI] =1.24-2.05); the OR of minor homozygotes to other was 2.71 (95% CI=1.31-5.61). Another SNP, PIGR-2, could affect promoter activity (χ[SUB2]=11.95, P=0.00055, OR=1.60, 95% CI=1.22- 2.08); the OR of minor homozygotes to others was 2.08 (95% CI=0.94-4.60). Pairwise analyses demonstrated that all six SNPs were in almost complete linkage disequilibrium. Biopsy specimens from IgAN patients were positively stained by antibody against the secretory component of PIGR, but corresponding tissues from non-IgAN patients were not. Our results suggest that a gene associated with susceptibility to IgAN lies within or close to the PIGR gene locus on chromosome 1q in the Japanese population. [ABSTRACT FROM AUTHOR]