Influence of azole antifungal drugs on blood tacrolimus levels after switching from intravenous tacrolimus to once-daily modified release tacrolimus in patients receiving allogeneic hematopoietic stem cell transplantation.

WHAT IS KNOWN AND OBJECTIVE: Azole antifungal drugs are often co-administered with tacrolimus after allogeneic hematopoietic stem cell transplantation (HSCT). However, the influence of azole antifungal drugs on variation in tacrolimus pharmacokinetics when switching from intravenous tacrolimus (Tac-iv) to once-daily modified release tacrolimus (Tac-MR) remains to be elucidated. This study was performed to evaluate the effects of oral azole antifungal drugs on variation in tacrolimus pharmacokinetics after conversion to Tac-MR in HSCT patients. METHODS: Patients concomitantly receiving fluconazole (FLCZ) or voriconazole (VRCZ) along with tacrolimus were evaluated retrospectively. Blood tacrolimus concentrations before and after changing to oral administration were compared between FLCZ and VRCZ groups. RESULTS AND DISCUSSION: A total of 52 patients (34 FLCZ and 18 VRCZ) were included in the analysis. There were no significant differences in the most recent daily dose (Div ) and blood level (Civ ) of Tac-iv, Civ /Div , and ratio of daily dose of tacrolimus on the first to second day after changing to Tac-MR (Dpo1-2 ) to Div between FLCZ and VRCZ groups (P > 0.2). The trough levels of tacrolimus on the first to second day after switching to Tac-MR (Cpo1-2 ) and on the third to fifth day after the switch (Cpo3-5 ) were significantly higher in the VRCZ group than the FLCZ group (P < 0.05). The values of (Civ /Div )/(Cpo1-2 /Dpo1-2 ) and (Civ /Div )/(Cpo3-5 /Dpo3-5 ) in the VRCZ group were significantly lower compared with those in the FLCZ group (P < 0.05). Furthermore, individual values of (Civ /Div )/(Cpo3-5 /Dpo3-5 ) in the FLCZ group varied widely. WHAT IS NEW AND CONCLUSION: Voriconazole increased blood tacrolimus level more markedly than FLCZ after switching to Tac-MR, whereas FLCZ caused a large variation in tacrolimus blood level. These results suggest that therapeutic monitoring of tacrolimus after the switch may need to be performed carefully considering that orally co-administered VRCZ and FLCZ exhibit different change in blood tacrolimus level just after the switch.

Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD.

Graft-versus-host disease (GVHD) is among the most challenging complications in unrelated donor hematopoietic cell transplantation (HCT). The highly polymorphic MHC class I chain-related gene A, MICA, encodes a stress-induced glycoprotein expressed primarily on epithelia. MICA interacts with the invariant activating receptor NKG2D, expressed by cytotoxic lymphocytes, and is located in the MHC, next to HLA-B Hence, MICA has the requisite attributes of a bona fide transplantation antigen. Using high-resolution sequence-based genotyping of MICA, we retrospectively analyzed the clinical effect of MICA mismatches in a multicenter cohort of 922 unrelated donor HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 10/10 allele-matched HCT pairs. Among the 922 pairs, 113 (12.3%) were mismatched in MICA MICA mismatches were significantly associated with an increased incidence of grade III-IV acute GVHD (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.50-2.23; P < .001), chronic GVHD (HR, 1.50; 95% CI, 1.45-1.55; P < .001), and nonelapse mortality (HR, 1.35; 95% CI, 1.24-1.46; P < .001). The increased risk for GVHD was mirrored by a lower risk for relapse (HR, 0.50; 95% CI, 0.43-0.59; P < .001), indicating a possible graft-versus-leukemia effect. In conclusion, when possible, selecting a MICA-matched donor significantly influences key clinical outcomes of HCT in which a marked reduction of GVHD is paramount. The tight linkage disequilibrium between MICA and HLA-B renders identifying a MICA-matched donor readily feasible in clinical practice.

Successful induction of therapeutic urinary concentration by intravenous ganciclovir and oral valganciclovir with remission of adenoviral hemorrhagic cystitis after cord blood transplantation.

AdV11-HC is one of the major complications after allogeneic HSCT in Japan. We previously reported that the intravenous infusion of ganciclovir was effective against AdV11-HC in a post-transplant patient. We here report a case of a 10-year-old boy who underwent cord blood transplantation for the treatment of relapsed lymphoblastic lymphoma. He developed AdV11-HC with an elevated AdV load in his urine and blood on day 14 after HSCT. He was immediately treated with intravenous ganciclovir; he rapidly achieved a remission of AdV11-HC with a decreased AdV load in his urine and blood. He remained in remission of AdV11-HC, even after we switched ganciclovir to oral valganciclovir on day 63. A pharmacokinetics study of his urine revealed that therapeutic concentrations of ganciclovir could be achieved by both intravenous ganciclovir and oral valganciclovir. These findings suggested that both intravenous ganciclovir and oral valganciclovir could be promising alternatives for the treatment of AdV11-HC in post-transplant patients.

Necrotizing Ulcer After BCG Vaccination in a Girl With Leukocyte-adhesion Deficiency Type 1.

Leukocyte-adhesion deficiency-1 is a recessively inherited disorder associated with recurrent bacterial infections, severe periodontitis, peripheral leukocytosis, and impaired wound healing. We diagnosed moderate-type leukocyte-adhesion deficiency-1 in a 7-year-old girl who developed a necrotizing ulcer after Bacillus Calmette-Guerin vaccination. The patient showed moderate expression of CD18 in neutrophils with a homozygous splice mutation with c.41_c.58+2dup20 of ITGB2 and experienced recurrent severe infections complicated with systemic lupus erythematosus. She received hematopoietic stem cell transplantation from a matched elder brother with heterozygous mutation of ITGB2, and has since remained free of infection and systemic lupus erythematosus symptoms without immunosuppression therapy.

Preoperative Treatment With Pazopanib in a Case of Chemotherapy-Resistant Infantile Fibrosarcoma.

Clinical and radiological diagnosis of infantile fibrosarcoma (IFS) is challenging because of its similarity to vascular origin tumors. Treatment involves complete resection. Although chemotherapy may allow more conservative resection, treatment guidelines are not strictly defined. One IFS patient with an unresectable tumor had disease progression during chemotherapy. A primary tumor sample showed high VEGFR-1/2/3 and PDGFR-α/ß expression. After pazopanib therapy, most tumor showed necrosis within 29 days and could be removed completely, with no relapse in 8 months post-resection. When IFS features hypervascularity, VEGFR and PDGFR expression may be high, thus allowing consideration of VEGFR inhibitors such as pazopanib.

Sunitinib-induced severe toxicities in a Japanese patient with the ABCG2 421 AA genotype.

BACKGROUND: Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor that acts against receptors for vascular endothelial growth factor and platelet-derived growth factor. Common toxicities of sunitinib treatment include hypertension, hand-foot syndrome, vomiting, and diarrhea, and the proportion of grade 3 or 4 adverse events relating to sunitinib treatment range from 1 to 13% for all categories. It is reported that increased exposure to sunitinib is associated with improved clinical outcomes but also carries an increased risk of adverse effects. CASE PRESENTATION: A 73-year-old Japanese woman with metastatic renal cell carcinoma who received sunitinib at a dose of 50 mg once daily suffered a high-grade fever on day 11 of treatment. Sunitinib treatment was discontinued on day 12; however, severe thrombocytopenia and transaminase elevation occurred and persisted more than a week. Additionally, severe hypoxia due to pleural effusion and pulmonary edema developed despite immediate discontinuation of sunitinib. On day 14, three days after the discontinuation of sunitinib, the plasma concentrations of sunitinib and its major active metabolite N-desethyl sunitinib (SU12662) were extremely high (131.9 ng/mL and 28.4 ng/mL, respectively). By day 25, all toxicities had resolved, and a CT scan revealed marked tumor shrinkage. Genotyping of seven single-nucleotide polymorphisms that are potentially relevant to the pharmacokinetics of sunitinib was performed. The patient's genotype of ABCG2 (ATP-binding cassette, sub-family G (WHITE), member 2) 421C > A was homozygous for the variant allele (AA), which was reported to be associated with high exposure to sunitinib. Therefore, we speculated that the extremely high plasma concentrations of sunitinib and SU12662 caused by the ABCG2 421 AA genotype might have resulted in severe toxicities to the patient. CONCLUSION: The minor allele frequencies of ABCG2 421C > A are approximately three-fold higher in Asians than in Caucasians. Our report suggests that pharmacogenetic factors should be considered when severe and rapid-onset adverse drug reactions occur in Asian patients, including Japanese treated with sunitinib.

Serum levels of interleukin-22 and hepatitis B core-related antigen are associated with treatment response to entecavir therapy in chronic hepatitis B.

AIM: We sought to clarify the associations between serum cytokines and chemokines, hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg), and hepatitis B virus (HBV) DNA and response to entecavir therapy in chronic hepatitis B. METHODS: We analyzed six cytokines (interleukin [IL]-2, IL-6, IL-10, IL-12p70, IL-21 and IL-22) and five chemokines (CCL2, CCL3, CXCL9, CXCL10 and CXCL11) before and at 6, 12 and 24 months during entecavir therapy in 48 chronic hepatitis B patients. Quantitative measurement of HBsAg, HBcrAg and HBV DNA was performed. A virological response (VR) was defined as serum HBV DNA of less than 2.1 log copies/mL by treatment month 24. RESULTS: Thirty-nine patients (81%) achieved a VR. Serum IL-6 (P = 0.031), CXCL-9 (P = 0.002), and CXCL-10 (P = 0.001) were high in chronic HBV and correlated positively with transaminases and bilirubin. Before treatment, elevated IL-22 (P = 0.031) and lower HBsAg (P = 0.001) and HBcrAg (P < 0.001), but not HBV DNA, were associated with a favorable treatment outcome. In multivariate analysis, high IL-22 (hazard ratio = 13.67, P = 0.046) and low HBcrAg (hazard ratio = 10.88, P = 0.048) were independently associated with a VR. The levels of IL-22 (P < 0.001), HBsAg (P < 0.001), and HBcrAg (P < 0.001) all decreased from baseline to 24 months of treatment in virological responders. CONCLUSION: Serum IL-22 and HBcrAg are predictive markers of a VR to entecavir therapy in patients with chronic hepatitis B.

Human leukocyte antigen class II molecules confer both susceptibility and progression in Japanese patients with primary biliary cirrhosis.

UNLABELLED: Along with twin and family studies, recent genome-wide association studies suggest that genetic factors contribute to the susceptibility and severity of primary biliary cirrhosis (PBC). Although several reports have demonstrated that the human leukocyte antigen (HLA) DRB1*08:03 allele is associated with disease susceptibility in Japan, the precise analysis of HLA haplotypes and the role of amino acid alignment have not been fully clarified. We investigated HLA class I A, B, and C and HLA class II DRB1 and DQB1 alleles and haplotypes in 229 Japanese patients with PBC and compared them with the published data of 523 healthy subjects. Significant associations were found with PBC susceptibility for the DRB1*08:03-DQB1*06:01 (13% versus 6%; P = 0.000025; odds ratio [OR] = 2.22) and DRB1*04:05-DQB1*04:01 haplotypes (17% versus 13%; P = 0.044; OR = 1.38). Conversely, there were significant protective associations with the DRB1*13:02-DQB1*06:04 (2% versus 5%; P = 0.00093; OR = 0.27) and DRB1*11:01-DQB1*03:01 haplotypes (1% versus 4%; P = 0.03; OR = 0.37). The frequency of the DRB1*09:01-DQB1*03:03 haplotype was significantly higher in patients who had received orthotopic liver transplantation (33% versus 11%; P = 0.0012; OR = 3.96). Furthermore, the frequency of serine at position 57 (P = 0.0000015; OR = 1.83) of the DRßchain differed the most in patients with PBC, compared with healthy subjects. CONCLUSION: This study established the role of HLA haplotypes in determining PBC susceptibility and progression in the Japanese population. Further resequencing of the HLA region is required to more precisely identify the genetic components of PBC.

Long-term outcome of Japanese patients with type 1 autoimmune hepatitis.

UNLABELLED: The long-term outcome of patients with autoimmune hepatitis (AIH) in Japan has not been well-defined. The aim of this study was to clarify the outcome of this disease over a long follow-up period compared with that of the general Japanese population as well as that among patients. A total of 203 AIH patients were enrolled for a mean follow-up period of 131 months. All patients were treated with corticosteroids with or without azathioprine. The overall survival of AIH patients was similar to that of the general population in Japan. The prognosis of AIH subgroups divided according to disease severity, sex, incidence of relapse, liver histology, presence of cirrhosis, probable or definite AIH score, antibody to hepatitis B core antigen antibody positivity, or human leukocyte antigen DR4-positivity did not differ greatly among patients. However, the prognosis of patients experiencing two or more relapses was significantly poorer than that of patients with remission or a single relapse both in univariate (P < 0.001) and multivariate (P = 0.020) analyses. The development of liver malignancy was also a possibility among AIH patients with multiple relapses. Severe adverse effects of corticosteroids were rare, even in patients who underwent long-term treatment. CONCLUSION: Repeated relapses of AIH are significantly associated with a poorer long-term prognosis in Japan. AIH patients can expect a similar prognosis to that of the general population, provided they are adequately managed with continuous low doses of immunosuppressive therapy, especially after the first relapse.

Safety and effectiveness of low-dose propofol sedation during and after esophagogastroduodenoscopy in child A and B cirrhotic patients.

BACKGROUND: Effective and safe sedation for patients with liver cirrhosis is problematic. AIM: To examine the safety and effectiveness of low-dose propofol sedation during and after esophagogastroduodenoscopy (EGD) in cirrhotic patients. METHODS: Study 1 was a prospective study in cirrhotic patients who underwent diagnostic EGD under propofol sedation. Propofol was given by bolus injection with an age-adjusted standard protocol consisting of 40 mg for patients <70 years, 30 mg for patients aged 70-89 years; additional injections of 20 mg propofol were given up to a maximum of 120 mg. The principal parameter was the occurrence of adverse events within 24 h after EGD. Secondary parameters included successful procedures, complications, and full recovery within 60 min. In Study 2, the residual effects of propofol were evaluated using a driving simulator and blood propofol concentrations in a subset of cirrhotic patients undergoing EGD and compared with healthy individuals. The principal parameter was driving ability. RESULTS: Study 1: Consecutive cirrhotic patients were entered and all 163 successfully completed EGD. The mean dose of propofol was 46 mg (range 30-120 mg). No complications occurred. Full recovery had occurred in 100 % 60 min after the procedure. No adverse events occurred within 24 h after EGD. Study 2: There were no significant differences in blood propofol levels between cirrhotic patients (n = 21) and healthy individuals (n = 20) after sedation. In cirrhotic patients, there was no deterioration in driving ability as compared with healthy individuals. CONCLUSION: Low-dose propofol sedation provided safe and effective sedation for EGD in cirrhotic patients with rapid recovery.

Psychomotor recovery and blood propofol level in colonoscopy when using propofol sedation.

BACKGROUND: It is commonly recommended that patients refrain from driving for 24 hours after endoscopy for which sedation is given. OBJECTIVE: The aim of this study was to evaluate psychomotor recovery and blood propofol concentrations after colonoscopy with propofol sedation to determine whether driving might be safe. DESIGN: A prospective, consecutive study. SETTING: Municipal hospital outpatients. PATIENTS: This study involved 48 consecutive patients scheduled for colonoscopy with propofol sedation. INTERVENTION: Patient clinical features, psychomotor recovery, and blood concentrations of propofol were assessed. Psychomotor recovery was assessed before colonoscopy and 1 and 2 hours after colonoscopy by using the number connection test and a driving simulator test. MAIN OUTCOME MEASUREMENTS: Clinical features, psychomotor recovery, and blood concentration of propofol. RESULTS: All patients successfully completed the post-sedation assessments. Although there was a significant difference in results of the number connection test between before colonoscopy and 1 hour after colonoscopy, all number connection test results were within normal limits (<40 seconds). Scores were as follows: mean time (standard deviation) before colonoscopy, 32.2 (2.0) seconds (range 29-36 seconds) versus after colonoscopy, 32.7 (2.0) seconds (range 27-38 seconds); P = .0019. Driving skills had recovered to the baseline levels 1 hour after colonoscopy. Scores were as follows: tracking error (%) before colonoscopy, 45.0 (5.6) versus after colonoscopy, 46.0 (5.5); P = .61; accelerating reaction time in seconds before colonoscopy, 0.65 (0.15) versus after colonoscopy, 0.62 (0.14); P = .40; braking reaction time in seconds before colonoscopy, 0.58 (0.13) versus after colonoscopy, 0.61 (0.13); P = .50. LIMITATIONS: Small sample size, single-center study. CONCLUSION: Although consistent findings on the number connection test and driving simulation (psychomotor recovery) test are present as early as 1 hour after propofol sedation, a study of additional numbers of patients as well as different patient populations are needed before these results can be universally recommended.

Association of serum cytokine levels with treatment response to pegylated interferon and ribavirin therapy in genotype 1 chronic hepatitis C patients.

BACKGROUND: We sought to clarify the associations among serum cytokines, amino acid substitutions in the interferon sensitivity-determining region (ISDR) and core region, and treatment outcome of pegylated interferon and ribavirin therapy in genotype 1 hepatitis C virus (HCV)-infected patients. METHODS: We quantified a total of 8 serum cytokines before, during, and after treatment in 79 genotype 1 chronic HCV patients. Viral ISDR and core region variants were determined by direct sequencing. RESULTS: High levels of interleukin (IL)-12 and IL-18 and more than 2 mutations in the ISDR were associated with a sustained virological response (SVR). Conversely, high baseline IL-10 levels and glutamine at amino acid 70 of the HCV core protein (Gln70) were significantly associated with a nonresponse to treatment, and patients with Gln70 had significantly higher IL-10 levels. In multivariate analysis, low IL-10, high IL-12, and high IL-18 levels were independently associated with an SVR. These 3 cytokine levels were decreased from baseline levels 4 weeks into treatment and remained low in patients with an SVR. CONCLUSION: Serum IL-10, IL-12, and IL-18 levels are predictive of the response to HCV treatment with pegylated interferon and ribavirin and are associated with amino acid substitutions in the ISDR and core region.

Toll-like receptor 2 (TLR2) gene polymorphisms are not associated with sarcoidosis in the Japanese population.

PURPOSE: Sarcoidosis is a systemic inflammatory disease characterized by the formation of non-caseating granulomas, with varied clinical manifestations. The common etiology of sarcoidosis is uncertain, but it is thought to be triggered by an exogenous antigenic stimulus, such as some bacterial proteins. Toll-like receptors (TLRs) recognize microbial components and elicit innate as well as adaptive immune responses. It has been reported that polymorphisms in TLR2 might be important in a small group of Caucasian sarcoidosis patients. The present study aimed to establish whether these findings are relevant to the Japanese population. METHODS: We genotyped 5 single-nucleotide polymorphisms (SNPs) in TLR2 and assessed the allelic diversity between 257 Japanese sarcoidosis patients and 193 Japanese healthy controls. RESULTS: No significant differences in the frequency of TLR2 alleles and haplotypes in the sarcoidosis cases were found in comparison with the controls. However, marginal associations were observed for TLR2 at rs3804099 and rs3804100 in sarcoidosis patients with cutaneous manifestations. CONCLUSIONS: Our results suggest that TLR2 polymorphisms are not significantly related to the pathogenesis of sarcoidosis in the Japanese population.

Association analysis of cytotoxic T-lymphocyte antigen 4 gene polymorphisms with primary biliary cirrhosis in Japanese patients.

BACKGROUND & AIMS: Primary biliary cirrhosis (PBC) is an organ-specific autoimmune disease of still unidentified genetic etiology that is characterized by chronic inflammation of the liver. Since cytotoxic T-lymphocyte antigen 4 (CTLA4) polymorphisms have recently been linked with PBC susceptibility in studies on Caucasians, we investigated the genetic association between CTLA4 polymorphisms and PBC in a Japanese population. METHODS: Five single nucleotide polymorphisms (SNPs) in the CTLA4 gene (rs733618, rs5742909, rs231775, rs3087243, and rs231725) were genotyped in 308 patients with PBC and 268 healthy controls using a TaqMan assay. RESULTS: One CTLA4 gene SNP (rs231725) was significantly associated with susceptibility to anti-mitochondrial antibody (AMA)-positive PBC, but clinical significance disappeared after correction for multiple testing. Moreover, CTLA4 gene SNPs did not influence AMA development or disease progression to orthotopic liver transplantation in our Japanese cohort. In haplotype analyses, one haplotype [haplotype 1 (CGGA)] at rs5742909, rs231775, rs3087243, and rs231725, was significantly associated with susceptibility to both AMA-positive PBC and overall PBC. CONCLUSIONS: This study showed that CTLA4 gene polymorphisms had a modest, but significant association with susceptibility to PBC in the Japanese population. The connection between genetic variants and the function of the CTLA4 gene remains to be addressed in future investigations.

Genetics of Behçet disease inside and outside the MHC.

BACKGROUND: Behçet disease (BD) is a rare, chronic, systemic, inflammatory disorder characterised by recurrent ocular, genital and skin lesions. Although its aetiology is still uncertain, an intricate interplay between the environment (eg, viruses) and the host seems to initiate and/or perpetuate the disease, although the mechanism remains speculative. Since the identification of HLA-B*5101 (and more recently of MICA) as a susceptibility locus for BD, the identification of additional genetic locus/loci, whether inside, or perhaps more importantly outside the MHC has clearly stalled. OBJECTIVE: To carry out a genome-wide association study (GWAS) of BD. METHODS: 300 Japanese patients with BD and an equal number of controls were recruited. The samples were screened using a dense panel of 23 465 microsatellites (MS) covering the entire genome. RESULTS: The six best (of a total of 147) positively associated MS with BD were identified. Of these six, two were located within the human leucocyte antigen (HLA) class I region itself. Although one of these was clearly reminiscent of the association with HLA-B, the second, not in linkage disequilibrium with the former, was in the telomeric side of the class I region and remained to be formally identified. HLA genotyping and haplotype analysis conclusively led to the deciphering of a dual, independent, contribution of two HLA alleles to the pathogenesis of BD: HLA-B*5101 and HLA-A*26. CONCLUSIONS: This GWAS highlights the premier genetic susceptibility locus for BD as the major histocompatibility complex itself, wherein reside two independent loci: HLA-B and HLA-A.

Investigation of the association between Toll-like receptor 2 gene polymorphisms and Behçet's disease in Japanese patients.

Behçet's disease (BD) is a chronic systemic inflammatory disorder characterized by recurrent ocular symptoms, oral and genital ulcers, and skin lesions. The etiology of BD is still uncertain, but genetic and environmental factors likely both play an important role in BD development. In the present study, we investigated whether polymorphisms of Toll-like receptor 2 (TLR2), previously reported to recognize BD candidate antigens, are associated with BD. Two hundred Japanese patients with BD and 128 Japanese healthy controls were recruited. We genotyped five single-nucleotide polymorphisms (SNPs) in the TLR2 gene and assessed the allele/genotype diversity between cases and controls for all SNPs. No significant differences in the frequency of TLR2 alleles, genotypes, and haplotypes in the BD cases were detected compared with the controls. These data indicate that TLR2 polymorphisms do not play an important role in the development of BD.

Complex divergence at a microsatellite marker C1_2_5 in the lineage of HLA-Cw/-B haplotype.

The human leukocyte antigen (HLA) complex locus has shaped a framework for evolutionary processes because of the dense clustering and strong linkage disequilibrium (LD) of polymorphic genes. Although the landscape of LD among conventional single-nucleotide polymorphisms (SNPs) has been described, the data on the lineage of major histocompatibility complex (MHC) haplotype are limited to pairwise comparisons of several haplotypes in Caucasoid populations. Multi-allelic markers, including microsatellite markers, may provide us with a larger power to analyze the MHC haplotype lineage because the mutation rate of microsatellite exceeds that of SNPs by several orders of magnitude. In this study, we investigated the complex structure of repeat motifs in a microsatellite to figure out the structural lineage of HLA-Cw/-B segments in Japanese. It was found that the genetic differences of HLA-Cw/-B haplotype lineage were reflected by repeat motif patterns at C1_2_5 locus, suggesting that unique mutational dynamics of microsatellites may be a useful marker to chase the haplotype lineage.

HLA-DPB1 and NFKBIL1 may confer the susceptibility to chronic thromboembolic pulmonary hypertension in the absence of deep vein thrombosis.

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by pulmonary hypertension caused by thromboembolism of the pulmonary artery. Etiology of CTEPH may be heterogeneous and is largely unknown, but genetic factors are considered to be involved in the etiology. It has been reported that deep vein thrombosis (DVT) and/or coagulation factor variants are predisposing factors to CTEPH. However, more than half of the CTEPH patients, especially the Japanese, do not have prior DVT or coagulation abnormality, suggesting that there should be other risk factors for CTEPH. Moreover, there are several reports on the association between CTEPH and human leukocyte antigen (HLA). To further clarify the HLA-linked gene(s) controlling the susceptibility to CTEPH, 160 patients (99 without DVT and 61 with DVT) and 380 healthy controls were analyzed for polymorphisms in 15 microsatellite markers and 5 genes in the HLA region. We found a strong association of HLA markers with the DVT-negative CTEPH, DPB1(*)0202 (odds ratio (OR)=5.07, 95% confidence interval (CI)=2.52-10.19, P=0.00000075, corrected P-value (Pc)=0.00014), IKBL-p(*)03 (OR=2.33, 95% CI=1.49-3.66, P=0.00017, Pc=0.033) and B(*)5201 (OR=2.47, 95% CI=1.56-3.90, P=0.000086, Pc=0.016), whereas no significant association was observed for the DVT-positive CTEPH. The comparison of clinical characteristics of patients stratified by the presence of susceptibility genes implied that the DPB1 gene controlled the severity of the vascular lesion, whereas the IKBL gene (NFKBIL1) was associated with a relatively mild phenotype.

Association of TLR4 polymorphisms with Behcet's disease in a Korean population.

OBJECTIVES: HLA-B51 is strongly associated with Behçet's disease (BD) in any ethnic background. We recently reported that another gene, Toll-like receptor-4 (TLR4) is also implicated in BD in a Japanese population. To confirm these results, we investigated polymorphisms in the TLR4 gene in Korean patients with BD. METHODS: In this study, 119 patients with BD and 141 healthy controls were enrolled; every participant was a Korean. Nine single nucleotide polymorphisms previously detected in TLR4 by direct sequencing were analysed for an association with BD. RESULTS: The most frequent haplotype, TAGCGGTAA, was significantly increased in HLA-B*51-positive BD patients (49.5%), compared with healthy control participants [32.3%; P = 0.029; odds ratio (OR) = 2.01; 95% CI 1.25-3.23]. This haplotype was also significantly increased in BD patients with arthritis (48.2%; P = 0.003; OR = 1.96; 95% CI 1.26-3.26). There were no significant differences in the allele and genotype frequencies of patients and controls for each single nucleotide polymorphism. CONCLUSIONS: The haplotype of TLR4 may increase the risk for developing BD and the complication of arthritis in the Korean population.

Evaluation of PTPN22 polymorphisms and Vogt-Koyanagi-Harada disease in Japanese patients.

PURPOSE: Vogt-Koyanagi-Harada (VKH) disease is an autoimmune disorder against melanocytes. Polymorphisms of the protein tyrosine phosphatase non-receptor 22 gene (PTPN22) have recently been reported to be associated with susceptibility to several autoimmune diseases. In this study, genetic susceptibility to VKH disease was investigated by screening for single nucleotide polymorphisms (SNPs) of PTPN22. METHODS: A total of 167 Japanese patients with VKH disease and 188 healthy Japanese controls were genotyped by direct sequencing methods for six SNPs (rs3811021, rs1217413, rs1237682, rs3761935, rs3789608, and rs2243471) of PTPN22 including the uncoding exons. RESULTS: The six SNPs in PTPN22 showed no significant association with susceptibility to VKH disease or its ocular, neurologic, or dermatological manifestation. CONCLUSIONS: Further studies are needed to clarify the genetic mechanisms underlying VKH disease.