Effect of VKORC1, CYP2C9, CFP4F2, and GGCX Gene Polymorphisms on Warfarin Dose in Japanese Pediatric Patients.

BACKGROUND: Warfarin dosage requirements show considerable inter-individual variability. There are some reports of warfarin dose regimens correlating with single nucleotide polymorphisms (SNP) for CYP2C9, VKORC1 and other genes in adults. In children, however, reports are scarcer than in adults and the number of genes examined is more limited. We explored the effects of genetic variation on warfarin dose requirement in Japanese pediatric patients. METHODS: A total of 45 patients who were prescribed warfarin at the Yokohama City University Hospital were included in this study. The influence of genetic polymorphisms on stable warfarin dosage requirement was investigated by genotyping SNPs of the VKORC1, CYP2C9, CYP4F2, and GGCX genes (rs9923231, rs1057910, rs2108622, and rs699664, respectively) in each patient. RESULTS: Patients with the TT genotype in rs9923231 in VKORC1 required significantly lower maintenance dosages than those with the TC genotype (p = 0.001). Multiple regression analysis showed that, while VKORC1 status and patient height account for 78.2 % of the variability in maintenance warfarin dosage, genetic polymorphisms in VKORC1 account for 27 %, although polymorphisms in CYP4F2 and GGCX had no effect on dosage and the effect of CYP2C9 could not be evaluated. CONCLUSIONS: Polymorphisms in VKORC1 partially affected daily warfarin dosage requirements. VKORC1 genotype and height are the primary determinants influencing warfarin dosage in Japanese pediatric patients. Further studies with larger sample sizes are needed to confirm our results.

Postnatal changes of cytokines in premature infants with or without funisitis.

OBJECTIVE: Fetal inflammatory response syndrome (FIRS), which induces hypercytokinemia, is important for the outcomes of premature infants. It is necessary to focus on the fetal inflammatory environments. METHODS: A total of 37 premature infants (gestational age ≤32 weeks) were divided into three groups: (1) 15 without chorioamnionitis (CAM) and funisitis; C(-)F(-) group, (2) 15 with CAM but without funisitis; C(+)F(-) group and (3) 7 with CAM and funisitis; C(+)F(+) group. Blood interleukin (IL)-1ß, IL-6 and IL-8 levels were measured on day 0 (= in umbilical cord blood), 3, 7, 14, 21 and 28. RESULTS: (1) day 0: Cord blood concentrations of IL-1ß, IL-6 and IL-8 were significantly higher in the C(+)F(+) group than in the C(+)F(-) group and C(-)F(-) group. On the other hand, they were comparable between the C(+)F(-) group and C(-)F(-) group. (2) Days 3-28: elevated cytokines levels in the C(+)F(+) group with funisitis decreased on day 3 and later. CONCLUSIONS: We suggested that hypercytokinemia in the cord blood in premature infants were greatly related with funisitis. Diagnosis of funisitis would be important to find the premature infants who need to be managed their risk of FIRS. In addition, hypercytokinemia disappeared in a few days after birth; therefore, cord blood data analysis of cytokines and/or inflammation-related proteins concentrations is necessary to evaluate the fetal inflammatory environments in premature infants after birth.

Analysis of gender differences in genetic risk: association of TNFAIP3 polymorphism with male childhood-onset systemic lupus erythematosus in the Japanese population.

BACKGROUND: Systemic lupus erythematosus (SLE) is a systemic multisystem autoimmune disorder influenced by genetic background and environmental factors. Our aim here was to replicate findings of associations between 7 of the implicated single nucleotide polymorphisms (SNPs) in IRF5, BLK, STAT4, TNFAIP3, SPP1, TNIP1 and ETS1 genes with susceptibility to childhood-onset SLE in the Japanese population. In particular, we focused on gender differences in allelic frequencies. METHODOLOGY/PRINCIPAL FINDINGS: The 7 SNPs were genotyped using TaqMan assays in 75 patients with childhood-onset SLE and in 190 healthy controls. The relationship between the cumulative number of risk alleles and SLE manifestations was explored in childhood-onset SLE. Logistic regression was used to test the effect of each polymorphism on susceptibility to SLE, and Wilcoxon rank sum testing was used for comparison of total risk alleles. Data on rs7574865 in the STAT4 gene and rs9138 in SPP1 were replicated for associations with SLE when comparing cases and controls (corrected P values ranging from 0.0043 to 0.027). The rs2230926 allele of TNFAIP3 was associated with susceptibility to SLE in males, but after Bonferroni correction there were no significant associations with any of the other four SNPs in IRF5, BLK, TNIP1 and ETS1 genes. The cumulative number of risk alleles was significantly increased in childhood-onset SLE relative to healthy controls (P = 0.0000041). Male SLE patients had a slightly but significantly higher frequency of the TNFAIP3 (rs2230926G) risk allele than female patients (odds ratio [OR] = 4.05, 95% confidence interval [95%CI] = 1.46-11.2 P<0.05). CONCLUSIONS: Associations of polymorphisms in STAT4 and SPP1 with childhood-onset SLE were confirmed in a Japanese population. Although these are preliminary results for a limited number of cases, TNFAIP3 rs2230926G may be an important predictor of disease onset in males. We also replicated findings that the cumulative number of risk alleles was significantly increased in childhood-onset SLE.

Clinical features of Mycoplasma pneumoniae infections in the 2010 epidemic season: report of two cases with unusual presentations.

Mycoplasma pneumoniae (Mp) is one of the main pathogens causing community-acquired pneumonia, particularly in young individuals. Host immune response appears to play an important role in prolonged symptoms, as well as in the recent increasing prevalence of drug-resistant Mp isolated from patients. Case 1 had a prolonged clinical course caused by drug-resistant Mp and received steroid therapy despite Mp susceptibility to some antimicrobial agents. Serum cytokine profiles revealed elevation of interleukin-6/-10 and interferon-γ in acute phase. Case 2 had mycoplasmal myocarditis without any respiratory symptoms, which resolved spontaneously without the administration of any antimicrobial agent. These observations suggest that host immune response probably contributes to the etiology of Mp-associated complications.

[Febrile responses in patients with pediatric rheumatic diseases].

Fever is one of the critical symptoms of patients in pediatrics field. It indicates inflammatory focus somewhere in the body, and the major causes of fever are infectious diseases. Recent progresses of our knowledge about autoinflammatory syndrome promoted the investigation of the mechanism of fever, and suggested that the pro-inflammatory cytokines are the direct causative agents of fever. The basic science revealed that cooperation of IL-6 and IL-1ß induces febrile response. Fever of unknown origin (FUO) remains a challenging problem. Rheumatic diseases, rare infectious diseases, and benign tumors and malignancies are diagnoses to be differentiated. FDG-PET is recently proved a valuable tool for the identification of the etiology in patients with FUO. Since the introduction of biological response modifiers into the treatment of patients with pediatric rheumatic diseases has shifted the therapeutic paradigm, a new concept that the blockade of a unique pro-inflammatory cytokine brings cessation of whole inflammatory responses affected tremendously the clinical medicine. A more investigation of inflammation and its pathophisiology will be needed in pediatric rheumatology.

Association of IRF5 polymorphisms with susceptibility to hemophagocytic lymphohistiocytosis in children.

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome and has a varied genetic background. The polymorphism of interferon regulatory factor 5 gene (IRF5) was reported to be associated with susceptibility to macrophage activation syndrome. IRF5 acts as a master transcription factor in the activation of pro-inflammatory cytokines. We assessed associations of IRF5 gene polymorphisms with susceptibility to secondary HLH. METHODS: Three IRF5 single nucleotide polymorphisms (rs729302, rs2004640, and rs2280714) were genotyped using TaqMan assays in 82 secondary HLH patients and 188 control subjects. RESULTS: There was a significant association of the GT/TT genotype at rs2004640 with secondary HLH susceptibility (p < 0.01). The IRF5 haplotype (rs729302 A, rs2004640 T, and rs2280714 T) was associated with secondary HLH susceptibility (p < 0.01). CONCLUSIONS: These findings indicate that IRF5 is a genetic factor influencing the susceptibility to secondary HLH and that the IRF5-associated immune response contributes to the pathogenesis of HLH.