CYP3A5 genotypes affect tacrolimus pharmacokinetics and infectious complications in Chinese pediatric liver transplant patients

Little information is available regarding the impact of cytochrome P450 (CYP) 3A5 on the metabolism of TAC in infant LTx. Therefore, the CYP3A5 genotype of Chinese pediatric recipients (intestine) as well as donors (graft liver) was performed for the purpose of establishing an optimal dosage regimen in children. Sixty‐four patients were divided according to CYP3A5 genotype (expression of *1 allele: EX and NEX) for each recipient (R) and donor (D), EX‐R/EX‐D (n = 21), EX‐R/NEX‐D (n = 8), NEX‐R/EX‐D (n = 8) and NEX‐R/NEX‐D (n = 27). Results indicated that initial TAC daily dose requirement was higher among EX‐R/EX‐D children compared with those who did not express CYP3A5 (0.28 ± 0.10 vs. 0.19 ± 0.08 mg/kg/day, p < 0.01). CYP3A5 expression contributed an overall of 38.35% to its C/D ratios, and graft liver was a key determinant. Additionally, the EX‐R/EX‐D group showed significantly higher incidence of infectious complications, lower immune response and was an independent risk factor for the development of infections (odds ratio 3.86, p = 0.025). Donor CYP3A5 expression partially explains TAC dose requirement, the effect of CYP3A5 variation may influence clinical outcomes; therefore, monitoring immune response may be important for preventing risks associated with under‐ and over‐immunosuppression.     

Association of MBL2 polymorphism with asthma after bronchiolitis in infancy

Background: Mannose‐binding lectin (MBL) is a component of innate immunity and has been linked with the pathogenesis of asthma. The aim of the present study was to evaluate the association of MBL genotypes with preschool asthma and allergy in children with bronchiolitis in early infancy. Methods: In all, 205 infants were hospitalized for bronchiolitis at <6 months of age. Asthma and allergy were studied from a total of 166 children at 6.4 years (mean). A total of 141 (85%) frozen whole blood samples were available for MBL genotyping and MBL2 gene mutations were determined on pyrosequencing for detection of three single‐nucleotide polymorphisms. Results: Ninety‐five children (67.4%) had the wild‐type MBL genotype A/A and 46 had A/O or O/O genotypes. Asthma was present in 16 children (11.3%) at 5–7 years of age. Nine children (19.6%) with non‐AA genotype had asthma (vs 7.4% of those with genotype AA, P= 0.03). The result remained significant after adjustment for age, gender and atopy. There were no significant associations between MBL genotypes and asthma at any age before the study. Atopic dermatitis, allergic rhinitis or paternal and/or maternal asthma had no significant associations with MBL genotypes. Conclusions: The variant non‐A/A MBL genotype is associated with asthma after bronchiolitis in infancy, but not earlier than at 5–7 years of age.     

Effects of <Emphasis Type="Italic">CYP3A5</Emphasis> polymorphisms on tacrolimus pharmacokinetics in pediatric kidney transplantation: a systematic review and meta-analysis of observational studies

Background

CYP3A5 genetic polymorphisms have been reported to be strongly associated with the tacrolimus pharmacokinetics in adult kidney transplantation. However, there is no published meta-analysis in the influence of CYP3A5 variants on the requirements of the tacrolimus dose in pediatric renal-transplant recipients (RTRs). We wished to determine the effects of CYP3A5 polymorphisms on tacrolimus pharmacokinetics in pediatric RTRs.

Methods

A literature search was conducted to include relevant articles by searching PubMed, EMBASE and the Cochrane Central Register of Controlled Trials. Pharmacokinetic-associated parameters such as dose administration, as well as concentrations and dose-adjusted concentrations of tacrolimus were extracted and the meta-analysis undertaken.

Results

The meta-analysis involved four studies and one study series involving 268 pediatric RTRs. A significant difference was observed in the mean trough concentration/dose of tacrolimus between recipients carrying CYP3A5* 3/*3 variants (referred to as "non-expressers") and those carrying CYP3A5*1 (referred to as "expressers") [standard mean difference (SMD)=-1.09, 95% confidence interval (CI): -1.92 to -0.25, P=0.011]. Moreover, significance was observed in the mean daily dose of tacrolimus between non-expressers and expressers in pediatric RTRs (SMD=0.44, 95% CI: 0.20 to 0.68, P<0.001).

Conclusion

Our meta-analysis identified a positive correlation between CYP3A5 genotypes and tacrolimus pharmacokinetics in pediatric RTRs.

     

CYP1A1*2A多态性与儿童急性淋巴细胞白血病易感性的Meta分析

目的通过Meta分析,探讨CYP1A1*2A基因多态性与儿童急性淋巴细胞白血病(ALL)易感性的关系。方法制定纳入、排除标准,全面检索中英文数据库(Pub Med、OVID数据库、中国生物医学文献数据库、中国知网和万方数据库),收集CYP1A1*2A多态性与儿童ALL易感性的相关研究(1999年1月至2015年4月),应用STATA 12.0软件对纳入文献相关结果进行Meta分析。结果最终纳入12篇文献(英文11篇,中文1篇),包含的总病例数为3 355例。Meta分析结果显示,CYP1A1*2A等位基因模型(OR=1.31,95%CI:1.07~1.61)、显性模型(OR=1.33,95%CI:1.13~1.56)和共显性模型(OR=1.30,95%CI:1.10~1.54)中基因多态性与儿童ALL易感性相关。基于种族来源的亚组分析结果发现,亚洲人的显性模型(OR=1.57,95%CI:1.19~2.08)和共显性模型(OR=1.61,95%CI:1.20~2.17),以及白种人的等位基因模型(OR=1.31,95%CI:1.04~1.63)和显性模型(OR=1.22,95%CI:1.00~1.49)与增加儿童ALL发生风险相关。结论 CYP1A1*2A多态性可能是儿童ALL发生的遗传易感因素。     

CYP3A5基因在急性白血病儿童中的表达及临床意义

目的：CYP3A5参与多种常用化疗药物的代谢反应。目前对于CYP3A5基因参与急性白血病的研究主要限于细胞系的体外研究。该文通过检测急性白血病患儿CYP3A5-6986位点的基因型分布特点和基因表达水平,探讨其基因表达水平对白血病患者治疗、预后评价的意义。方法：①应用聚合酶链-限制性片段长度多态性方法（PCR-RFLP）及PCR产物序列测定,检测66例初治急性白血病患儿和20例对照儿童的CYP3A5-6986位点基因型分布;②实时定量PCR法检测病例组及对照组儿童骨髓单核细胞内wt-CYP3A5和SV1-CYP3A5 mRNA的表达水平。结果：①对照组和急性白血病儿童CYP3A5-6986多态性位点存在野生型（CYP3A5*1/*1）、杂合突变型(CYP3A5*1/*3)、纯合突变型（CYP3A5*3/*3）3种基因型;②66例初治急性白血病患儿按基因型分组后对其mRNA表达水平进行检测,3组间的wt-CYP3A5 mRNA差异有显著性意义(P<0.05);③ALL组wt-CYP3A5 mRNA低表达者第1次化疗后的缓解率高于wt-CYP3A5 mRNA高表达者,两者比较差异有显著性意义（P<0.05）;④对两例急性淋巴细胞性白血病患儿的CYP3A5 mRNA表达水平动态监测显示,1例复发前wt-CYP3A5 mRNA表达水平较缓解时升高。另1例wt-CYP3A5 mRNA表达一直处于较低水平,患儿目前仍处于缓解状态。结论：wt-CYP3A5 mRNA表达与白血病患儿的化疗疗效及预后密切相关,动态监测wt-CYP3A5 mRNA表达水平变化有助于判断病情变化。［中国当代儿科杂志,2009,11（7）：549-554］     

Association of adrenergic receptor gene polymorphisms with adolescent obesity in Taiwan

Background: Polymorphisms of β2‐adrenergic receptor (ADRB2) and β3‐adrenergic receptor (ADRB3) have been reported to be associated with obesity in adults and adolescents, although study results have been controversial. The aim of the present study was to investigate the association of polymorphisms of ADRB2 (Arg16Gly, Gln27Glu) and ADRB3 (Trp64Arg) with adolescent obesity in Taiwan. Methods: A total of 559 adolescent volunteers with equal numbers female and male were enrolled. Participants were divided into two groups: obese (body mass index [BMI]≥ 95th percentile) and normal weight (BMI 15th–85th percentile). Genomic DNA was extracted from buccal mucosa cells and genotyped in TaqMan assays. Genotype results and clinical subject characteristics were analyzed. Results: Among the three ADRB polymorphisms, only Arg16Gly polymorphism was found to be significantly correlated with adolescent obesity, especially in girls. Girls with genotype Gly/Gly had a lower probability of obesity than those with genotypes Arg/Gly or Arg/Arg (P= 0.006; Arg/Gly: odds ratio [OR], 2.57, 95% confidence interval [95%CI]: 1.22–5.41; Arg/Arg: OR, 3.03, 95%CI: 1.50–6.12). Girls with genotype Gly/Gly had lower BMI than those with genotype Arg/Arg (P= 0.049). Obese adolescents with genotype Gly/Gly had a lower probability of hypertension than those with genotype Arg/Gly or Arg/Arg (P= 0.005). Conclusions: Arg16Gly polymorphism of ADRB2 was significantly associated with obesity in female adolescents, and those with the Gly/Gly genotype were associated with a lower possibility of obesity and lower BMI. This polymorphism was also associated with a lower probability of hypertension in obese adolescents. The other two polymorphisms of ADRB (Gln27Glu and Trp64Arg) were not associated with adolescent obesity in Taiwan.     

6-巯基嘌呤致急性淋巴细胞白血病患儿不良反应及其与TPMT基因多态性的关系

目的 分析6-巯基嘌呤（6-MP）维持治疗急性淋巴细胞白血病（ALL）患儿不良反应的发生情况,探讨巯嘌呤甲基转移酶（TPMT）基因多态性与6-MP毒副作用的关系。方法 提取46例ALL患儿骨髓细胞总RNA并逆转录成cDNA。应用变性梯度凝胶电泳（DGGE）结合DNA测序,对ALL患儿TPMT*S和*3C基因型进行检测。采用美国国立癌症研究所第3版常规毒性判定标准（NCI CTC 3.0）行药物毒性分级,分析TPMT基因多态性与6-MP不良反应发生的关系。结果 在维持治疗阶段,22%（10/46）患儿因6-MP所致严重不良反应停药,不良反应主要表现为骨髓抑制、肝脏毒性和胃肠道反应。2例TPMT*3C突变基因型（AG+GG）患儿均出现重度不良反应,其中1例纯和突变患儿出现与6-MP剂量相关的骨髓抑制和肝脏毒性。TPMT*1S各基因型与6-MP所致的重度骨髓抑制及肝脏毒性无明显相关性（P>0.05）。结论 TPMT*3C多态性可能与6-MP所致严重不良反应发生有关。     

CD40基因多态性与川崎病及其冠状动脉损伤的相关性研究

目的 探讨CD40 基因两个SNP 位点rs4810485 和rs1535045 的多态性与我国中部地区儿童川崎病（KD）以及动脉损伤遗传易感性的关系。方法 采取病例对照研究方法,分别选取184 例KD 患儿和206例正常体检儿童作为研究对象。利用PCR-RFLP 的方法测定两个SNP 位点多态性分布。结果 KD 患儿SNP位点rs4810485 的基因型（GG、GC、CC）频率及等位基因频率与正常对照组相比差异均无统计学意义（均P>0.05）;SNP 位点rs1535045 基因型（TT、TC、CC）与对照相比差异有统计学意义（P=0.011）,T 等位基因为风险因子（OR=1.592,95%CI：1.182~2.144,P=0.004）。患者中两个SNP 位点多态性均不与冠状动脉损伤相关（均P>0.05）。结论 CD40 基因SNP 位点rs4810485 与KD 无相关性, rs1535045 与KD 的易感性相关。     

A Modified Protocol with Vincristine,Topotecan, and Cyclophosphamide for Recurrent/Progressive Ewing Sarcoma Family Tumors

Purpose: Topotecan has recently been used in the treatment of pediatric cancer. We evaluated our experience with the modified combination of vincristine, topotecan, and cyclophosphamide (VTC) given in 3 days, in children with recurrent Ewing sarcoma. Method: Children received vincristine (1.5 mg/m²/1st day), cyclophosphamide (600 mg/m²/day × 2 days) + mesna, and topotecan (1 mg/m²/day × 3 days) every 21 days. Result: A total of 118 courses of VTC were given to 13 patients. One patient received VTC both at first and at second relapse. Thus, 14 relapse episodes in 13 patients were evaluated. After three courses of VTC chemotherapy (CT), two achieved complete response (CR), five achieved partial response, thus an objective response was attained in 7/14 (50%) episodes. Two patients had stable disease and two patients progressed. In three episodes, CR was achieved by surgery before CT. One of them had a second relapse and attained CR with VTC. Median time from diagnosis to relapse was 23 months (5–45 months). Site of relapse was local in four patients, and metastatic in 10 episodes of nine patients. Seven patients are alive, three with no evidence of disease and four alive with disease; six have died of disease. Local treatment was used in 11 episodes. The toxicity of the VTC combination was limited mainly to the hematopoietic system. Conclusion: In conclusion, the modified VTC protocol in 3 days every 3 weeks seems to be effective and tolerable in children and adolescents with recurrent/progressive Ewing sarcoma.     

MyD88和TICAM1基因多态性及其交互作用与儿童社区获得性肺炎的关联研究

目的 探讨髓样分化因子88(myeloid differentiation factor 88,MyD88)和Toll样受体衔接分子1(Toll-like receptor adaptor molecule 1,TICAM1)基因的单核苷酸多态性及其交互作用与儿童社区获得性肺炎（community-acquired pneumonia,CAP）的相关性。方法 前瞻性采用改良多重高温连接酶检测反应技术对2015年8月—2017年9月在延安大学医学院第二附属医院儿科就诊的375例CAP患儿和306例健康体检儿童的MyD88和TICAM1基因的9个标签位点进行分型,并采用logistic回归分析评价各位点基因型及其交互作用与儿童CAP的关联。结果 TICAM1基因rs11466711T/C位点多态性与儿童CAP易感性密切相关（P<0.05）;rs35747610G/A位点AA基因型可显著降低CAP患儿并发脓毒症的风险（P<0.05）;rs6510826G/A位点AA基因型与CAP患儿急性期C反应蛋白水平的增高显著关联（P<0.05）。MyD88基因rs7744A/G位点GG...     

Association between CYP4F2 genotype and circulating plasma vitamin K concentration in children on chronic warfarin therapy: Possible long‐term implications for bone development and vascular health

Vitamin K is essential, for the activation of clotting proteins, as well as the biosynthesis of osteocalcin in bones and the activation of matrix‐Gla protein needed in maintaining vasculature health. Cytochrome p450 4F2 (CYP4F2) enzyme is involved in vitamin K catabolism. Genetic polymorphism in CYP4F2 is thus likely to affect vitamin K systemic availability. We show that children on chronic warfarin therapy have low levels of vitamin K and vitamin K levels are linked to CYP4F2 genotype. Long‐term low levels of vitamin K, influenced by CYP4F2 genotype, might affect bone development and vascular health in children on chronic warfarin therapy.     

中国急性白血病儿童的细胞色素P450-3A4基因型多态性分析

目的阐明中国急性白血病(AL)和健康儿童中细胞色素P450-3A4(CYP3A4)的基因型分布特点,探讨CYP3A4基因型多态性与儿童白血病的易感性及化疗效应之间可能的相关性。方法应用PCR-RFLP及DNA测序法检测120例AL和85例健康儿童的CYP3A4基因型,分析两组CYP3A4基因型差异。结果85例健康儿童中仅1例为CYP3A4*1B的杂合子基因型,均为野生型,杂合子型的突变频率为1.2%;120例AL儿童中5例(4例ALL和1例AML)表现为杂合子基因型,1例ALL为纯合子基因型,其杂合子基因型突变率为4.2%,纯合子基因型突变率为0.8%。经PCR-RFLP检测并经DNA测序验证,所有受检者的CYP3A4*3基因型均为野生型。结论虽然AL患儿的CYP3A4*1B基因突变率高于健康儿童,但差异无显著性,因此尚不能推论CYP3A4*1B基因型与中国儿童AL发病相关。CYP3A4*3基因在中国健康和AL儿童中是一种罕见的等位基因,其对于CYP3A4酶活性的影响及其在白血病发生中的作用有待进一步探讨。     

Incidence of vincristine induced neurotoxicity in children with acute lymphoblastic leukemia and its correlation with nutritional deficiencies

Abstract

Injection vincristine is an important component of therapy for acute lymphoblastic leukemia (ALL). An important adverse effect of vincristine is neurotoxicity. The incidence of this adverse effect is well studied. The present was undertaken to determine the incidence of vincristine-induced neurotoxicity in children with ALL after the induction of remission phase of chemotherapy and to ascertain its correlation with undernutrition, vitamin B12, folate and iron deficiency. Thirty children (1–18?years) with ALL were enrolled at the commencement of chemotherapy. The electrophysiological evaluation was done at baseline and repeated after four doses of vincristine (1.5?mg/m²/dose). Clinical evaluation was done regularly. Anthropometry and serum B12, folate and ferritin levels were assessed at baseline. Twelve children over a 4-week period of observation had peripheral neuropathy clinically. The autonomic system was most commonly involved followed by motor and sensory system respectively. On electrophysiological testing, half of the patients had evidence of neuropathy. Micronutrient deficiencies were present in a significant number of patients—63.3% had a B12 deficiency, 20% were deficient in folate and 43.3% in iron. The incidence of vincristine-induced neuropathy in patients with/without these micro-nutrient deficiencies was not statistically significantly different. Vincristine-induced neuropathy is common in Indian children with ALL. The present study did not find any correlation between the occurrences of vincristine-induced neuropathy and nutritional deficiencies. Larger studies are warranted to evaluate the contribution of micronutrient deficiencies to the development of peripheral neuropathy in childhood ALL.     

Vincristine induced neurotoxicity in cancer patients

Ten out of 20 children, treated with usual doses of vincristine for various types of childhood cancers, developed neurotoxicity during treatment. Peripheral neurotoxicity (mixed motor-sensory 4/10, pure motor 3/10, pure sensory 3/10) was seen in the form of weakness of lower limbs, areflexia, neuropathic pain, or sensory loss. Autonomic neuropathy presented as constipation and urinary retention in 2 children, while 2 children developed encephalopathy in form of seizures, confusion, aphasia, and transient blindness. In children with severe neuropathy, vincristine administration was withheld/dose reduced till clinical improvement started, which took about 2–3 weeks time. Nerve conduction velocity showed motor-sensory axonal polyneuropathy. Electrophysiological abnormalities were found to persist even six months after clinical recovery in children with neurotoxicity. We found a relatively higher incidence of vincristine induced neuropathy in Indian children, which was probably due to coexistence of severe malnutrition in them.     

Impact of undernutrition on the pharmacokinetics of chemotherapy in children with cancer: A systematic review

Objectives

This systematic review provides an overview of the effect of undernutrition on the pharmacokinetics of chemotherapy in children with cancer.

Methods

PubMed, Embase, and Cochrane were searched to identify eligible studies. This study uses the definition for undernutrition from the World Health Organization and the Gomez classification.

Results

Four studies with a total of 668 children with cancer were included and n = 121 (18%) were undernourished. Significant decreased clearance rates were found for vincristine in undernourished children compared to children with a normal nutritional status.

Conclusion

Presenting outcomes only show significant changes in the pharmacokinetics of vincristine in undernourished children with cancer. However, data are scarce, groups were small, and none of the studies included severely undernourished children. In order to improve outcomes for (severely) undernourished children with cancer, more pharmacokinetic research is needed. The ultimate goal would be to develop subgroups, and ultimately individualized drug dosing in order to improve outcomes for children with cancer worldwide.     

Perinatal risk factors interacting with catechol O‐methyltransferase and the serotonin transporter gene predict ASD symptoms in children with ADHD

Background: Symptoms of autism spectrum disorder (ASD) and attention‐deficit/hyperactivity disorder (ADHD) often co‐occur. Given the previously found familiality of ASD symptoms in children with ADHD, addressing these symptoms may be useful for genetic association studies, especially for candidate gene findings that have not been consistently replicated for ADHD. Methods: We studied the association of the catechol O‐methyltransferase (COMT) Val158Met polymorphism and the serotonin transporter (SLC6A4/SERT/5‐HTT) 5‐HTTLPR insertion/deletion polymorphism with ASD symptoms in children with ADHD, and whether these polymorphisms would interact with pre‐ and perinatal risk factors, i.e., maternal smoking during pregnancy and low birth weight. Analyses were performed using linear regression in 207 Dutch participants with combined type ADHD of the International Multicenter ADHD Genetics (IMAGE) study, and repeated in an independent ADHD sample (n = 439) selected from the TRracking Adolescents’ Individual Lives Survey (TRAILS). Dependent variables were the total and subscale scores of the Children’s Social Behavior Questionnaire (CSBQ). Results: No significant main effects of COMT Val158Met, 5‐HTTLPR, maternal smoking during pregnancy and low birth weight on ASD symptoms were found. However, the COMT Val/Val genotype interacted with maternal smoking during pregnancy in increasing stereotyped behavior in the IMAGE sample (p = .008); this interaction reached significance in the TRAILS sample after correction for confounders (p = .02). In the IMAGE sample, the 5‐HTTLPR S/S genotype interacted with maternal smoking during pregnancy, increasing problems in social interaction (p = .02), and also interacted with low birth weight, increasing rigid behavior (p = .03). Findings for 5‐HTTLPR in the TRAILS sample were similar, albeit for related CSBQ subscales. Conclusions: These findings suggest gene–environment interaction effects on ASD symptoms in children with ADHD.     

Mild axonal neuropathy of children during treatment for acute lymphoblastic leukaemia.

Neurophysiological functioning was studied prospectively in children treated for acute lymphoblastic leukaemia with a low dose vincristine regime (8 x 1.5 mg/m2/dose), to obtain more insight into vincristine neuropathy. A WHO neurotoxicity score was estimated and vibration sense and electrophysiological measurements were taken at standardized times during vincristine treatment. The WHO neurotoxicity score showed decreased or disappearance of Achilles tendon reflexes, and mild sensory disturbances, but a grade 3-4 neurotoxicity was not demonstrated by any of the children. Vibration perception thresholds increased progressively during treatment and amplitudes of action potentials of peroneal and sensory ulnar and median nerves decreased, whereas nerve conduction velocities stayed unchanged. Both vibration perception thresholds and the electrophysiological findings hardly exceeded the limits of normality. We conclude that children treated for acute lymphoblastic leukaemia with a low dose vincristine regimen have mild axonal neuropathy which may be responsible for the motor problems in these children.     

Genetic and Clinical Determinants Influencing Warfarin Dosing in Children With Heart Disease

Warfarin is a common anticoagulant with narrow therapeutic window and variable anticoagulation effects. Single gene polymorphisms in cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) have been shown to impact warfarin dosing in adults. Insufficient data exists on genetic and clinical factors which influence warfarin dosing in children. Pediatric patients with heart disease who received long-term warfarin therapy were tested for VKORC1 and CYP2C9 polymorphisms. Clinical and demographic data were reviewed in those children who achieved stable therapeutic international normalized ratio (INR). Multiple linear regression modeling was used to assess relationships between stable warfarin doses and genetic or clinical variables. Fifty children were tested for VKORC1 and CYP2C9 polymorphisms; 37 patients (M 26: F 11) had complete data, achieved stable therapeutic INR, and were included in dose variability analysis. There were predominance of white race 73% and male sex 70.3%. The mean age was 9.6 years (1.8–18.6 years). The mean weight was 37.8 kg (7.7–95 kg). Fontan physiology and mechanical cardiac valves were two most common indications for chronic warfarin therapy (25/37 or 67.6%). Twelve patients (32.4%) had ≥2 indications for warfarin therapy. Three patients had documented venous or arterial clots, and 5 patients had strokes. Congenital heart disease was present in 29 patients (78.4%), including Fontan physiology (20), complex biventricular physiology (4), and congenital mitral valve disease (5). Acquired heart disease was present in 8 patients (21.6%), including Kawasaki disease with coronary aneurysms (3), acquired mitral valve disease (3), and Marfan syndrome (2). Stable warfarin dose (mg/kg/day) was strongly associated with VKORC1 polymorphism (p < 0.0001) and goal therapeutic INR (p = 0.009). Negative correlations were observed between stable warfarin dose and age, weight, height, and BSA (p = 0.04, 0.02, 0.02, and 0.02 respectively). Factors which did not influence warfarin dose included CYP2C9 polymorphism (p = 0.17), concurrent medications (p = 0.85), sex (p = 0.4), race (p = 0.14), congenital heart disease (p = 0.09), and Fontan physiology (p = 0.76). The gene-dose effect was observed in children with homozygous wild type VKORC1 CC, who required higher warfarin dose compared to those carrying heterozygous TC or homozygous TT (p = 0.028 and 0.0004 respectively). The full multiple linear regression model revealed that VKORC1 genotypes accounted for 47% of dosing variability; CYPC29 accounted for 5%. Overall, the combination of VKORC1, CYP2C9, age, and target INR accounted for 82% of dosing variability. In children with heart disease, VKORC1 genotypes, age, and target INR are important determinants influencing warfarin dosing in children with heart disease. Future warfarin dosing algorithm in children should factor both genetic and clinical factors.     

ACE2基因多态性与儿童原发性肾病综合征的相关性研究

目的血管紧张素转换酶2(ACE2)基因多态性与高血压病、糖尿病肾病等多种疾病相关,是否参与儿童原发性肾病综合征(PNS)的发病尚不明确,该研究探讨广东汉族儿童ACE2基因A9570G多态性与PNS的相关性。方法选取广东汉族PNS患儿66例为肾病组,健康体检者60例为对照组,采用聚合酶链反应-限制性核酸内切酶片段长度多态性技术分析肾病组与对照组的ACE2基因A9570G基因型分布和等位基因频率。结果在女性和男性,两组间等位基因频率及基因型分布差异均无统计学意义(P0.05)。肾病组按糖皮质激素治疗反应分为激素敏感组和激素耐药组,亚组分析发现,在女性,激素敏感组GG基因型频率低于激素耐药组(17%vs 45%,P0.05),激素敏感组G等位基因频率亦低于激素耐药组(31%vs 61%,P0.05);在男性,激素敏感组G基因型/G等位基因频率低于激素耐药组(36%vs 64%,P0.05)。结论 ACE2基因A9570G多态性与儿童PNS的发生无明确关联,但可能与PNS患儿对糖皮质激素治疗的反应有关,G等位基因可能是儿童PNS激素耐药的遗传易感因素。     

Moderation of the association between childhood maltreatment and neuroticism by the corticotropin-releasing hormone receptor 1 gene

Background: Neuroticism is a personality trait reflecting the tendency to experience negative affect. It is a major risk for psychopathology, especially depression and anxiety disorders. Childhood maltreatment is another major risk factor for psychopathology and may influence personality. Maltreatment may interact with genotype to predict developmental outcomes. Variation in three polymorphisms of the CRHR1 gene has been found to moderate the association of childhood maltreatment with depression, and we hypothesized that it would also be linked to neuroticism. Methods: Variation in three CRHR1 SNPs (rs110402, rs242924, rs7209436) was assessed in 339 maltreated and 275 demographically similar nonmaltreated children, who participated in a day camp research program. Maltreated children were further categorized based on the number of types of maltreatment they had experienced and the most severe form of maltreatment experienced. Genotype and maltreatment status were used to predict the Big Five personality traits, as assessed by camp counselors following a week of interaction with children. Results: CRHR1 genotype significantly moderated the association of maltreatment with neuroticism but none of the other traits. Having two copies of the TAT haplotype of CRHR1 was associated with higher levels of neuroticism among maltreated children relative to nonmaltreated children, with the exception of sexually abused children and children who had experienced 3 or 4 types of abuse. Effects sizes of these interactions ranged from η² = .01 (p = .02) to η² = .03 (p = .006). Conclusions: Variation in CRHR1 moderates the association of maltreatment with neuroticism. The effects of specific types of maltreatment on neuroticism are differentially moderated by CRHR1 genotype, as are the effects of experiencing more or fewer types of maltreatment.