基因多态性对华法林抗凝治疗维持剂量的影响

目的研究中国汉族人群细胞色素P450酶4F2基因(cytochrome P-450 4F2.CYP4F2)多态性分布,并探讨其与华法林抗凝维持剂量的关系。方法采集112例心脏机械瓣膜置换术后服用华法林抗凝已达稳定剂量、凝血酶原时间国际标准化比值INR在目的范围(1.5-2.5)病人的外周血,采用用聚合酶链式反应(polymerase chain reaction,PCR)基因测序的方法检测CYP4F2 rs2108622基因位点的基因型和等位基因频率,探讨华法林抗凝维持剂量与该基因多态性的关系。结果在所有的样本中,CYP4F2 rs2108622基因共检出C(73.1%)和T(26.9%)2种等位基因,检出基因有CC、TT和CT 3种基因型,其基因频率分别为54.1%、41.2和4.7%,人群中CYP4F2 rs2108622基因多态性分布在性别和年龄上无差异;TT基因型患者所需华法林维持剂量最高(4.7±0.99)mg/d,其次为CT基因型患者(3.70±0.85)mg/d,最少的是CC基因型患者(2.46±0.75)mg/d。结论中国汉族人群CYP4F2 rs2108622基因位点具有遗传多态性,其基因型在华法林抗凝治疗中具有重要指导意义。     

miR-137 基因 rs1625579 位点多态性与精神分裂症患者 认知功能的关联性研究

摘要： 目的 探讨微小 RNA-137 （miR-137） 单核苷酸多态性 （SNP） 位点 rs1625579 多态性与精神分裂症患者认 知功能的相关性。方法 选取 250 例精神分裂症患者, 采用阳性和阴性症状量表（PANSS）评估精神分裂症患者症 状, 简明精神分裂症认知评估测验量表 （BACS） 评估精神分裂症患者的认知功能。并收集患者外周血液, 采用 SNaP⁃ shot 技术对 rs1625579 位点进行基因分型。比较该位点不同基因型的症状及认知功能差异。结果 TT、 GT、 GG 基 因型分别为 221 例 （88.4%）、 28 例 （11.2%）、 1 例 （0.4%）。TT 基因型和 G 等位基因 （GG+GT） 携带者 PANSS 评分差异 无统计学意义。BACS 测验结果显示, 除数字序列测验 TT 基因型患者得分低于 G 等位基因 （GG+GT） 携带者外 （P < 0.05）, 语义流畅性测验、 字词流畅性测验、 言语记忆测验、 代币运动、 伦敦塔测验、 符号编码测验得分 TT 基因型与 G 等位基因（GG+GT）携带者间差异均无统计学意义。结论 miR-137 基因 rs1625579 位点多态性可能与中国汉族人 群精神分裂症工作记忆能力有关.     

The FNTB promoter polymorphism rs11623866 as a potential predictive biomarker for lonafarnib treatment of ovarian cancer patients

Aim

Despite promising preclinical findings regarding clinical utility of farnesyltransferase inhibitors (FTI), such as lonafarnib, success of clinical trials is limited. A multicentre AGO-OVAR-15 phase II trial reported an unfavourable effect of lonafarnib on the outcome of patients with advanced ovarian cancer. This study was performed as a genetic subgroup analysis of the AGO-OVAR-15 trial, and investigated the utility of the promoter polymorphism rs11623866 of the farnesyltransferase ß-subunit gene (FNTB) in predicting the clinical effectiveness of lonafarnib.

Methods

The influence of rs11623866 (c.-609G > C) on FNTB promoter activity was investigated by electrophoretic-mobility-shift assay, luciferase-reporter assay and RT-qPCR. A total of 57 out of 105 patients from the AGO-OVAR-15 trial, treated with carboplatin and paclitaxel ± lonafarnib, was genotyped for rs11623866 by restriction fragment length polymorphism analysis. Genotype-dependent survival analysis was performed by Kaplan–Meier analysis.

Results

The presence of the G allele was associated with increased FNTB promoter activity compared with the C allele. An unfavourable effect of lonafarnib was limited to patients carrying a GG genotype (HR_PFS 6.2, 95%CI = 2.01, 19.41, P = 0.002; HR_OS 9.6, 95%CI = 1.89, 48.54, P = 0.006). Median progression free survival (PFS) for patients with the GG genotype in the lonafarnib treated arm was 10 months, whereas median PFS without FTI-treatment was 40 months. Median overall survival (OS) in the lonafarnib-treated group was 19 months, whereas median OS was not reached in the untreated group.

Conclusions

Discrepancies between preclinical success and clinical failure may be due to the patients'' genetic variability of FNTB. Therefore, our results may encourage retrospective evaluation of FNTB polymorphisms in previous FTI studies, especially those reporting positive FTI response.     

PPARD rs2016520 polymorphism affects repaglinide response in Chinese Han patients with type 2 diabetes mellitus

Repaglinide is a short‐acting insulin secretagogue, which often results in considerable interindividual variability in therapeutic efficacy when widely used in a clinical setting. Among various reasons under discussion is genetic polymorphism, especially the genes related to insulin secretion and resistance. Recent studies have described the importance of PPARD in regulating the secretion and resistance of insulin. However, little is known about the impacts of PPARD genetic polymorphism on the efficacy of repaglinide. Therefore, the current study was designed to investigate the associations of PPARD rs2016520 polymorphism with type 2 diabetes mellitus (T2DM) susceptibility and repaglinide therapeutic efficacy in Chinese Han T2DM patients. A total of 338 T2DM patients and 200 healthy subjects were genotyped for PPARD rs2016520 polymorphism by polymerase chain reaction–restriction fragment length polymorphism assay. A total of 84 patients with the same genotypes of CYP2C8*3 139Arg and OATP1B1 521TT were randomized to orally take repaglinide for 8 weeks. Then the pharmacodynamic parameters of repaglinide and biochemical indicators were determined before and after repaglinide treatment. No significant difference was found in either allelic frequency (P = 0.298) or genotype distribution (P = 0.151) of PPARD rs2016520 between T2DM patients and healthy subjects. However, T2DM patients carrying genotype TC showed a significantly lower increase in postprandial serum insulin (mU/L) than those with wild‐type TT (P < 0.05). These findings suggest that PPARD rs2016520 polymorphism might influence the therapeutic effect of repaglinide rather than T2DM susceptibility in Chinese Han T2DM patients.     

血红蛋白清道夫受体CD163基因rs4883263位点多态性对冠状动脉粥样硬化性心脏病患者血脂水平的影响

目的：探讨血红蛋白清道夫受体（CD163）基因rs4883263位点多态性对血脂水平的影响,以了解该位点多态性对冠状动脉粥样硬化性心脏病（coronary heart disease,CHD）所起的可能作用,确定CD163基因rs4883263位点与CHD的相关性。方法：选取2016年12月至2017年5月在青岛大学附属医院心血管内科诊疗的住院患者（其中男性116人,女性71人,人均63岁）外周血标本共187例,分为CHD组（n=97）和对照组（n=90）,抽提外周血基因组DNA,采用实时定量荧光聚合酶链式反应（real time-polymerase chain reaction,RT-PCR）技术检测CD163基因rs4883263位点多态性。利用统计学方法比较CHD患者和对照组的基因型分布的差异,分析该位点多态性对两组血脂各项指标的影响。结果：CHD组与对照组相比,三酰甘油（TG）和载脂蛋白A （apoA）显著升高,差异具有统计意义（P<0.05）。在CHD组和对照组共187名患者的CD163 rs4883263基因型检测结果中可以看出,CD163 rs4883263基因型以杂合型CC为主,等位基因以C为主要基因,2组人群中CD163 rs4883263基因型及等位基因的频率比较差异均无统计学意义（均为P>0.05）,进行性别分层后,2组人群中CD163 rs4883263基因型及等位基因的频率分布比较差异仍无统计学意义（均为P>0.05）。CHD组CC基因型表达患者胆固醇（TC）、低密度脂蛋白（LDL）、apoA水平明显高于对照组,而CT基因型表达患者高密度脂蛋白（HDL）水平显著低于对照组（P<0.05）。结论：两组人群中CD163基因rs4883263位点多态性明显影响血脂水平的高低。     

Genetic modification of ALAD and VDR on lead-induced impairment of hearing in children

Polymorphisms in the δ-aminolevulinic acid dehydratase (ALAD) and the vitamin D receptor (VDR) genes may modify lead metabolism and neurotoxicity.Two cohorts of children were examined for hearing [pure-tone audiometry (PTA), brain stem auditory evoked potentials (BAEP)], acoustic otoemission (transient emission evoked by a click) and blood-lead concentrations (B–Pb). The children were genotyped for polymorphisms in ALAD and VDR.The median B–Pbs were 55 and 36 μg/L in the two cohorts (merged cohort 45 μg/L). B–Pb was significantly associated with impaired hearing when tested with PTA (correlation coefficient r_S = 0.12; P < 0.01), BAEP (r_S = 0.18; P < 0.001) and otoemission (r_S = −0.24; P < 0.001).VDR significantly modified the lead-induced effects on PTA. Carriers of the VDR alleles BsmI B, VDR TaqI t and VDR FokI F showed greater toxic effects on PTA, compared to BsmI bb, VDR TaqI TT and VDR FokI ff carriers. No significant interaction was found for ALAD.Lead impairs hearing functions in the route from the cochlea to the brain stem at low-level exposure, and polymorphisms in VDR significantly modify these effects.     

Association of N-Methyl-D-Aspartate receptor 2B Subunit (GRIN2B) polymorphism with earlier age at onset of withdrawal symptoms in Indian alcohol dependent subjects

The associations of GRIN2B polymorphism (rs1806201) with alcohol withdrawal and related clinical parameters in alcohol dependent subjects were investigated. Cases were assessed using a semi-structured clinical pro forma for alcohol abuse and a questionnaire for family history of alcohol dependence and psychiatric disorders after obtaining informed consent. The study included alcohol dependent male cases (n = 220, age at onset of alcohol withdrawal symptoms = 32.4 ± 8.8 y) recruited at the Center for Addiction Medicine, National Institute of Mental Health and Neurosciences, Bangalore, India. The controls comprised of healthy unrelated males (n = 183) who were ethnically matched and selected randomly. The polymorphism rs1806201 was analyzed by polymerase chain reaction and restriction fragment length polymorphism. The presence of T allele at this locus was significantly associated with lower age at onset of alcohol withdrawal symptoms (p = .005) among the cases. Mean age at onset of alcohol withdrawal symptoms in subjects who were T carriers was 31.4 ± 8.5 y (n = 160) and non-T carriers was 35.2 ± 9.0 y (n = 60). The SNP rs1806201 in GRIN2B may play an important role in genetic susceptibility to earlier age of withdrawal in alcohol dependent patients.     

Antioxidative Defense Genes and Brain Structure in Youth Bipolar Disorder

BackgroundOxidative stress is implicated in the neuropathology of bipolar disorder (BD). We investigated the association of single-nucleotide polymorphisms (SNPs) in the antioxidative genes superoxide dismutase 2 (SOD2) and glutathione peroxidase 3 (GPX3) with structural neuroimaging phenotypes in youth BD.Methods SOD2 rs4880 and GPX3 rs3792797 SNP genotypes, along with structural magnetic resonance imaging, were obtained from 147 youth (BD = 75; healthy controls = 72). Images were processed using FreeSurfer, yielding surface area, volume, and thickness values for regions of interest (prefrontal cortex [PFC], caudal anterior cingulate cortex, hippocampus) and for vertex-wise whole-brain analysis. Analyses controlled for age, sex, race, and intracranial volume for volume, area, and thickness analyses.ResultRegions of interest analyses revealed diagnosis-by-SOD2 rs4880 interaction effects for caudal anterior cingulate cortex volume and surface area as well as PFC volume; in each case, there was lower volume/area in the BD GG genotype group vs the healthy controls GG genotype group. There was a significant BD diagnosis × GPX3 rs3793797 interaction effect for PFC surface area, where area was lower in the BD A-allele carrier group vs the other genotype groups. Vertex-wise analyses revealed significant interaction effects in frontal, temporal, and parietal regions related to smaller brain structure in the BD SOD2 rs4880 GG group and BD GPX3 rs3793797 A-allele carrier group.ConclusionWe found preliminary evidence that SOD2 rs4880 and GPX3 rs3792797 are differentially associated with brain structures in youth with BD in regions that are relevant to BD. Further studies incorporating additional neuroimaging phenotypes and blood levels of oxidative stress markers are warranted.     

KCNJ11 rs5219基因多态性对新发2型糖尿病患者二甲双胍及格列齐特联用疗效的研究

目的 探讨ATM(rs11212617)、KCNJ11(rs5219)、CYP2C9(rs1799853、rs1057910)、TCF7L2(rs12255372、rs290487)及IRS1(rs1801278)位点对二甲双胍及格列齐特联用治疗新诊断2型糖尿病患者疗效的影响。方法 在浙江中医药大学附属嘉兴中医院内分泌科标准化代谢性疾病管理中心门诊就诊,并使用盐酸二甲双胍片和格列齐特缓释片联合治疗的81例新诊断2型糖尿病患者被纳为研究对象,使用MassARRAY技术对上述位点进行分型,并进行为期3个月的随访,对比治疗前后空腹血糖、糖化血红蛋白及空腹胰岛素的变化。结果 上述单核苷酸多态性位点的基因频率符合Hardy-Weinberg遗传平衡,样本代表性良好。rs1799853、rs1057910、rs12255372与rs1801278位点突变频率较低,临床意义欠佳。rs5219C等位基因纯合患者在治疗后的空腹血糖达标率、空腹胰岛素上升量及糖化血红蛋白下降量上的获益均强于T等位基因携带患者(P<0.05)。而rs11212617和rs290487位点各基因型间并未显示出治疗效果的差...     

足月新生儿黄疸与维生素D及NADSYN1基因多态性的相关性研究

目的 研究足月新生儿黄疸、维生素D(VD)水平及NADSYN1基因rs12785878位点单核苷酸多态性（SNP）间的关系。方法 回顾性分析216例患有黄疸的足月新生儿的临床资料,利用液相色谱-串联质谱法（LC-MS/MS）检测血清VD水平,高分辨熔解曲线（HRM）分析NADSYN1基因rs12785878位点SNP。以患儿是否>14 d分组并分别分析高胆红素血症的影响因素。结果 对于≤14 d患儿,感染、剖宫产、母乳喂养为高胆红素血症发生的危险因素;对于>14 d患儿,感染、低血浆蛋白为高胆红素血症发生的危险因素。建立的rs12785878位点HRM方法扩增反应良好,GG、GT、TT基因型区分明显。高胆组患儿携带GG基因型、G等位基因的比例更高。≤14 d患儿,TT基因型新生儿VD水平高于GG基因型新生儿[（12.61±5.23）μg/L vs.(9.62±4.24)μg/L,P<0.05]。结论 NADSYN1基因rs12785878位点GG基因型为高胆红素血症、≤14 d新生儿低VD水平的危险因素,可作为足月新生儿高胆红素血症诊治的新参考。     

KCNQ1 gene polymorphisms are associated with the therapeutic efficacy of repaglinide in Chinese Type 2 diabetic patients

The present study evaluated the effects of KCNQ1 rs2237892 and rs2237895 polymorphisms on repaglinide efficacy in Chinese patients with Type 2 diabetes mellitus (T2DM). In all, 367 T2DM patients and 214 controls were genotyped. Forty of the T2DM patients were randomly selected to undergo 8 weeks repaglinide treatment. The frequency of the rs2237892 allele was lower in the T2DM patients than in the control group (P < 0.05). The frequency of the rs2237895 C allele was higher in T2DM patients than in healthy control subjects (P < 0.05). Diabetic patients with the rs2237892 risk C allele had lower fasting insulin levels (P < 0.01) and homeostasis model assessment of insulin resistance (HOMA-IR; P < 0.01) values than carriers of the T allele. Diabetic patients with the rs2237895 risk C allele had higher fasting plasma glucose (P < 0.01), postprandial plasma glucose (PPG) levels (P < 0.01) and HOMA-IR values (P < 0.01) than those with the A allele. Following repaglinide treatment, those T2DM patients with the rs2237892 T allele and rs2237895 C allele were more likely to have a positive response to repaglinide in terms of PPG levels (P < 0.05) than T2DM patients with the rs2237892 CC and rs2237895 AA genotypes. In conclusion, KCNQ1 rs2237892 and rs2237895 polymorphisms were found to be associated with the therapeutic efficacy of repaglinide in Chinese T2DM patients.     

ICU内呼吸机相关性肺炎的病原菌及耐药性分析

目的：分析重症监护室（ICU）呼吸机相关性肺炎（VAP）的病原菌分布及耐药情况。方法：分析2007年1月～2008年12月在重症监护室发生VAP的患者资料,对其病原菌分布及耐药情况进行汇总。结果：63例VAP患者中共检出138株致病菌,其中革兰阴性菌（G^-）67．4％,革兰阳性菌（G^＋）12．3％,真菌20．3％。大多数G^-菌对常用的抗菌药已表现出较高的耐药性。金黄色葡萄球菌耐药性严重,对苯唑西林的耐药率达92．9％,但对万古霉素、利奈唑烷均敏感。结论：VAP的病原菌以G^-杆菌占优势,并且致病菌呈多重耐药性。在采取经验性治疗时,应选择对常见致病菌有较好覆盖率且耐药率低的抗生素,并重视病原菌的检查,指导合理使用抗生素。     

CBR1 rs9024 genotype status impacts the bioactivation of loxoprofen in human liver

Loxoprofen is an anti‐inflammatory drug that requires bioactivation into the trans‐OH metabolite to exert pharmacological activity. Evidence suggests that carbonyl reductase 1 (CBR1) is important during the bioactivation of loxoprofen. This study examined the impact of the functional single nucleotide polymorphism CBR1 rs9024 on the bioactivation of loxoprofen in a collection of human liver samples. The synthesis ratios of trans‐OH loxoprofen/cis‐OH loxoprofen were 33% higher in liver cytosols from donors homozygous for the CBR1 rs9024 G allele in comparison with the ratios in samples from donors with heterozygous GA genotypes. Complementary studies examined the impact of CBR1 rs9024 on the bioactivation of loxoprofen in lymphoblastoid cell lines. CBR1 rs9024 genotype status impacts the synthesis of the bioactive trans‐OH metabolite of loxoprofen in human liver.     

Toll样受体 4基因单核苷酸多态性与白内障发病的相关性研究

目的 研究Toll样受体4(TLR4)基因单核苷酸多态性（SNPs）与白内障发病的相关性。方法 收集皖南医学院第二附属医院2021年1—12月100例年龄相关性白内障（ARC）病例为观察组,86例年龄、性别相匹配的无亲属关系的健康志愿者为对照组,采用单碱基延伸法（SNaPshot）对TLR4两个SNPs位点rs4986790及rs4986791进行基因分型,检验两组2个SNPs基因型与等位基因频率,分离被研究对象外周血单个核细胞（PBMC）,酶联免疫吸附法（ELISA）检测其PBMC上清液中肿瘤坏死因子-α(TNF-α)及白细胞介素-6(IL-6)水平,分析其与ARC病人TLR4基因SNPs之间的关系。结果 Hardy-Weinberg平衡试验结果提示,两组病人TLR4基因rs7986790位点及rs4986791位点的基因型频率分布实际值与理论值符合Hardy-Weinberg遗传平衡（P>0.05）;观察组与对照组TLR4基因rs7986790位点基因型及其等位基因占比比较,差异有统计学意义（P<0.05）。rs7986790基因分型为GA及GG者PBMC上清液中TNF...     

Association of two polymorphisms within and near SOCS3 gene with obesity in three nationalities in Xinjiang province of China

Aim:

SOCS3 gene plays an important role in the pathogenesis of obesity in animal models, but the data from human studies are relatively limited. To address this issue, a genetic association analysis on nationalities with different genetic background living in the similar environmental conditions was performed.

Methods:

Two thousand seven hundred eleven subjects were randomly recruited from the Kazakh, Uygur and Han nationalities in Xinjiang of China. SNP polymorphisms rs4969168 and rs9892622 within or near the SOCS3 gene were genotyped using TaqMan-MGB^™ assay. Association study between the two polymorphisms and obesity-related traits (body mass index [BMI]; waist-to-hip ratio [WHR]; weight; height, waist, and hip measurements) was conducted.

Results:

Significant association was found between rs4969168 and the obesity-related traits, including BMI (25.32±3.49 kg/m² for AA, 24.60±3.70 kg/m² for AG, 24.39±3.42 kg/m² for GG, P=0.042), weight (65.58±11.42 kg for AA, 63.50±11.30 kg for AG, 62.00±10.78 kg for GG, P=0.011) in the Han nationality, but not in the Kazakh or Uygur nationalities. Rs9892622 was significantly associated with BMI, WHR, and WAIST in the Uygur males. Rs9892622 was also associated with BMI in Kazakh males. Linear regression analysis verified the above findings. However, neither of the two polymorphisms was associated with obesity-related traits in the total population.

Conclusion:

The polymorphism rs4969168 within or near the SOCS3 gene has a significant effect in the Han nationality, while rs9892622 was associated with obesity in Uygur and Kazakh nationalities in Xinjiang of China.