• 【使用全基因组序列数据在谱系中进行基因型定相。】 复制标题 收藏 收藏
    DOI:10.1038/s41431-020-0574-3 复制DOI
    作者列表:Blackburn AN,Blondell L,Kos MZ,Blackburn NB,Peralta JM,Stevens PT,Lehman DM,Blangero J,Göring HHH
    BACKGROUND & AIMS: :Phasing is the process of inferring haplotypes from genotype data. Efficient algorithms and associated software for accurate phasing in pedigrees are needed, especially for populations lacking reference panels of sequenced individuals. We present a novel method for phasing genotypes from whole-genome sequence data in pedigrees, called PULSAR (Phasing Using Lineage Specific Alleles/Rare variants). The method is based on the property that alleles specific to a single founding chromosome within a pedigree are highly informative for identifying haplotypes that are shared identical by descent. Simulation studies are used to assess the performance of PULSAR with various pedigree sizes and structures, and the effect of genotyping errors and the presence of nonsequenced individuals is investigated. In pedigrees with complete sequencing and realistic genotyping error rates, PULSAR correctly phases >99.9% of heterozygous genotypes, excluding sites at which all individuals are heterozygous, and does so with a switch error rate frequently below 10-4. PULSAR is highly accurate, capable of genotype error correction and imputation, and computationally competitive with alternative phasing software applicable to pedigrees. Our method has the significant advantage of not requiring reference panels that are essential for other population-based phasing algorithms. A software implementation of PULSAR is freely available.
    背景与目标: : 定相是从基因型数据推断单倍型的过程。需要有效的算法和相关软件来对谱系进行精确定相,尤其是对于缺乏测序个体参考面板的人群。我们提出了一种新的方法,用于从谱系中的全基因组序列数据中定相基因型,称为脉冲星 (使用谱系特异性等位基因/稀有变体进行定相)。该方法基于以下特性: 谱系中特定于单个创始染色体的等位基因对于鉴定通过血统共享相同的单倍型具有高度的信息。模拟研究用于评估具有各种谱系大小和结构的脉冲星的性能,并研究了基因分型错误和非测序个体的影响。在具有完整测序和实际基因分型错误率的谱系中,脉冲星正确地阶段> 杂合基因型的99.9%,不包括所有个体都是杂合的位点,并且切换错误率通常低于10-4。PULSAR具有很高的准确性,能够进行基因型纠错和归因,并且与适用于谱系的替代定相软件在计算上具有竞争力。我们的方法具有不需要其他基于种群的定相算法必不可少的参考面板的显着优势。可以免费获得PULSAR的软件实现。
  • 【晚期结直肠癌患者的UGT1A1 * 28基因型和基于伊立替康的化疗的SN-38药代动力学分析: 来自上海的一项多中心回顾性研究的结果。】 复制标题 收藏 收藏
    DOI:10.1007/s00432-013-1480-7 复制DOI
    作者列表:Cai X,Cao W,Ding H,Liu T,Zhou X,Wang M,Zhong M,Zhao Z,Xu Q,Wang L
    BACKGROUND & AIMS: BACKGROUND:The UGT1A1*28 polymorphism, although closely linked with CPT-11-related adverse effects, cannot be used alone to guide individualized treatment decisions. However, CPT-11 dosage can be adjusted according to measured SN-38 pharmacokinetics. Our study is designed to investigate whether there is a relationship between SN-38 peak or valley concentrations and efficacy or adverse effects of CPT-11-based chemotherapy. We retrospectively studied 98 patients treated with advanced colorectal cancer in various UGT1A1*28 genotype groups (mainly (TA)6/(TA)6 and (TA)6/(TA)7 genotypes) treated with CPT-11 as first-line chemotherapy in Shanghai. METHODS:One hundred and sixty-four advanced colorectal cancer patients were enrolled. To understand differences in genotype expression, the frequency of UGT1A1*28 thymine-adenine (TA) repeats in TATA box arrangement was assessed by PCR with genomic DNA extracted from peripheral blood. For ninety-eight cases with the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes treated with CPT-11 as first-line chemotherapy, the plasma concentration of SN-38 was detected by HPLC 1.5 and 49 h after CPT-11 infusion. Efficacy and adverse effects were observed subsequently, and the relationship between SN-38 plasma concentration and efficacy or adverse effects within genotype groups, as well as differences in efficacy and adverse effects between (TA)6/(TA)6 and (TA)6/(TA)7 genotypes were analyzed statistically. RESULTS:One hundred and fourteen patients (69.51 %) were identified with the (TA)6/(TA)6 genotype, forty-eight patients (29.27 %) with the (TA)6/(TA)7 genotype, and two patients (1.22 %) with the (TA)7/(TA)7 genotype. The average peak and valley concentrations of SN-38 after CPT-11 infusion and plasma bilirubin average levels before and after CPT-11 treatment in the (TA)6/(TA)7 genotype group were all higher than those in (TA)6/(TA)6 group, and the difference was statistically significant (p = 0.00). Stepwise regression analysis showed that SN-38 peak and valley concentration was correlated with PFS in the (TA)6/(TA)6 genotype. In the (TA)6/(TA)7 group, SN-38 peak concentration was correlated with CPT-11 starting dose and OS, valley concentration correlated with plasma bilirubin levels before CPT-11 treatment, delayed diarrhea, and OS. For the (TA)6/(TA)6 genotype, mPFS of the SN-38 peak concentration >43.2 ng/ml subgroup was significantly longer than that of ≤43.2 ng/ml subgroup (8.0 ± 0.35 vs. 6.5 ± 0.79 months, χ (2) = 17.18, p = 0.00) with a relatively high incidence of Grade I/II° myelosuppression; for the (TA)6/(TA)7 genotype, there was no significant difference in mOS between the SN-38 valley concentration >16.83 ng/ml and ≤16.83 subgroups (17.3 ± 0.45 vs. 18.8 ± 0.50 months, χ (2) = 1.38, p = 0.24), but the former had a higher incidence of Grade III/IV° mucositis and delayed diarrhea. For 2 (TA)7/(TA)7 cases, although 25 % dose reduction of CPT-11, which is calculated according to body surface area, Grade IV° bone marrow suppression and Grade III° delayed diarrhea still occurred after CPT-11 treatment, though both adverse effects resolved and did not recur again after a 50 % dose reduction. CONCLUSION:The (TA)6/(TA)6 genotype and (TA)6/(TA)7 genotype accounted for the most, and (TA)7/(TA)7 genotype only account for a very small portion of advanced colorectal cancer patients in Shanghai. For the (TA)6/(TA)6 genotype, CPT-11 dosage can be increased gradually to improve efficacy for patients with SN-38 peak concentration ≤43.2 ng/ml after CPT-11 infusion; and for (TA)6/(TA)7 genotype patients, CPT-11 dosage may be lowered appropriately to reduce serious adverse effects such as bone marrow suppression and delayed diarrhea without affecting the efficacy for those with SN-38 valley concentration >16.83 ng/ml. For (TA)7/(TA)7 genotype patients, adverse effects should be closely observed after treatment even if CPT-11 dosage has been reduced.
    背景与目标:
  • 【HBeAg阴性CHB对聚乙二醇干扰素alfa-2a (40KD) 的反应: HBsAg血清水平的治疗动力学因HBV基因型而异。】 复制标题 收藏 收藏
    DOI:10.1016/j.jhep.2013.07.017 复制DOI
    作者列表:Brunetto MR,Marcellin P,Cherubini B,Yurdaydin C,Farci P,Hadziyannis SJ,Rothe V,Regep L,Bonino F
    BACKGROUND & AIMS: BACKGROUND & AIMS:We investigated whether HBV genotype influences on-treatment HBsAg kinetics and/or the end-of-treatment HBsAg levels associated with long-term virological response in HBeAg-negative chronic hepatitis B patients treated with peginterferon alfa-2a±lamivudine in the Phase III trial. METHODS:All patients (n=230) who participated in long-term follow-up were included according to the availability of HBsAg level measurements. Long-term virological response was defined as HBV DNA ≤ 10,000cp/ml (1786IU/ml) at 5 years post-treatment. Genotype-specific end-of-treatment HBsAg levels associated with long-term virological response (identified by ROC analysis) were assessed in 199 patients with HBsAg measurements available at baseline and end-of-treatment. HBsAg kinetics according to genotype and long-term virological response were investigated in the 117 patients with additional samples available at weeks 12, 24, and 72. RESULTS:Baseline HBsAg levels were significantly higher for A than B, C, and D genotypes (p<0.05). On-treatment HBsAg kinetics varied according to HBV genotype. The difference between responders and non-responders was greatest for genotype A from weeks 12-24; for genotypes B and D from baseline to week 12; there was no significant difference over any timeframe for genotype C. High positive predictive values for long-term virological response could be obtained by applying end-of-treatment genotype-specific cut-offs: 75%, 47%, 71%, and 75% for genotypes A (<400IU/ml), B (<50IU/ml), C (<75IU/ml), and D (<1000IU/ml), respectively. CONCLUSIONS:On-treatment HBsAg kinetics vary between HBV genotypes. Genotype-specific monitoring timeframes and end-of-treatment thresholds could ameliorate response-guided treatment of HBeAg-negative chronic hepatitis B.
    背景与目标:
  • 【ADHD患者和对照组中NOS1基因型与白质微结构的女性特异性关联。】 复制标题 收藏 收藏
    DOI:10.1111/jcpp.12742 复制DOI
    作者列表:van Ewijk H,Bralten J,van Duin EDA,Hakobjan M,Buitelaar JK,Heslenfeld DJ,Hoekstra PJ,Hartman C,Hoogman M,Oosterlaan J,Franke B
    BACKGROUND & AIMS: BACKGROUND:The nitric oxide synthase gene (NOS1) exon 1f (ex1f) VNTR is a known genetic risk factor for Attention-Deficit/Hyperactivity Disorder (ADHD), particularly in females. NOS1 plays an important role in neurite outgrowth and may thus influence brain development, specifically white matter (WM) microstructure, which is known to be altered in ADHD. The current study aimed to investigate whether NOS1 is associated with WM microstructure in (female) individuals with and without ADHD. METHODS:Diffusion Tensor Imaging (DTI) scans were collected from 187 participants with ADHD (33% female) and 103 controls (50% female), aged 8-26 years, and NOS1-ex1f VNTR genotype was determined. Whole-brain analyses were conducted for fractional anisotropy (FA) and mean diffusivity (MD) to examine associations between NOS1 and WM microstructure, including possible interactions with gender and diagnosis. RESULTS:Consistent with previous literature, NOS1-ex1f was associated with total ADHD and hyperactivity-impulsivity symptoms, but not inattention; this effect was independent of gender. NOS1-ex1f was also associated with MD values in several major WM tracts in females, but not males. In females, homozygosity for the short allele was linked to higher MD values than carriership of the long allele. MD values in these regions did not correlate with ADHD symptoms. Results were similar for participants with and without ADHD. CONCLUSIONS:NOS1-ex1f VNTR is associated with WM microstructure in females in a large sample of participants with ADHD and healthy controls. Whether this association is part of a neurodevelopmental pathway from NOS1 to ADHD symptoms should be further investigated in future studies.
    背景与目标:
  • 【西班牙丙型肝炎病毒基因型1a中NS5A相关耐药相关替代Elbasvir的频率较低: 一项横断面研究。】 复制标题 收藏 收藏
    DOI:10.1038/s41598-017-02968-7 复制DOI
    作者列表:Palladino C,Sánchez-Carrillo M,Mate-Cano I,Vázquez-Morón S,Jimenez-Sousa MÁ,Gutiérrez-Rivas M,Resino S,Briz V
    BACKGROUND & AIMS: :Relevant resistance-associated substitutions (RASs) to elbasvir, the new HCV NS5A inhibitor, may limit its efficacy and lead to virological failure in HCV-GT1a-infected patients. There are few data outside clinical trials evaluating their prevalence and impact of elbasvir/grazoprevir. A multicenter cross-sectional study of 617 HCV-GT1a-infected individuals attended in 84 Spanish hospitals from the 17 Autonomous Communities and two Autonomous cities was performed. HCV population sequencing was used to identify RASs to elbasvir and the mutational pattern and drug sensitivity were confirmed by geno2pheno[HCV]. Viruses bearing RASs to elbasvir were present in 6.2% of HCV-GT1a infected patients. The most common RASs were the Y93C/H/N and Q30E/H/R (2.4% and 2.3%; respectively). Only 3.4% of patients had viruses with RASs that confer reduced susceptibility to elbasvir by geno2pheno[HCV] that identified exclusively the positions Q30H/R (n = 7) and Y93C/H/N (n = 8) as single mutations and Q30H + Y93H (n = 4) and Q30R + Y93H (n = 2) as double mutations considered as RASs to elbasvir. Lower prevalence of RASs to elbasvir in our HCV-GT1a-Spanish cohort was observed than reported previously in clinical trials. This information may be essential to guiding the implementation of elbasvir/grazoprevir in Spain, expected at the beginning of 2017 and the management of GT1a-infected patients.
    背景与目标: : 新的HCV NS5A抑制剂elbasvir的相关耐药相关替代 (RASs) 可能会限制其功效并导致HCV-GT1a-infected患者的病毒学失败。在临床试验之外,很少有数据评估其对elbasvir/grazoprevir的患病率和影响。对来自17个自治社区和两个自治城市的84家西班牙医院的617名HCV-GT1a-infected进行了多中心横断面研究。HCV群体测序用于鉴定RASs至elbasvir,并通过geno2pheno[HCV] 确认突变模式和药物敏感性。在HCV-GT1a感染的患者中有6.2% 例存在带有RASs至elbasvir的病毒。最常见的RASs是Y93C/H/N和Q30E/H/R (分别为2.4% 和2.3%)。只有3.4% 的患者患有RASs病毒,该病毒通过geno2pheno[HCV] 降低了对elbasvir的敏感性,该病毒仅将Q30H/R (N   =   7) 和Y93C/H/N (N   =   8) 定位为单个突变和Q30H   Y93H (N   =   4) 和Q30R   +   Y93H (n   =   2) 作为双突变被认为是对elbasvir的RASs。在我们的HCV-GT1a-Spanish队列中观察到的RASs与elbasvir的患病率比以前在临床试验中报道的要低。这些信息对于指导在西班牙实施elbasvir/grazoprevir可能是必不可少的,预计在开始2017年和GT1a-infected患者的管理。
  • 【弓形虫引起的回肠和降结肠肌间神经丛的改变 (基因型III)。】 复制标题 收藏 收藏
    DOI:10.1590/s0004-282x2008000400015 复制DOI
    作者列表:Sugauara EY,Sant'Ana Dde M,Almeida EC,Reis AB,Silva AV,Araújo EJ
    BACKGROUND & AIMS: :Alterations caused by a genotype III strain of Toxoplasma gondii were assessed with respect to the number and the morphometry of the myenteric neurons in the terminal ileum and the descending colon. Eighteen rats were divided into four groups: Acute Control Group (ACG, n=4); Acute Experimental Group (AEG, n=4); Chronic Control Group (CCG, n=5) and Chronic Experimental Group (CEG, n=5). NaCl solution was administered through gavage to the animals in the ACG and CCG. Toxoplasma gondii tachyzoites (10(4)) from a genotype III strain were orally administered to the AEG and CEG. Acute Groups were died after 24 hours, and the Chronic Groups after 30 days. Neuronal loss was not observed in both organs. The neurons atrophied in the terminal ileum as the opposite occurred with the neurons at the descending colon during the chronic phase of infection. In the terminal ileum, the neurons atrophied during the chronic phase of the infection as no alteration was found during the acute phase. For the descending colon, the neurons became hypertrophic during the chronic infection in opposition to the atrophy found during the acute phase.
    背景与目标: : 根据回肠末端和降结肠中肌间神经元的数量和形态,评估了弓形虫III型菌株引起的改变。将18只大鼠分为四组: 急性对照组 (ACG,n = 4); 急性实验组 (AEG,n = 4); 慢性对照组 (CCG,n = 5) 和慢性实验组 (CEG,n = 5)。通过灌胃将NaCl溶液施用于ACG和CCG中的动物。将来自基因型III菌株的弓形虫速殖子 (10(4)) 口服给AEG和CEG。急性组在24小时后死亡,慢性组在30天后死亡。两个器官均未观察到神经元丢失。在感染的慢性阶段,降结肠的神经元在回肠末端萎缩,相反。在回肠末端,由于在急性期未发现任何改变,因此在感染的慢性期神经元萎缩。对于降结肠,神经元在慢性感染期间变得肥厚,与急性期发现的萎缩相反。
  • 【HFE的纯合缺失产生类似于HFE p.C282Y/p.C282Y基因型的表型。】 复制标题 收藏 收藏
    DOI:10.1182/blood-2008-07-167296 复制DOI
    作者列表:Le Gac G,Gourlaouen I,Ronsin C,Géromel V,Bourgarit A,Parquet N,Quemener S,Le Maréchal C,Chen JM,Férec C
    BACKGROUND & AIMS: :Hemochromatosis is predominantly associated with the HFE p.C282Y homozygous genotype, which is carried by approximately 1 person in 200 in Northern European populations. However, p.C282Y homozygosity is often characterized by incomplete penetrance. Here, we describe the case of a woman who had a major structural alteration in the HFE gene. Molecular characterization revealed an Alu-mediated recombination leading to the loss of the entire HFE gene sequence. Although homozygous for the HFE deleted allele, the woman had a phenotype similar to that seen in most women homozygous for the common p.C282Y mutation. Contrasting with previously reported results in Hfe knockout and Hfe knockin mice, our report gives further evidence that progression of the disease depends on modifying factors.
    背景与目标: : 血色病主要与HFE p.C282Y纯合基因型有关,在北欧人群中,200年约有1人携带。然而,p.C282Y纯合性通常以不完全外显率为特征。在这里,我们描述了一名女性的情况,该女性的HFE基因发生了重大结构改变。分子表征揭示了Alu介导的重组导致整个HFE基因序列的丢失。尽管HFE缺失等位基因是纯合的,但该妇女的表型与大多数常见p.C282Y突变纯合的女性相似。与先前报道的Hfe基因敲除和Hfe基因敲除小鼠的结果相比,我们的报告提供了进一步的证据,表明疾病的进展取决于修饰因子。
  • 【基因型MTBDR检测直接在痰标本上的应用。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Hillemann D,Rüsch-Gerdes S,Richter E
    BACKGROUND & AIMS: :The Genotype MTBDR assay was tested for its capability to detect rifampicin (RMP) and isoniazid (INH) resistance (r) and susceptibility (s) directly from 42 smear-positive sputum specimens (15 RMPr/INHr, 2 RMPs/INHr and 25 RMPs/INHs Mycobacterium tuberculosis complex strains). The concordance between the MTBDR assay and conventional drug susceptibility testing was 100%.
    背景与目标: : 测试了基因型MTBDR测定的能力,以直接从42个涂片阳性痰标本 (15个RMPr/INHr,2个RMPs/INHr) 中检测利福平 (RMP) 和异烟肼 (INH) 的耐药性 (r) 和易感性 (s)/INHr和25个RMPs/INHs结核分枝杆菌复合菌株)。100% 了MTBDR测定与常规药物敏感性试验之间的一致性。
  • 【载脂蛋白E基因型是慢性淋巴细胞性白血病生存的决定因素。】 复制标题 收藏 收藏
    DOI:10.1038/leu.2008.241 复制DOI
    作者列表:Weinberg JB,Volkheimer AD,Mihovilovic M,Jiang N,Chen Y,Bond K,Moore JO,Gockerman JP,Diehl LF,de Castro CM,Rizzieri DA,Levesque MC,Dekroon R,Strittmatter WJ
    BACKGROUND & AIMS: :Survival of chronic lymphocytic leukemia (CLL) cells requires sustained activation of the antiapoptotic PI-3-K/Akt pathway, and many therapies for CLL cause leukemia cell death by triggering apoptosis. Blood lipoprotein particles are either pro- or antiapoptotic. High-density lipoprotein particles are antiapoptotic through sphingosine-1-phosphate receptor 3-mediated activation of the PI-3-K/Akt pathway. Apolipoprotein E4 (apoE4)-very low density lipoproteins (VLDL) increase apoptosis, but the apoE2-VLDL and apoE3-VLDL isoforms do not. As increased B-cell apoptosis favors longer survival of CLL patients, we hypothesized that APOE4 genotype would beneficially influence the clinical course of CLL. We report here that women (but not men) with an APOE4 genotype had markedly longer survival than non-APOE4 patients. VLDL is metabolized to low-density lipoprotein through lipoprotein lipase. Higher levels of lipoprotein lipase mRNA in these CLL patients correlated with shorter survival. The beneficial effect of APOE4 in CLL survival is likely mediated through APOE4 allele-specific regulation of leukemia cell apoptosis. The APOE allele and genotype distribution in these CLL patients is the same as in unaffected control populations, suggesting that although APOE genotype influences CLL outcome and response to therapy, it does not alter susceptibility to developing this disease.
    背景与目标: 慢性淋巴细胞白血病 (CLL) 细胞的存活需要抗凋亡PI-3-K/Akt途径的持续激活,并且许多CLL疗法通过触发凋亡而导致白血病细胞死亡。血液脂蛋白颗粒是促凋亡或抗凋亡的。高密度脂蛋白颗粒通过sphingosine-1-phosphate受体3介导的PI-3-K/Akt途径的激活而抗凋亡。载脂蛋白E4 (apoE4)-极低密度脂蛋白 (VLDL) 增加细胞凋亡,但apoE2-VLDL和apoE3-VLDL同工型不会。由于增加的b细胞凋亡有利于CLL患者更长的生存期,我们假设APOE4基因型将有利地影响CLL的临床进程。我们在这里报告说,具有APOE4基因型的女性 (而非男性) 比non-APOE4患者具有明显更长的生存期。VLDL通过脂蛋白脂肪酶代谢为低密度脂蛋白。这些CLL患者中较高的脂蛋白脂肪酶mRNA水平与较短的生存期相关。APOE4在CLL存活中的有益作用可能是通过APOE4等位基因特异性调节白血病细胞凋亡介导的。这些CLL患者的APOE等位基因和基因型分布与未受影响的对照人群相同,这表明尽管APOE基因型会影响CLL的结果和对治疗的反应,但它不会改变患此病的敏感性。
  • 【雄性基因型影响果蝇的雌性寿命。】 复制标题 收藏 收藏
    DOI:10.1554/0014-3820(2001)055[0834:mgafli]2.0.co;2 复制DOI
    作者列表:Sawby R,Hughes KA
    BACKGROUND & AIMS: :Several recent studies suggest that interactions with conspecific males can reduce the longevity of female Drosophila melanogaster or support the idea that male and female fitness components are involved in antagonistic interactions. Here we report that males from third-chromosome isogenic lines demonstrated significant genetic variation in male reproductive performance and in the longevity of their mates. Increased male performance was marginally significantly associated with one measure of increased female survival rate. However, there was no indication of tradeoffs or negative correlations between male reproductive success and female survival. We discuss alternative hypotheses for the cause of the induced variation in female longevity.
    背景与目标: : 最近的几项研究表明,与同种雄性的相互作用可以减少雌性果蝇的寿命,或者支持雄性和雌性健身成分参与拮抗相互作用的观点。在这里,我们报告说,来自第三染色体等基因系的雄性在雄性生殖性能和配偶寿命方面表现出显着的遗传变异。男性表现的提高与女性存活率提高的一种指标略有显着相关。但是,没有迹象表明男性生殖成功与女性存活率之间存在权衡或负相关关系。我们讨论了引起女性寿命变化的原因的替代假设。
  • 【GSTT1 (rs4025935) 无效基因型与沙特阿拉伯Tabuk-西北地区人群中镰状细胞疾病的风险增加有关。】 复制标题 收藏 收藏
    DOI:10.1080/10245332.2016.1201631 复制DOI
    作者列表:Abu-Duhier F,Mir R
    BACKGROUND & AIMS: BACKGROUND:Glutathione system plays an important role in the protection of cells and tissue against damage from oxidative stress. Impairment of the glutathione system due to genetic polymorphism of GST genes may increase the risk and severity of sickle cell disease (SCD). Present study was, therefore, undertaken to examine the relative impact of the genetic polymorphism of GSTT1 and GSTM1 (rs4025935 and rs71748309) on susceptibility and hematological aspects of the patients with SCD. METHODS:Present study included 100 patients with SCD and 200 healthy controls from northwestern region of Saudi Arabia. GSTM1 and GSTT1 (rs4025935 and rs71748309) genotypes were investigated by using single-tube multiplex PCR technique. RESULTS:It was observed that patients with SCD possessed significantly higher frequency of GSTT1 null genotype (26%) than healthy controls (15%), (P = 0.00001). Compared to the presence of GSTT1 genotype, the OR for the GSTT1 null genotype were estimated to be 4.3 (2.17-8.64, P = 0.00001). However, such association was not observed with respect to the presence of GSTM1 null genotype. In addition, it was observed that SCD in patients with GSTT1 genotype, the mean percentage levels for HbF and HbS were 0.48 and 35.4%, respectively; however, among SCD patients with GSTT1 null genotype, the mean percentage levels were significantly higher 1.62% (P = 0.004) and 39.38% (P = 0.02), respectively. CONCLUSION:GSTT1 null genotype is significantly associated with increased risk of SCD among the population of northwestern region of Saudi Arabia. In addition, it may be one of the important factors responsible for hematological manifestations of SCD.
    背景与目标:
  • 【脂质,脂蛋白和载脂蛋白与载脂蛋白E基因型之间的上下文依赖性和不变关联。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Frikke-Schmidt R,Nordestgaard BG,Agerholm-Larsen B,Schnohr P,Tybjaerg-Hansen A
    BACKGROUND & AIMS: :Variation in apolipoprotein (apo)E genotypes predicts variation in plasma cholesterol and apoB; however, the context-dependent associations between high density lipoprotein (HDL) cholesterol, apoA-I, triglycerides, and lipoprotein[a] (Lp[a]) and this polymorphism remain unsettled. We genotyped 5,025 women and 4,035 men sampled to represent a white general population in the age range 20 to 80+ years (mean ages 58 and 57 years for women and men, respectively). The relative frequencies of the varepsilon22, varepsilon32, varepsilon42, varepsilon33, varepsilon43, and varepsilon44 genotypes were 0.005, 0.127, 0.027, 0.564, 0.251, and 0. 027, respectively. Variations in apoE genotype (in the order listed above) predicted stepwise increases in cholesterol and apoB in both genders (all ANOVAs: P < 0.001), and stepwise decreases in HDL cholesterol and apoA-I in women (both ANOVAs: P < 0.001), but not in men. In both genders varepsilon33 individuals had the lowest levels of nonfasting triglycerides, whereas the highest levels were found in individuals with varepsilon22 and varepsilon44 genotypes (both ANOVAs: P < 0.001). Finally, a stepwise increase in Lp[a] was seen in women (ANOVA: P < 0.001), but not in men. In women, the association between variation in nonfasting triglycerides and Lp[a], and variation in apoE genotypes was mainly seen in those with the highest alcohol consumption, similar to the consumption of most men. Variations in apoE genotype predicted 5% and 11% in women, and 2% and 6% in men, of the total variation in plasma cholesterol and apoB, respectively. Variation in levels of plasma lipoproteins is associated with variation in apoE genotypes in the population at large, with the most pronounced association in women, except for nonfasting triglycerides, for which the association is most pronounced in men.Whereas the associations between variation in plasma cholesterol and apoB and the variation in apoE genotypes seem invariant, the associations with variation in plasma HDL cholesterol, apoA-I, nonfasting triglycerides, and Lp[a] seem context dependent.
    背景与目标: : 载脂蛋白 (apo)E基因型的变化可预测血浆胆固醇和apoB的变化; 然而,高密度脂蛋白 (HDL) 胆固醇,apoA-I,甘油三酸酯,和脂蛋白 [a] (Lp[a]) 和这种多态性仍未解决。我们对5,025名女性和4,035名男性进行了基因分型,以代表年龄在20至80岁之间的白人普通人群 (女性和男性的平均年龄为58和57岁,分别)。varepsilon22、varepsilon32、varepsilon42、varepsilon33、varepsilon43和varepsilon44基因型的相对频率分别为0.005、0.127、0.027、0.564、0.251和0.027,apoE基因型的变化 (按上面列出的顺序) 预测两种性别的胆固醇和apoB的逐步增加 (所有anova: P <0.001),以及女性HDL胆固醇和apoA-I的逐步减少 (两个anova: P <0.001),但不是在男性中。在两个性别中,varepsilon33个体的非空腹甘油三酯水平最低,而在varepsilon22和varepsilon44基因型的个体中发现最高水平 (两者的方差: P <0.001)。最后,在女性中发现Lp[a] 的逐步增加 (方差分析: P <0.001),但男性没有。在女性中,非空腹甘油三酯和Lp[a] 的变异与apoE基因型的变异之间的关联主要见于饮酒量最高的人群,与大多数男性的消费相似。apoE基因型的变化分别预测了女性的5% 和11%,以及男性的2% 和6% 血浆胆固醇和apoB的总变化。血浆脂蛋白水平的变化与整个人群中apoE基因型的变化有关,与女性最明显的关联,除了非空腹甘油三酯,男性最明显。血浆胆固醇和apoB的变化与apoE基因型的变化之间的关联似乎是不变的,与血浆HDL胆固醇,apoA-I,非空腹甘油三酯的变化的关联,lp [a] 似乎取决于上下文。
  • 【CYP2D6基因型对阿米替林治疗糖尿病周围神经病变疗效的影响: 一项初步研究。】 复制标题 收藏 收藏
    DOI:10.2217/pgs-2016-0185 复制DOI
    作者列表:Chaudhry M,Alessandrini M,Rademan J,Dodgen TM,Steffens FE,van Zyl DG,Gaedigk A,Pepper MS
    BACKGROUND & AIMS: AIM:Therapy with low-dose amitriptyline is commonly used to treat painful diabetic peripheral neuropathy. There is a knowledge gap, however, regarding the role of variable CYP2D6-mediated drug metabolism and side effects (SEs). We aimed to generate pilot data to demonstrate that SEs are more frequent in patients with variant CYP2D6 alleles. METHOD:To that end, 31 randomly recruited participants were treated with low-dose amitriptyline for painful diabetic peripheral neuropathy and their CYP2D6 gene sequenced. RESULTS:Patients with predicted normal or ultra-rapid metabolizer phenotypes presented with less SEs compared with individuals with decreased CYP2D6 activity. CONCLUSION:Hence, CYP2D6 genotype contributes to treatment outcome and may be useful for guiding drug therapy. Future investigations in a larger patient population are planned to support these preliminary findings.
    背景与目标:
  • 【功能变异组学和网络扰动: 将基因型与癌症表型联系起来。】 复制标题 收藏 收藏
    DOI:10.1038/nrg.2017.8 复制DOI
    作者列表:Yi S,Lin S,Li Y,Zhao W,Mills GB,Sahni N
    BACKGROUND & AIMS: :Proteins interact with other macromolecules in complex cellular networks for signal transduction and biological function. In cancer, genetic aberrations have been traditionally thought to disrupt the entire gene function. It has been increasingly appreciated that each mutation of a gene could have a subtle but unique effect on protein function or network rewiring, contributing to diverse phenotypic consequences across cancer patient populations. In this Review, we discuss the current understanding of cancer genetic variants, including the broad spectrum of mutation classes and the wide range of mechanistic effects on gene function in the context of signalling networks. We highlight recent advances in computational and experimental strategies to study the diverse functional and phenotypic consequences of mutations at the base-pair resolution. Such information is crucial to understanding the complex pleiotropic effect of cancer genes and provides a possible link between genotype and phenotype in cancer.
    背景与目标: 蛋白质在复杂的细胞网络中与其他大分子相互作用,以实现信号转导和生物学功能。在癌症中,传统上认为遗传畸变会破坏整个基因功能。人们越来越认识到,基因的每个突变都可能对蛋白质功能或网络重新布线产生微妙但独特的影响,从而导致癌症患者人群的各种表型后果。在这篇综述中,我们讨论了当前对癌症遗传变异的理解,包括广泛的突变类别以及在信号网络背景下对基因功能的广泛机械影响。我们重点介绍了计算和实验策略的最新进展,以研究碱基对分辨率下突变的各种功能和表型后果。这些信息对于理解癌症基因的复杂多效性作用至关重要,并提供了癌症基因型和表型之间的可能联系。
  • 【确定主要虫媒病毒载体埃及伊蚊中拟除虫菊酯抗性基因型的适应性成本。】 复制标题 收藏 收藏
    DOI:10.1186/s13071-020-04238-4 复制DOI
    作者列表:Rigby LM,Rašić G,Peatey CL,Hugo LE,Beebe NW,Devine GJ
    BACKGROUND & AIMS: BACKGROUND:Effective vector control measures are essential in a world where many mosquito-borne diseases have no vaccines or drug therapies available. Insecticidal tools remain the mainstay of most vector-borne disease management programmes, although their use for both agricultural and public health purposes has resulted in selection for resistance. Despite this, little is known about the fitness costs associated with specific insecticide-resistant genotypes and their implications for the management of resistance. In Aedes aegypti, the primary vector of dengue, chikungunya, and Zika, the best-characterised resistance mechanisms are single-point mutations that protect the voltage-gated sodium channel from the action of pyrethroids. METHODS:We evaluated the fitness cost of two co-occurring, homozygous mutations (V1016G and S989P) by back-crossing a resistant strain of A. aegypti from Timor-Leste into a fully susceptible strain from Queensland. The creation of the backcross strain allowed us to isolate these kdr mutations in an otherwise susceptible genetic background. RESULTS:In comparison to the susceptible strain, the backcrossed colony exhibited longer larval development times (5 days, P < 0.001), 24% fewer mosquitoes reached the adult stage (P = 0.005), had smaller wing lengths (females, P = 0.019 and males, P = 0.007) and adult female mosquitoes had a shorter average lifespan (6 days, P < 0.0006). CONCLUSIONS:These results suggest specific and significant fitness costs associated with the double homozygous V1016G/S989P genotype in the absence of insecticides. The susceptibility of a population may recover if the fitness costs of resistant genotypes can be emphasised through the use of insecticide rotations and mosaics or the presence of untreated spatial or temporal refuges.
    背景与目标:

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