Human leukocyte antigen class I polymorphisms influence the mild clinical manifestation of Plasmodium falciparum infection in Ghanaian children

A prospective study that included 429 children for active detection of mild malaria was conducted in a coastal region of Ghana to reveal whether the incidence of malaria is affected by human leukocyte antigen (HLA) polymorphism. During 12 months of follow-up, 85 episodes of mild clinical malaria in 74 individuals were observed, and 34 episodes among them were accompanied with significant parasitemia at >5000 infected red blood cells per cubic millimeter. Attributable and relative risks conferred by genetic factors in the HLA region were evaluated by comparison of the incidence in children, stratified by carrier status, of a given allele of HLA-A, -B, -DRB1 and TNFA promoter polymorphism. HLA-B*35:01 reduced the incidence by 0.178 events per person per year (0.060 versus 0.239 for B*35:01-positive and -negative subpopulations, respectively), and a relative risk of 0.25, which remained statistically significant after Bonferroni's correction for multiple testing (p(c) = 8.2 × 10(-5)). Further, HLA-B*35:01 and -B*53:01 exhibited opposite effects on the incidence of malaria with significant parasitemia. When parasite densities in different HLA carriers status were compared, HLA-A*01 conferred an increase in parasite load (p = 6.0 × 10(-7)). In addition, we found a novel DRB1 allele that appears to have emerged from DRB1*03:02 by single nucleotide substitution.     

The effect of IL-10 genetic variation and interleukin 10 serum levels on Crohn's disease susceptibility in a New Zealand population

Interleukin (IL)-10 has important effects in immunoregulation and inflammation, and previous studies have provided evidence for the involvement of IL-10 in the pathogenesis of Crohn's disease (CD). In this study, we investigated whether genetic variants of the IL-10 gene were associated with CD in a New Zealand population. Three single nucleotide polymorphisms (SNPs) in the promoter region of IL-10 (rs1800871, rs1800872, and rs1800896) and a flanking SNP, rs3024505, were genotyped in a well-characterized New Zealand dataset consisting of 342 CD cases and 610 controls. Furthermore, we measured serum IL-10 levels in a number of the CD patients and controls and examined whether a relationship existed between these polymorphisms and serum IL-10 levels. We demonstrated an association with CD for SNPs rs3024505 and rs1800896, and phenotypic analysis indicated an association of rs3024505 with an early age at first diagnosis, stricturing CD behavior, and requirement for bowel resection. We also observed that IL-10 concentration was significantly higher in CD patients than in the controls and that the T allele of rs1800896, the A allele of rs1800871, and the T allele of rs1800872 were associated with increased serum IL-10 levels.     

纤溶酶原激活物抑制物-1基因4G/5G多态性与冠心病的关联研究

目的探讨纤溶酶原激活物抑制物-1（PAI-1）基因4G/5G多态性与冠状动脉疾病的关系。方法采用病例对照研究的方法。病例组146例,72例行冠状动脉造影证实患有CAD;正常对照组113例,选自人群健康体检者,所有入选病例均排除CAD史,脑卒中短暂性脑缺血发作病史及相似病史,排除周围血管疾病史。均用PCR-RFLP的方法判断各组基因型,最后进行统计学分析。结果与5G/5G相比,4G/5G,4G/4G的OR呈增加趋势,提示4G等位基因与冠心病的危险性相关。具有4G/4G基因型比具有5G/5G基因型的人患冠心病的危险性增加2.06倍（95%CI：1.03～4.14）。结论 PAI-1基因4G/4G基因型与中国汉族人群冠心病发生相关。     

心钠素基因多态性与老年冠状动脉病变的关系

目的研究我国青岛地区人群心钠素(ANP)基因T2238C多态性与老年冠状动脉病变的关系。方法选择150例冠心病患者为研究对象,行多层螺旋CT冠脉成像并计算冠脉钙化积分(CACS),根据CACS结果分组。应用基因芯片技术测定测定患者ANP基因型并进行分析和比较。结果冠脉钙化积分不同者,ANP基因型不同,差异有统计学意义(P<0.01)。多元线性回归示ANP基因CT型、吸烟史、高血脂、冠心病家族史是影响冠脉钙化积分值的因素,标准回归系数(Beta)分别为0.171,0.210,0.205,0.307(P<0.01),协方差分析扣除高血脂、吸烟史、冠心病家族史的线性影响,ANP基因CT型仍为冠状动脉病变的危险因素(P<0.01)。结论 ANP基因T2238C多态性、高血脂、吸烟、冠心病家族史共同参与冠状动脉病变的发生,ANP基因T2238C可能是冠状动脉病变的遗传易感基因。     

伏立康唑人体药代动力学的特征与差异研究

目的:研究健康受试者口服伏立康唑的药代动力学特征和差异.方法:70名健康志愿者单次口服伏立康唑200 mg后,用HPLC-MS/MS方法测定血中的伏立康唑浓度,分析不同个体伏立康唑的体内代谢过程与动力学差异.结果:伏立康唑药代动力学个体差异很大.其代谢特征可分为四种类型,A型占21%,达峰时间最短,而峰浓度最高,分布容积最小,属于快分布型;B型占53%,所有参数均为中间水平;C型占11%,为慢代谢型;D型占14%,峰浓度最低,达峰时间最晚,AUC最低,清除最快,为强代谢型.结论:伏立康唑个体代谢差异很大,需要进行血药浓度监测.     

超声造影评估肾占位病变的临床应用

目的探讨术前超声造影能否预测肾脏占位病变的组织类型。方法 27例肾脏占位病变患者术前行灰阶超声、彩色多普勒、八氟丙烷超声造影,超声造影结果与外科病理结果相比较。结果 18例患者为透明细胞癌,3例为1型乳头状瘤,1例为嫌色细胞癌,1例为未分类病变,3例为嗜酸细胞瘤,1例为良性血管肌脂肪瘤。不均匀回声和延迟洗出相联合、造影增强度、病变峰值强度联合延迟洗出诊断肾占位病变病理类型有高的的阳性预测值、敏感度和特异度。结论不均匀回声、延迟洗出、造影增强度、病变峰值强度有助于鉴别诊断肾透明细胞癌和非透明细胞癌。     

Gender differences in the risk of familial parkinsonism: Beyond LRRK2?

G2019S mutations in the LRRK2 gene are responsible for up to 18% of PD in individuals of Jewish descent. While a male preponderance of Parkinson disease (PD) has been consistently reported, this gender difference is not noted in LRRK2 G2019S mutation carriers. In order to test whether there is an increased genetic component in women of Jewish background in general, we examined family history of parkinsonism in 175 Jewish PD patients (82 female and 93 male) and assessed whether parkinsonism was more frequent in family members of women with PD in comparison with family members of men with PD, adjusting for LRRK2 G2019S mutations in the proband. Using Cox proportional hazard models to evaluate the risk of parkinsonism among family members of PD subjects, having a daughter with PD compared with a son was associated with increased risk of parkinsonism in the parent (HR 2.59, p=0.014) as was having a child with a LRRK2 G2019S mutation (HR 3.19, p=0.003). The increased risk among parents of women with PD persisted when adjusting for LRRK2 status (HR 2.19, p=0.023). Among individuals of Jewish descent, there is a relatively greater genetic load in women with PD, and this is not fully accounted for by the G2019S mutation. Further study that evaluates family information bias and assesses the role of glucocerebrosidase mutations is indicated.     

The prevention of behavioral consequences of idiopathic generalized epilepsy: evidence from rodent models

Comorbidity in the affective domain seems rather typical for idiopathic epilepsy. Whether seizures are causative for the behavioral abnormalities or whether they are a common genetic cause remains to be established. Although the most proper control groups are not always available, there seems to be some consistency in the behavioral patterns seen in rats with absence epilepsy. Formal behavioral testing has shown that genetic absence models such as WAG/Rij's and GAERS, but also other rat lines endowed with spontaneous occurring spike-wave discharges (APO-SUS and Long-Evans rats), show all signs of depression-like behavior, while some lines show an even more complex affective comorbidity. The availability of a treatment that prevents both the neurodevelopment of the genetically programmed seizure and the comorbid symptomatology may help in answering whether seizures are causative for or epiphenomena of changes in affective behavior. If absence seizures and depressive-like behavior is indeed caused by the same underlying factors, then it is predicted that preventing environmental stress in absence epileptic rats will also prevent the affective disturbances.     

Induction of pluripotent stem cells from autopsy donor-derived somatic cells

Human induced pluripotent stem cells (iPSCs) have become an intriguing approach for neurological disease modeling, because neural lineage-specific cell types that retain the donors’ complex genetics can be established in vitro. The statistical power of these iPSC-based models, however, is dependent on accurate diagnoses of the somatic cell donors; unfortunately, many neurodegenerative diseases are commonly misdiagnosed in live human subjects. Postmortem histopathological examination of a donor's brain, combined with premortem clinical criteria, is often the most robust approach to correctly classify an individual as a disease-specific case or unaffected control. In this study, we describe iPSCs generated from a skin biopsy collected postmortem during the rapid autopsy of a 75-year-old male, whole body donor, defined as an unaffected neurological control by both clinical and histopathological criteria. These iPSCs were established in a feeder-free system by lentiviral transduction of the Yamanaka factors, Oct3/4, Sox2, Klf4, and c-Myc. Selected iPSC clones expressed both nuclear and surface antigens recognized as pluripotency markers of human embryonic stem cells (hESCs) and were able to differentiate in vitro into neurons and glia. Statistical analysis also demonstrated that fibroblast proliferation was significantly affected by biopsy site, but not donor age (within an elderly cohort). These results provide evidence that autopsy donor-derived fibroblasts can be successfully reprogrammed into iPSCs, and may provide an advantageous approach for generating iPSC-based neurological disease models.     

Genetics and epigenetics of obesity

Obesity results from interactions between environmental and genetic factors. Despite a relatively high heritability of common, non-syndromic obesity (40-70%), the search for genetic variants contributing to susceptibility has been a challenging task. Genome wide association (GWA) studies have dramatically changed the pace of detection of common genetic susceptibility variants. To date, more than 40 genetic variants have been associated with obesity and fat distribution. However, since these variants do not fully explain the heritability of obesity, other forms of variation, such as epigenetics marks, must be considered. Epigenetic marks, or "imprinting", affect gene expression without actually changing the DNA sequence. Failures in imprinting are known to cause extreme forms of obesity (e.g. Prader-Willi syndrome), but have also been convincingly associated with susceptibility to obesity. Furthermore, environmental exposures during critical developmental periods can affect the profile of epigenetic marks and result in obesity. We review the most recent evidence for genetic and epigenetic mechanisms involved in the susceptibility and development of obesity. Only a comprehensive understanding of the underlying genetic and epigenetic mechanisms, and the metabolic processes they govern, will allow us to manage, and eventually prevent, obesity.