Exploratory activity: genetic analysis of its modification by scopolamine and amphetamine

Short-term exploratory activity was found to be significantly higher in C57BL/6By than in BALB/cBy inbred mice. Scopolamine reversed the activity levels in these strains. Basal exploratory activity levels and the effects of scopolamine on this behavioral measure assessed in these two strains, their reciprocal F₁ hybrids, their recombinant inbred strains and three C57BL/6 congenic lines permitted characterization of a gene exerting a major effect on short-term exploratory activity [Exa, linked to H(w26), chromosome 4 (LG VIII)] and of a gene modulating the effects of scopolamine in this behavior, [Sco, linked to H-2, chromosome 17 (LG IX)]. Amphetamine exerted opposite effects in relation to those exerted by scopolamine on activity and its action was found to be determined by a polygenic system.     

Distinctions among sedative,disinhibitory, and ataxic properties of ethanol in inbred and selectively bred mice

Three different domains of behavioral action of ethanol (ETOH) were examined in a battery of seven inbred strains and in the selectively bred Long-Sleep (LS) and Short-Sleep (SS) mice. Sedative effects were examined with the loss of the righting reflex test at 3.8 g/kg. The variation among inbred strains was only half the size of the difference between LS and SS mice which were selectively bred for extremes in this phenotype; such a result is expected for phenotypes controlled polygenically. Blood ETOH levels at waking from the narcosis also showed a range of differences among the inbred strains that was less than the LS/SS difference. Ataxia was measured with the grid test, and the inbred strains fell into two groups, resembling the highly ataxic LS line, and the less ataxic SS line. Biphasic effects of ETOH on locomotor activity were strongly genotype dependent. Variation in degree of activation/disinhibition produced by doses up to 1.5 g/kg (IP) ranged from no activation, in the C57BL/6Abg strain, to a stimulation effect in the MOLD/RkAbg strain which was larger than that seen for SS mice. The patterns of strain differences for both ataxia and activation were highly different from the duration of loss of righting reflex measure, suggesting multiple independent genetically based sensitivities to ETOH.     

Rats bred for ethanol sensitivity: Impairment of swimming by ethanol and pentobarbital

Rats selectively bred for disparate degrees of ethanol-induced depression of spontaneous locomotor activity (most affected = MA; least affected = LA) were trained on a swim task. Undrugged rats of the MA line swam significantly faster than rats of the LA line. Ethanol, 0.0–2.25 g/kg i.p., produced dose-dependent increases in swim time in rats of the 13th generation (F13). Averaged over trials, these increases were greater in LA than in MA rats and greater in males than in females, but there was no sex difference in peak impairment. Increases in swim time were uncorrelated with predrug performance. These findings were confirmed in younger F17 rats receiving 1.75 g EtOH/kg i.p. Although the lines differed in ethanol-induced impairment, F17 males of the two lines were not differentially impaired by pentobarbital (12.5–22.5 mg/kg, i.p.). The existence of task-dependent line differences in ethanol sensitivity emphasizes the nonunitary nature of ethanol-induced behavioral depression.     

How will insights from genetics translate to clinical practice in inflammatory bowel disease?

Inflammatory bowel disease, consisting of Crohn's disease and ulcerative colitis, is a chronic inflammatory disease of the gut, which arises through an excessive immune response to the normal gut flora in a genetically susceptible host. The disease affects predominantly young adults and due to its chronic and relapsing nature gives rise to a high disease burden both financially, physically and psychologically. Current therapy still cannot prevent the need for surgical intervention in more than half of IBD patients. Consequently, advances in IBD therapy are of high importance. Recently, several new forms of targeted therapy have been introduced, which should improve surgery-free prognosis of IBD patients. Recent identification of genetic risk variants for IBD has led to new insights into the biological mechanisms of the disease, which will, in the future, lead to new targeted therapy. In the meantime repositioning of drugs from biologically similar diseases towards IBD might lead to new IBD therapies.     

Quick Method for Confirmation of Quantitative Trait Loci

Numerous algorithms for the identification and genetic mapping of quantitative trait loci (QTL) have been developed. Methods for confirming QTL maps involve either examination of independent segregating populations or the construction of congenic lines differing only in the QTL of interest. Because these projects require a minimum of several years or thousands of marker assessments in laboratory mice, an alternative, faster congenic method has been pro: posed. In a preliminary study, we tested this method for confirming QTLs identified in crosses between the ILS and ISS selected lines of mice for differential sensitivity to the hypnotic effects of ethanol. Herein, we report the construction of "segregating congenic" strains in which each QTL is made homozygous in a single generation, whereas the remainder of the genetic background is allowed to segregate. Sensitivity to ethanol among the progeny of such mice is consistent with predictions. Phenotypic variation is high, as expected, due to the background segregation, and statistical significance was attained in only 2 of 7 comparisons. Such segregating congenic populations may be a valuable research tool for confirming QTL map positions and for subsequent assessment of individual pathways and mechanisms of action of individual QTLs.     

Pharmacogenetics of warfarin: regulatory, scientific, and clinical issues

Using pharmacogenetics-based therapy, clinicians can estimate the therapeutic warfarin dose by genotyping patients for single nucleotide polymorphisms (SNPs) that affect warfarin metabolism or sensitivity. SNPs in the cytochrome P450 complex (CYP2C9) affect warfarin metabolism: patients who have the CYP2C9*2 and/or CYP2C9*3 variants metabolize warfarin slowly and are more likely to have an elevated International Normalized Ratio INR or to hemorrhage during warfarin initiation than patients without these variants. SNPs in vitamin K epoxide reductase (VKORC1) correlate with warfarin sensitivity. Patients who are homozygous for a common VKORC1 promoter polymorphism, −1639 G>A (also designated as VKOR 3673, haplotype A, or haplotype*2), are warfarin sensitive and typically require lower warfarin doses. By providing an estimate of the therapeutic warfarin dose, pharmacogenetics-based therapy may improve the safety of anticoagulant therapy. To improve drug safety, the FDA updates labels of previously approved drugs as new clinical and genetic evidence accrues. The labels of medical products serve to inform prescribers and patients about potential ways to improve the benefit/risk ratio and/or optimize doses of medical products. On August 16, 2007, the FDA updated the label of warfarin to include information on pharmacogenetic testing and to encourage, but not require, the use of this information in dosing individual patients initiating warfarin therapy. The FDA completed the label update in August 2007. Disclosure: A portion of this article was adapted from an education handout that Dr. Gage has retained copyright of: Gage, B.F. (2006). Pharmacogenetics-based coumarin therapy. Hematology Am Soc Hematol Educ Program: 467–473. Dr. Gage has served as a consultant to Bristol-Myers Squibb. Funding: NIH R01 HL074724.     

Are <Emphasis Type="Italic">Thymidylate synthase</Emphasis> and <Emphasis Type="Italic">Methylene tetrahydrofolate reductase</Emphasis> genes linked with methotrexate response (efficacy,toxicity) in Indian (Asian) rheumatoid arthritis patients?

Methotrexate (MTX) is among the best-tolerated disease-modifying antirheumatic drugs for the treatment of rheumatoid arthritis (RA); major drawbacks of MTX therapy are the large interpatient variability in clinical response and the unpredictable appearance of a large spectrum of side effects. Several studies have demonstrated gene polymorphism that may regulate intracellular methotrexate metabolic pathway enzymes linked to drug efficacy and safety, but the evidence available is not yet conclusive. We decided to run a pilot study to determine the incidence of Methylene tetrahydrofolate (MTHFR; C677T, A1298C) and Thymidylate synthase (TS; 5′ UTR repeat, 3′ UTR deletion) gene polymorphism in rheumatoid arthritis patients in our community (Indian Asian) and further explore its association with MTX response (efficacy, toxicity). Thirty-four naïve RA patients on supervised MTX therapy and 139 healthy controls were genotyped for A1298C and C677T polymorphism of the MTHFR gene and 5′ UTR repeat and 3′ UTR deletion polymorphism of the TYMS gene by polymerase chain reaction-restriction fragment length polymorphism. Association, if any, between gene polymorphism and MTX response in RA patients was analyzed. The MTHFR A1298C ‘C’ allele incidence among RA patients (46%) was significantly higher (χ ²?=?4.24, P?相似文献   

Screening of Dihydropyrimidine Dehydrogenase Genetic Variants by Direct Sequencing in Different Ethnic Groups

Dihydropyrimidine dehydrogenase (DPYD) is an enzyme that regulates the rate-limiting step in pyrimidine metabolism, especially catabolism of fluorouracil, a chemotherapeutic agent for cancer. In order to determine the genetic distribution of DPYD, we directly sequenced 288 subjects from five ethnic groups (96 Koreans, 48 Japanese, 48 Han Chinese, 48 African Americans, and 48 European Americans). As a result, 56 polymorphisms were observed, including 6 core polymorphisms and 18 novel polymorphisms. Allele frequencies were nearly the same across the Asian populations, Korean, Han Chinese and Japanese, whereas several SNPs showed different genetic distributions between Asians and other ethnic populations (African American and European American). Additional in silico analysis was performed to predict the function of novel SNPs. One nonsynonymous SNP (+199381A > G, Asn151Asp) was predicted to change its polarity of amino acid (Asn, neutral to Asp, negative). These findings would be valuable for further research, including pharmacogenetic and drug responses studies.