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1.
Genomewide quantitative-trait locus (QTL) linkage analysis was performed using a continuous measure of relative hand skill (PegQ) in a sample of 195 reading-disabled sibling pairs from the United Kingdom. This was the first genomewide screen for any measure related to handedness. The mean PegQ in the sample was equivalent to that of normative data, and PegQ was not correlated with tests of reading ability (correlations between minus sign0.13 and 0.05). Relative hand skill could therefore be considered normal within the sample. A QTL on chromosome 2p11.2-12 yielded strong evidence for linkage to PegQ (empirical P=.00007), and another suggestive QTL on 17p11-q23 was also identified (empirical P=.002). The 2p11.2-12 locus was further analyzed in an independent sample of 143 reading-disabled sibling pairs, and this analysis yielded an empirical P=.13. Relative hand skill therefore is probably a complex multifactorial phenotype with a heterogeneous background, but nevertheless is amenable to QTL-based gene-mapping approaches.  相似文献   

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Asthma is a common respiratory disease that is characterized by variable airways obstruction caused by acute and chronic bronchial inflammation; associated phenotypes include bronchial hyperresponsiveness (BHR), elevated total serum immunoglobulin E (IgE) levels, and skin tests positive to common allergens. Binding of interleukin-13 (IL13) or interleukin-4 (IL4) to the IL4 receptor (IL4R) induces the initial response for Th2 lymphocyte polarization. Both IL13 and IL4 are produced by Th2 cells and are capable of inducing isotype class-switching of B-cells to produce IgE after allergen exposure. These cytokines also share a common receptor component, IL4R alpha. We have investigated five IL4RA single-nucleotide polymorphisms in a population of Dutch families ascertained through a proband with asthma. By considering the probands and their spouses as an unrelated sample, we observed significant associations of atopy and asthma-related phenotypes with several IL4RA polymorphisms, including S478P and total serum IgE levels (P=.0007). A significant gene-gene interaction between S478P in IL4RA and the -1111 promoter variation in IL13, previously shown to be associated with BHR (P=.003), was detected. Individuals with the risk genotype for both genes were at almost five times greater risk for the development of asthma compared to individuals with both non-risk genotypes (P=.0004). These data suggest that variations in IL4RA contribute to elevated total serum IgE levels, and interaction between IL4RA and IL13 markedly increases an individual's susceptibility to asthma.  相似文献   

4.
Reading disability (RD), or dyslexia, is a common heterogeneous syndrome with a large genetic component. Several studies have consistently found evidence for a quantitative-trait locus (QTL) within the 17 Mb (14.9 cM) that span D6S109 and D6S291 on chromosome 6p21.3-22. To characterize further linkage to the QTL, to define more accurately the location and the effect size, and to identify a peak of association, we performed Haseman-Elston and DeFries-Fulker linkage analyses, as well as transmission/disequilibrium, total-association, and variance-components analyses, on 11 quantitative reading and language phenotypes. One hundred four families with RD were genotyped with a new panel of 29 markers that spans 9 Mb of this region. Linkage results varied widely in degree of statistical significance for the different linkage tests, but multipoint analysis suggested a peak near D6S461. The average 6p QTL heritability for the 11 reading and language phenotypes was 0.27, with a maximum of 0.66 for orthographic choice. Consistent with the region of linkage described by these studies and others, there was a peak of transmission disequilibrium with a QTL centered at JA04 (chi2=9.48; empirical P=.0033; orthographic choice), and there was strong evidence for total association at this same marker (chi2=11.49; P=.0007; orthographic choice). Although the boundaries of the peak could not be precisely defined, the most likely location of the QTL is within a 4-Mb region surrounding JA04.  相似文献   

5.
Schizophrenia candidate regions 33-51 cM in length on chromosomes 5q, 6q, 10p, and 13q were investigated for genetic linkage with mapped markers with an average spacing of 5.64 cM. We studied 734 informative multiplex pedigrees (824 independent affected sibling pairs [ASPs], or 1,003 ASPs when all possible pairs are counted), which were collected in eight centers. Cases with diagnoses of schizophrenia or schizoaffective disorder (DSM-IIIR criteria) were considered affected (n=1,937). Data were analyzed with multipoint methods, including nonparametric linkage (NPL), ASP analysis using the possible-triangle method, and logistic-regression analysis of identity-by-descent (IBD) sharing in ASPs with sample as a covariate, in a test for intersample heterogeneity and for linkage with allowance for intersample heterogeneity. The data most supportive for linkage to schizophrenia were from chromosome 6q; logistic-regression analysis of linkage allowing for intersample heterogeneity produced an empirical P value <.0002 with, or P=.0004 without, inclusion of the sample that produced the first positive report in this region; the maximum NPL score in this region was 2.47 (P=.0046), the maximum LOD score (MLS) from ASP analysis was 3.10 (empirical P=.0036), and there was significant evidence for intersample heterogeneity (empirical P=.0038). More-modest support for linkage was observed for chromosome 10p, with logistic-regression analysis of linkage producing an empirical P=. 045 and with significant evidence for intersample heterogeneity (empirical P=.0096).  相似文献   

6.
This study aimed to identify potential immunological markers for predicting type 1 diabetes in patients with gestational diabetes mellitus (GDM) and any immunological impairment in their newborn. In 62 GDM patients and 74 women with normal glucose tolerance (NGT), and their babies, we assessed total lymphocytes, T lymphocyte subsets CD3 and CD8 expressing T cell receptor (TCR) alpha/beta or gamma/delta, CD16 and CD19, pancreatic autoantibodies and cytokines (IL-5, IL-2, soluble receptor IL-2). At delivery, umbilical cord blood samples were taken for lymphocyte subpopulations and cytokine measurements. GDM mothers had higher levels of total lymphocytes, CD8 expressing TCR gamma/delta, and lower levels of CD3 expressing TCR alpha/beta than NGT controls. Insulin-treated GDM mothers had lower CD4 and CD4/CD8 ratios, and higher CD8 and IL-5 than diet-treated GDM or controls. Five women were positive for pancreatic autoantibodies, with lower CD4 (p<0.01) and CD4/CD8 ratios (p<0.05), and higher CD8 (p<0.03) and CD19 than GDM and control mothers negative for autoantibodies. GDM newborn had higher CD8 gamma/delta and lower CD16 than NGT babies. There were no significant differences in TNF-alpha concentrations in the cord blood obtained from the GDM and NGT newborn. In conclusion, GDM women and their newborn have lymphocyte subset impairments, which are more important in patients positive for autoantibodies and/or treated with insulin.  相似文献   

7.
Immunophenotyping of different lymphocyte populations was carried out in parallel on 113 consecutively received specimens of human peripheral blood using 2 different data acquisition and analysis systems (EPICS C and 4Cyte-Acmecyte) on the same flow cytometer (EPICS C). The phenotypes analyzed were CD3+, CD4+, CD8+ CD56+ CD16+ CD3-, TCR-gamma delta+ CD8-, and TCR-gamma delta+ CD8+. Both HIV- and HIV+ specimens were used for this study, including some with CD4 levels as low as 2% of all lymphocytes. Despite differences in gating procedures and shapes of bitmap (rectilinear vs. "amorphous"), the 2 methods agreed to within 2% positive cells in 97% of the cases. Although some statistically significant biases in the methods were observed, these were small and not biologically important. We conclude that both methods of data acquisition and analysis, as employed by experienced operators on the EPICS C flow cytometer, gave essentially equivalent results for lymphocyte sub-populations in peripheral blood preparations.  相似文献   

8.
《Small Ruminant Research》2007,72(1-3):255-263
A genomic screen for quantitative trait loci (QTL) affecting conformation traits was performed by genotyping 288 Angora goats offspring from 8 half-sub families with 76 microsatellite markers. The following traits were recorded: weaning weight (WW, Kg); stature (S, cm); chest depth (CD, cm); shoulder width (SW, cm); rump length (RL, cm); rump width (RW, cm); head length (HL, cm); head width (HW, cm); shin circumference (SC, cm); chest circumference (CC, cm) and body length (BL, cm). Data were analyzed using the QTL Express program. A total of 5 QTL were detected in five chromosomes with chromosome wide significance level. For the 11 analysed traits the results were: evidence of two possible QTL for HL were found in chromosomes 1 and 4, a putative QTL for trait CD was found in chromosome 2, evidence for BL was found in chromosome 8 and a possible QTL was found for trait CC in chromosome 9. The results reported here show the existence of chromosomal regions in Angora goats involved in conformation traits and represent the first in depth search in some specific-genome sections in order to identify and characterize the genetic variability involved in these traits.  相似文献   

9.
The B10.RIII mouse strain (H-2(r)) develops chronic experimental autoimmune encephalomyelitis (EAE) upon immunization with the myelin basic protein 89-101 peptide. EAE was induced and studied in a backcross between B10.RIII and the EAE-resistant RIIIS/J strain (H-2(r)), and a complete genome scan with microsatellite markers was performed. Five loci were significantly linked to different traits and clinical subtypes of EAE on chromosomes 1, 5, 11, 15, and 16, three of the loci having sex specificity. The quantitative trait locus on chromosome 15 partly overlapped with the Eae2 locus, previously identified in crosses between the B10.RIII and RIIIS/J mouse strains. The loci on chromosomes 11 and 16 overlapped with Eae loci identified in other mouse crosses. By analyzing the backcross animals for lymphocyte phenotypes, the proportion of B and T cells in addition to the levels of CD4(+)CD8(-) and CD4(-)CD8(+) T cells and the CD4(+)/CD8(+) ratio in spleen were linked to different loci on chromosomes 1, 2, 3, 5, 6, 11, and 15. On chromosome 16, we found significant linkage to spleen cell proliferation. Several linkages overlapped with the quantitative trait loci for disease phenotypes. The identification of subphenotypes that are linked to the same loci as disease traits could be most useful in the search for candidate genes and biological pathways involved in the pathological process.  相似文献   

10.
T cells have a central role in the pathogenesis of autoimmune arthritis, and several abnormalities in T cell homeostasis have been described in rheumatoid arthritis (RA). We hypothesized that T cell phenotypes, including frequencies of different subsets of T regulatory (Treg) cells and in vitro functional responses could be genetically determined. Furthermore, we considered that the genetic contribution would be accounted for by one of the arthritis regulatory quantitative trait loci (QTL), thus providing novel clues to gene mode of action. T cells were isolated from thymus, peripheral blood, and spleen from DA (arthritis-susceptible) and ACI and F344 (arthritis-resistant) strains and from F344.DA(Cia1), DA.F344(Cia5a), and DA.F344(Cia5d) rats congenic for arthritis QTL. T cell subpopulations differed significantly between DA, F344, and ACI. DA rats had an increased frequency of CD4(+) cells, and a reduction in CD8(+) and CD4(+)CD45RC(|o) Treg cells, compared with F344. The differences in CD4/CD8 and CD4(+)CD45RC(|o) Treg cells were accounted for by Cia5a. DA rats also had a reduced frequency of CD8(+)CD45RC(|o) CD25(+) Treg cells compared with F344, and that difference was explained by Cia5d. DA rats also had a significantly lower frequency of CD4(+)CD25(+) and CD8(+)CD25(+) thymocytes, and of peripheral blood CD8(+)CD45RC(|o) Treg cells, compared with F344 rats, and that difference was accounted for by the MHC. This is the first identification of arthritis severity QTL regulating numbers of CD4(+)CD45RC(|o) (Cia5a) and CD8(+)CD45RC(|o) CD25(+) (Cia5d) Treg cells. The MHC effect on CD8(+) Treg cells and CD25(+) thymocytes raises a novel potential explanation for its association with arthritis.  相似文献   

11.
Natural polyamines, spermine, spermidine, and putrescine, play a pivotal role in the regulation of gene expression; therefore, the age-dependent decreases and the disease-dependent increases in polyamine synthesis suggest a possible contribution of polyamines to the age-related and disease-associated changes in cellular function. In this study, we examined the effects of polyamines on the cellular function and the expression of adhesion molecules on human PBMCs from healthy volunteers. Flow cytometry revealed that PBMCs cultured with spermine decreased mean fluorescent intensities (MFIs) of CD11a and CD18 in the lymphocyte light-scattered region, but not in the monocyte region. This suppression was observed in a dose- and time-dependent manner and found nonspecifically on all cell subsets we tested (CD3(+), CD4(+), CD8(+), CD19(+), CD45RA(+), CD45RO(+), CD4(+)CD45RA(+), CD4(+)CD45RO(+), CD8(+)CD45RA(+), CD8(+)CD45RO(+)). The decreases of CD11a and CD18 MFIs were accompanied by the decrease in adherent capacity of PBMCs to HUVECs. Spermine did not hinder cell activities or cell viability. Among 42 healthy volunteers (mean, 49.5 years old; from 26 to 69), blood spermine levels inversely correlated with the CD11a MFIs of cells in the lymphocyte region (r = -0.48; p = 0.001), but not with those in the monocyte region. The effects of spermidine seemed weaker than those of spermine, and blood spermidine levels had no correlation with CD11a MFIs of the lymphocyte region. Putrescine had no effect on the expressions of membrane molecules. Polyamines, especially spermine, decrease LFA-1 (CD11a/CD18) expression on human lymphocyte and adhesion capacity of PBMCs to HUVECs.  相似文献   

12.
Abnormal expansion or depletion of particular lymphocyte subsets is associated with clinical manifestations such as HIV progression to AIDS and autoimmune disease. We sought to identify genetic predictors of lymphocyte levels and reasoned that these may play a role in immune-related diseases. We tested 2.3 million variants for association with five lymphocyte subsets, measured in 2538 individuals from the general population, including CD4+ T cells, CD8+ T cells, CD56+ natural killer (NK) cells, and the derived measure CD4:CD8 ratio. We identified two regions of strong association. The first was located in the major histocompatibility complex (MHC), with multiple SNPs strongly associated with CD4:CD8 ratio (rs2524054, p = 2.1 × 10−28). The second region was centered within a cluster of genes from the Schlafen family and was associated with NK cell levels (rs1838149, p = 6.1 × 10−14). The MHC association with CD4:CD8 replicated convincingly (p = 1.4 × 10−9) in an independent panel of 988 individuals. Conditional analyses indicate that there are two major independent quantitative trait loci (QTL) in the MHC region that regulate CD4:CD8 ratio: one is located in the class I cluster and influences CD8 levels, whereas the second is located in the class II cluster and regulates CD4 levels. Jointly, both QTL explained 8% of the variance in CD4:CD8 ratio. The class I variants are also strongly associated with durable host control of HIV, and class II variants are associated with type-1 diabetes, suggesting that genetic variation at the MHC may predispose one to immune-related diseases partly through disregulation of T cell homeostasis.  相似文献   

13.
目的:建立山西省健康成人外周血淋巴细胞亚群的正常参考值范围,为机体免疫状态的分析和肿瘤患者的免疫评估提供理论依据。方法:选取山西省1 238例健康成人体检人群,采用流式细胞术测定外周血淋巴细胞亚群的绝对计数和相对计数。结果:确定了健康成人外周血淋巴细胞表达水平,并发现CD3~+T细胞相对计数和绝对计数、CD4~+T细胞相对计数、CD8~+T细胞相对计数和绝对计数、NK细胞相对计数和绝对计数、CD19细胞相对计数和绝对计数、CD4/CD8比值在不同年龄组间存在显著差异性(P0.05);不同性别之间CD8~+T细胞相对计数、CD4~+T细胞绝对计数和CD19细胞绝对计数无统计学意义,CD3~+T细胞、CD8~+T细胞、NK细胞相对计数和绝对计数、CD4~+T细胞、CD19细胞相对计数均存在显著差异(P0.05)。结论:初步建立了山西省健康成年人外周血淋巴细胞亚群参考值范围,为机体免疫功能的评价和肿瘤免疫治疗、诊断提供了参考依据。  相似文献   

14.
For 22 carcass traits, we identified 16 QTLs (based on data for pig resource population no. 214, including 180 F2 hybrids of 3 Yorkshire boars and 8 Meishan sows) and mapped them with the use of 39 microsatellite marker loci on chromosomes 4, 6, 7, 8 and 13. Five QTLs were highly significant (P < or = 0.01 at chromosome level): for skin weight (on chromosome 7 at SW1856 and on chromosome 13 at SW1495), skin percentage (on chromosome 7 between SW2155 and SW1856 and on chromosome 13 between SW1495 and SW520), and ratio of leg and butt to carcass (on chromosome 4 at SW1996). The remaining 11 QTLs were significant (P < or = 0.05 at chromosome level): for backfat thickness at shoulder, loin eye width, loin eye height, fat meat weight, lean meat weight, skin weight, bone weight, skin percentage, fat meat percentage, and ratio of lean meat to fat meat. The proportion of phenotypic variance explained by these QTLs ranged from 0.06% (QTL for loin eye width on chromosome 8 between SW1037 and SW1953) to 18.04% (QTL for ratio of lean meat to fat meat on chromosome 7 between SW252 and SW581). Seven of the QTLs reported here are novel.  相似文献   

15.
Autism is a syndrome characterized by deficits in language and social skills and by repetitive behaviors. We hypothesized that potential quantitative trait loci (QTLs) related to component autism endophenotypes might underlie putative or significant regions of autism linkage. We performed nonparametric multipoint linkage analyses, in 152 families from the Autism Genetic Resource Exchange, focusing on three traits derived from the Autism Diagnostic Interview: "age at first word," "age at first phrase," and a composite measure of "repetitive and stereotyped behavior." Families were genotyped for 335 markers, and multipoint sib pair linkage analyses were conducted. Using nonparametric multipoint linkage analysis, we found the strongest QTL evidence for age at first word on chromosome 7q (nonparametric test statistic [Z] 2.98; P=.001), and subsequent linkage analyses of additional markers and association analyses in the same region supported the initial result (Z=2.85, P=.002; chi(2)=18.84, df 8, P=.016). Moreover, the peak fine-mapping result for repetitive behavior (Z=2.48; P=.007) localized to a region overlapping this language QTL. The putative autism-susceptibility locus on chromosome 7 may be the result of separate QTLs for the language and repetitive or stereotyped behavior deficits that are associated with the disorder.  相似文献   

16.
This study was performed to build region-specific reference ranges of peripheral blood lymphocyte subsets for Chinese healthy adults from the young to the elderly and analyze the trends of changes in lymphocyte subsets for evaluating the impact of age on the values.151 healthy adults aged 19—86 were recruited based on the SENIEUR protocol.Three sets of reference ranges were finally built applicable for the healthy young(19—44 years),middle-aged(45—64 years) and elder adults(≥65).Comparisons in parameters am...  相似文献   

17.
The effects of physical fitness on leukocyte demargination and cellular adhesion molecule (CAM) responses to moderate exercise were examined. We assessed leukocyte subsets and CAM expression before, immediately after, and 10 min after a 20-min treadmill exercise at 65-70% peak oxygen consumption in fit vs. nonfit individuals. Physical fitness was determined by peak oxygen consumption during a treadmill test. Catecholamine levels were determined by radioenzymatic assay, and enumeration of cells and detection of CAM expression were assessed by flow cytometry. As expected, exercise led to significant increases in numbers of leukocyte subsets, regardless of fitness level (P < 0.01). Values returned to near resting levels 10 min after exercise. More importantly, physically fit individuals showed attenuated responses to the moderate-exercise challenge in numbers of CD3(+), CD4(+), CD8(+), memory (CD45RO(+)) CD4, and naive (CD45RA(+)62L(+)) CD4 and CD8 lymphocytes. Postexercise human leukocyte antigen-DR absent memory CD4(+) cell numbers were also lower in fit subjects. Increases in CD62L-expressing CD4(+) and CD8(+) lymphocytes and CD11a- expressing lymphocytes after exercise were also attenuated in fit individuals compared with nonfit individuals (P < 0.05). Catecholamine levels increased to a similar extent (P < 0.01) in both fitness groups. The findings suggest that physical fitness attenuates demargination of selected lymphocyte subsets in response to moderate exercise. Although the differences in plasma catecholamine responses were not significant between the groups, a possible mediating role of the sympathetic system remains to be further investigated. Being physically fit may offset exaggerated immune cell responses to stress.  相似文献   

18.
Selective DNA pooling was employed in a daughter design to screen all bovine autosomes for quantitative trait loci (QTL) affecting estimated breeding value for milk protein percentage (EBVP%). Milk pools prepared from high and low daughters of each of seven sires were genotyped for 138 dinucleotide microsatellites. Shadow-corrected estimates of sire allele frequencies were compared between high and low pools. An adjusted false discovery rate (FDR) method was employed to calculate experimentwise significance levels and empirical power. Significant associations with milk protein percentage were found for 61 of the markers (adjusted FDR = 0.10; estimated power, 0.68). The significant markers appear to be linked to 19--28 QTL. Mean allele substitution effects of the putative QTL averaged 0.016 (0.009--0.028) in units of the within-sire family standard deviation of EBVP% and summed to 0.460 EBVP%. Overall QTL heterozygosity was 0.40. The identified QTL appear to account for all of the variation in EBVP% in the population. Through use of selective DNA pooling, 4400 pool data points provided the statistical power of 600,000 individual data points.  相似文献   

19.
One approach to the identification of genetic loci that influence complex diseases is through the study of quantitative risk factors correlated with disease susceptibility. Factor XII (FXII) plasma levels, a related phenotype correlated with thrombosis, is such a risk factor. We conducted the first genomewide linkage screen to localize genes that influence variation in FXII levels. Two loci were detected: one on chromosome 5 and another on chromosome 10 (LOD scores 4.73 and 3.53, respectively). On chromosome 5, the peak LOD score occurred in the 5q33-5ter region, near the FXII gene. Addition of a 46C/T mutation in the FXII gene increased the multipoint LOD score to 10.21 (P=3.6 x 10(-12)). A bivariate linkage analysis of FXII activity and thrombosis further improved the linkage signal (LOD = 11.73) and provided strong evidence that this quantitative-trait locus (QTL) has a pleiotropic effect on the risk of thrombosis (P=.004). Linkage analysis conditional on 46C/T indicated that this mutation alone cannot explain the chromosome 5 signal, implying that other functional sites must exist. These results represent the first direct genetic evidence that a QTL in or near the FXII gene influences both FXII activity and susceptibility to thrombosis and suggest the presence of one or more still unknown functional variants in FXII.  相似文献   

20.
目的 通过对儿童传染性单核细胞增多症(infectious mononucleosis,IM)外周血淋巴细胞亚群的检测,探讨其细胞免疫功能变化与疾病的关系.方法 采用流式细胞仪对35例IM患儿外周血T、B和NK淋巴细胞亚群进行检测,30例健康儿童作为对照组;对患儿中的7例进行治疗2周后细胞亚群的测定以观察动态变化;对患儿进行外周血异型淋巴细胞计数.结果 IM患儿CD3、CD8 T淋巴细胞水平明显升高,CD19、NK、CD4和CD4/CD8值水平明显降低,分别与正常对照组比较差异均有统计学意义.7例IM患儿治疗2周后T细胞亚群的测定值与入院时比较差异有统计学意义,治疗前CD4、CD4/CD8值低于治疗后,治疗前CD8高于治疗后.IM患儿急性期CD8、CD4/CD8水平与患儿外周血异型淋巴细胞百分率(≤10%和>10%)的差异有统计学意义.结论 检测淋巴细胞亚群对评估IM患儿的细胞免疫状况,辅助诊断和指导治疗具有重要的临床价值.  相似文献   

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