基于HLA等位基因频率的全球人群亲缘关系初探

目的：探讨不同实验方法、不同统计方法的HLA配型数据在分析全球人群亲缘关系中的作用和效能,为运用HLA基因的多态性分析全球人群的遗传关系提供理论依据。方法：收集了全球6大洲10个地理分区中的110个人群HLA-A,-B和-DRB1座位的高分辨率配型数据,并对这些等位基因命名进行了归一化处理,用统一的统计方法重新统计了各人群的等位基因频率,用N-J法构建了全球人群的关系树,进而对全球人群间的亲缘关系进行了初步分析。结果：同一地理区域内的人群相互聚类,不同区域间的人群完全分离。关系树不仅能很好地分析局部地区相似人群的异同,也能有效地分析全球各区域人群间的亲缘关系。结论：HLA基因的多态性适合对全球人群的亲缘关系进行研究,也是一种高效的研究人类学的分子标记物。     

Phage display of environmental protein toxins and virulence factors reveals the prevalence,persistence, and genetics of antibody responses

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Personalized vaccines: the emerging field of vaccinomics

The next ‘golden age’ in vaccinology will be ushered in by the new science of vaccinomics. In turn, this will inform and allow the development of personalized vaccines, based on our increasing understanding of immune response phenotype: genotype information. Rapid advances in developing such data are already occurring for hepatitis B, influenza, measles, mumps, rubella, anthrax and smallpox vaccines. In addition, newly available data suggest that some vaccine-related adverse events may also be genetically determined and, therefore, predictable. This paper reviews the basis and logic of personalized vaccines, and describes recent advances in the field.     

Common variants in genes that mediate immunity and risk of multiple myeloma

Multiple myeloma (MM) is a B-cell malignancy characterized by aberrant immune function. Using genomic DNA extracted from 127 MM cases aged 21-84 years and 545 population-based controls, we examined the risk of MM associated with 82 common variants in 45 genes that mediate immunity among women of European American descent. Genotyping was determined using validated and optimized TaqMan assays. We estimated haplotype frequencies from unphased genotype data for 20 of these genes using the expectation-maximization progressive insertion algorithm. Compared with controls, MM risk was positively associated with homozygotes of single loci, IL4R (-28120T, rs2107356) and FCGR2A (-120G, rs1801274) (OR = 1.91, 95% CI 1.08-3.38 and 1.95, 95% CI 1.06-3.60, respectively). For genes in which linkage disequilibrium was observed between multiple loci, MM risk was positively associated with the haplotype block covering part of the LTA*TNF complex (LTA -82C/-90G *TNF -1036C/-487G/-417G, OR = 1.63, 95% CI 1.02-2.16) compared with the most frequently occurring haplotype observed among controls (LTA -82A/-90A *TNF -1036C/-487G/-417G). Our findings provide preliminary evidence that common genetic variants in specific immune-mediated pathways could influence the risk of MM.     

From the Cover: Distinctive properties of identical twins' TCR repertoires revealed by high-throughput sequencing

Adaptive immunity in humans is provided by hypervariable Ig-like molecules on the surface of B and T cells. The final set of these molecules in each organism is formed under the influence of two forces: individual genetic traits and the environment, which includes the diverse spectra of alien and self-antigens. Here we assess the impact of individual genetic factors on the formation of the adaptive immunity by analyzing the T-cell receptor (TCR) repertoires of three pairs of monozygous twins by next-generation sequencing. Surprisingly, we found that an overlap between the TCR repertoires of monozygous twins is similar to an overlap between the TCR repertoires of nonrelated individuals. However, the number of identical complementary determining region 3 sequences in two individuals is significantly increased for twin pairs in the fraction of highly abundant TCR molecules, which is enriched by the antigen-experienced T cells. We found that the initial recruitment of particular TCR V genes for recombination and subsequent selection in the thymus is strictly determined by individual genetic factors. J genes of TCRs are selected randomly for recombination; however, the subsequent selection in the thymus gives preference to some α but not β J segments. These findings provide a deeper insight into the mechanism of TCR repertoire generation.Adaptive immunity is provided by B and T cells bearing B-cell receptors (BCRs) and Ig-like T-cell receptors (TCRs), respectively. These hypervariable molecules are the key part of the adaptive immune system as they can potentially recognize any alien agent and drive specific immune responses. The α/β TCRs recognize short peptides in the complex with major histocompatibility complex (MHC) molecules and play the key role in the targeted immune response. The total diversity of TCR molecules in an individual human organism is initially formed via genomic recombination with subsequent positive and negative selection at several stages of maturation and activation. The maximal theoretical diversity of TCRβ chain’s amino acid sequences in humans is estimated between 5 × 10¹¹ (1) and 10¹⁴ (2), whereas the maximal number of α/β pairs reaches 10¹⁸ (3). This huge number of variants is probably never achieved: the whole TCRβ chain repertoire size in a single human organism is estimated at 1–5 × 10⁶ (1, 4–6), although this is only a lower bound estimate. Two driving forces shape the final face of individual TCR repertoire: the individual genetics and the complexity of environmental factors. The genes coding for proteins involved in VDJ recombination, antigen processing and presentation, and products of genes participating in the immune response signaling belong to the first type of the repertoire-forming factors. The spectrum of the organism’s self-peptides presented in the thymus also depends on the individual’s set of the MHC molecules. Moreover, this spectrum of peptides is determined by the amino acid sequences of the organism’s proteins, which thus can also be considered a genetic factor. Furthermore, TCRs arising to the same alien antigenic peptides are known to be MHC restricted (7). The environmental factors include the whole range of pathogens met by the individual including disease-causing bacteria and viruses, as well as vaccines, symbionts, etc. The genetic component can potentially have a major impact on the initial recombination and selection in the thymus forming the naïve TCR repertoire, whereas the subsequent interference with antigens provides the selective expansion of some TCRs and forms the final repertoire structure. However, the particular impact of genetic factors on TCR repertoire structure and diversity is unknown.All genes of monozygous (MZ) twins are identical (including those responsible for the TCR repertoire formation), and therefore, MZ twins are widely used in the studies where the genetic impact is evaluated. Several studies of TCR repertoires were performed mainly focusing on diseases concordant and discordant MZ twins and using complementarity determining region 3 (CDR3) spectra-typing and/or low depth sequencing (8–11). Some of these studies reported the common use of particular V genes and common clonotypes. In recent years, the high-throughput sequencing technologies paved the way to whole-repertoire studies of individual TCRs that led to new findings in the field of adaptive immunity (1, 5, 6, 12–22). In this study, for the first time to the best of our knowledge, we obtain and compare the α and β chain TCR repertoires of three pairs of MZ twins using next-generation sequencing (NGS).     

Immunotherapy for recurrent spontaneous abortions in a Chinese population

The efficacy of immunotherapy for the treatment of recurrent spontaneous abortions was tested in patients selected from the same ethnically homogeneous population of Chinese in Taiwan in whom the immunogenetics of gestational trophoblastic tumors and of recurrent spontaneous abortion had been studied. The patients, who included both primary and secondary aborters, were randomly assigned to three groups: those who were immunized with their own lymphocytes (controls) (49); those who were immunized with their husbands' lymphocytes (39); and those who were immunized with third party lymphocytes (11). The data were analyzed individually for the primary and secondary aborters and collectively for both groups combined. The number of babies born, the number of current pregnancies, and the number of recurrent abortions were not statistically significantly different between the control and the immunized groups, and a similar small number of congenital abnormalities (4-9%) occurred in both the control and immunized groups. The increase in the blocking effect for the mixed lymphocyte reaction was not related to the success of the postimmunization pregnancies. Thus, this study does not show any significant improvement in the rate of livebirths in women immunized with their husbands' lymphocytes or with third party lymphocytes compared to that in a placebo-controlled group of women.     

Beyond the HLA typing age: genetic polymorphisms predicting transplant outcome

Although histocompatibility testing and matching for histocompatibility leukocyte antigens (HLA) remains the "state of the art" for determining donor selection, non-HLA encoded genes such as those for minor histocompatibiity antigens also play an important role in determining haematopoietic stem cell transplantation (HSCT) outcome. Single nucleotide polymorphisms (SNPs) within the promoter regulatory regions of non-HLA encoded genes such as those for cytokines and cytokine receptors which regulate the production of such molecules may also play a role in determining the extent of post-transplant complications. Mannose binding lectin genes (MBL) and other genes such as those for myeloperoxidase (MPO) and Fcgamma receptor may aid in the control of infection post transplant. This review will summarise the latest research concerning this area of predicting HSCT outcome and indicate the potential clinical use of the results.