Complex Linkage Disequilibrium Effects in HLA-DPB1 Expression and Molecular Mismatch Analyses of Transplantation Outcomes.

BACKGROUND: HLA molecular mismatch (MM) is a risk factor for de novo donor-specific antibody (dnDSA) development in solid organ transplantation. HLA expression differences have also been associated with adverse outcomes in hematopoietic cell transplantation. We sought to study both MM and expression in assessing dnDSA risk. METHODS: One hundred three HLA-DP-mismatched solid organ transplantation pairs were retrospectively analyzed. MM was computed using amino acids (aa), eplets, and, supplementarily, Grantham/Epstein scores. DPB1 alleles were classified as rs9277534-A (low-expression) or rs9277534-G (high-expression) linked. To determine the associations between risk factors and dnDSA, logistic regression, linkage disequilibrium (LD), and population-based analyses were performed. RESULTS: A high-risk AA:GX (recipient:donor) expression combination (X = A or G) demonstrated strong association with HLA-DP dnDSA (P = 0.001). MM was also associated with HLA-DP dnDSA when evaluated by itself (eplet P = 0.007, aa P = 0.003, Grantham P = 0.005, Epstein P = 0.004). When attempting to determine the relative individual effects of the risk factors in multivariable analysis, only AA:GX expression status retained a strong association (relative risk = 18.6, P = 0.007 with eplet; relative risk = 15.8, P = 0.02 with aa), while MM was no longer significant (eplet P = 0.56, aa P = 0.51). Importantly, these risk factors are correlated, due to LD between the expression-tagging single-nucleotide polymorphism and polymorphisms along HLA-DPB1. CONCLUSIONS: The MM and expression risk factors each appear to be strong predictors of HLA-DP dnDSA and to possess clinical utility; however, these two risk factors are closely correlated. These metrics may represent distinct ways of characterizing a common overlapping dnDSA risk profile, but they are not independent. Further, we demonstrate the importance and detailed implications of LD effects in dnDSA risk assessment and possibly transplantation overall.

Regulatory noncoding RNAs and the major histocompatibility complex.

The Major Histocompatibility Complex (MHC) is a 4 Mbp genomic region located on the short arm of chromosome 6. The MHC region contains many key immune-related genes such as Human Leukocyte Antigens (HLAs). There has been a growing realization that, apart from MHC encoded proteins, RNAs derived from noncoding regions of the MHC-specifically microRNAs (miRNAs) and long noncoding RNAs (lncRNAs)-play a significant role in cellular regulation. Furthermore, regulatory noncoding RNAs (ncRNAs) derived from other parts of the genome fine-tune the expression of many immune-related MHC proteins. Although the field of ncRNAs of the MHC is a research area that is still in its infancy, ncRNA regulation of MHC genes has already been shown to be vital for immune function, healthy pregnancy and cellular homeostasis. Dysregulation of this intricate network of ncRNAs can lead to serious perturbations in homeostasis and subsequent disease.

Computational assessment of miRNA binding to low and high expression HLA-DPB1 allelic sequences.

Cell surface expression of HLA-DP is allele specific. SNP rs9277534 (A/G), located in the 3'UTR of the DPB1 gene, has been associated with either low (A) or high (G) expression of DP on the cell surface. Considering the role of miRNAs in the regulation of gene expression, we computationally identified the miRNAs of two BLCLs, PGF and COX, predicted to interact with their corresponding DPB1 transcripts, DPB1 * 04:01:01:01-low expression and DPB1 * 03:01:01:01-high expression. The identified target sequences are located primarily in intron 2 and the 3'UTR. We hypothesize that gene expression may be influenced first by nuclear pre-mRNA events involving intronic regions, followed by the usual 3'UTR-associated events in the cytoplasm. The low DP expression allele was found to interact in silico with a larger number of miRNAs than the high expression allele. This pattern holds when examining either the entire transcript unit or simply the polymorphic sites that differentiate the alleles. Interestingly, the rs9277534 A/G polymorphism appears to be in linkage disequilibrium with polymorphisms targeted by the identified miRNAs. The multiplicity of sites targeted by different miRNAs suggests that the expression of DPB1 may be a dynamic process, influenced by different miRNAs under different states of the cell.

Human Leukocyte Antigen and Disease Associations: A Broader Perspective.

HLA molecules play a significant role in immunity and disease susceptibility. GWAS studies underline the critical role of the MHC region in a wide range of diseases and remind us that the HLA genes, included within the MHC, interact extensively with other genomic regions which influence their functions. Recently, MHC/HLA genomic sequences encoding for miRNAs have been reported to interact with targets within and outside the MHC, influencing the expression of many transcripts. High throughput sequencing technologies provide unique opportunities for complete HLA/MHC sequence characterization, helping to elucidate their interactive relationships in a plethora of physiological and disease processes.

Computer-aided diagnosis of hyperacute stroke with thrombolysis decision support using a contralateral comparative method of CT image analysis.

New and improved techniques have been continuously introduced into CT and MR imaging modalities for the diagnosis and therapy planning of acute stroke. Nevertheless, non-contrast CT (NCCT) is almost always used by every institution as the front line diagnostic imaging modality due to its high affordability and availability. Consequently, the potential reward of extracting as much clinical information as possible from NCCT images can be very great. Intravenous tissue plasminogen activator (tPA) has become the gold standard for treating acute ischemic stroke because it is the only acute stroke intervention approved by the FDA. ASPECTS scoring based on NCCT images has been shown to be a reliable scoring method that helps physicians to make sound decisions regarding tPA administration. In order to further reduce inter-observer variation, we have developed the first end-to-end automatic ASPECTS scoring system using a novel method of contralateral comparison. Due to the self-adaptive nature of the method, our system is robust and has good generalizability. ROC analysis based on evaluation of 103 subjects who presented to the stroke center of Chang Gung Memorial Hospital with symptoms of acute stroke has shown that our system's dichromatic classification of patients into thrombolysis indicated or thrombolysis contraindicated groups has achieved a high accuracy rate with AUC equal to 90.2 %. The average processing time for a single case is 170 s. In conclusion, our system has the potential of enhancing quality of care and providing clinical support in the setting of a busy stroke or emergency center.

The impact of globalisation on teleradiology practice.

Some advocates of globalisation argue that a free market with little regulation is the best approach for achieving cost-effective healthcare. Healthcare, however, is different from other business activities in that it is typically less profit-driven; instead, it often involves the goal of providing equitable care to the underprivileged. Traditionally, the government has subsidised the expenses of delivering affordable healthcare to underserved communities. Because of the many recent advances in telecommunications technology, telemedicine has gained increasing attention. Teleradiology, in particular, is by far the maturest of all telemedicine disciplines and, thus, it may serve as a pivotal indicator of whether telemedicine on a global scale is feasible or not. In this paper, a prediction of the future landscape of globalised teleradiology operations is attempted based on the extrapolation of the historical trends in teleradiology practice as well as the growing pressure on federal and local governments to reduce their regulatory power under the General Agreement on Trade in Services (GATS).