Associations between human leukocyte antigen class I variants and the Mycobacterium tuberculosis subtypes causing disease

BACKGROUND. The development of active tuberculosis disease has been shown to be multifactorial. Interactions between host and bacterial genotype may influence disease outcome, with some studies indicating the adaptation of M. tuberculosis strains to specific human populations. Here we investigate the role of the human leukocyte antigen (HLA) class I genes in this biological process. METHODS. Three hundred patients with tuberculosis from South Africa were typed for their HLA class I alleles by direct sequencing. Mycobacterium tuberculosis genotype classification was done by IS6110 restriction fragment length polymorphism genotyping and spoligotyping. RESULTS. We showed that Beijing strain occurred more frequently in individuals with multiple disease episodes (P < .001) with the HLA-B27 allele lowering the odds of having an additional episode (odds ratio, 0.21; P = .006). Associations were also identified for specific HLA types and disease caused by the Beijing, LAM, LCC, and Quebec strains. HLA types were also associated with disease caused by strains from the Euro-American or East Asian lineages, and the frequencies of these alleles in their sympatric human populations identified potential coevolutionary events between host and pathogen. CONCLUSIONS. This is the first report of the association of human HLA types and M. tuberculosis strain genotype, highlighting that both host and pathogen genetics need to be taken into consideration when studying tuberculosis disease development.Web of Scienc

ДИФФЕРЕНЦИРОВАННАЯ ХИРУРГИЧЕСКАЯ ТАКТИКА ПРИ ПОРАЖЕНИИ МОЧЕВОГО ПУЗЫРЯ У БОЛЬНЫХ МЕСТНО-РАСПРОСТРАНЕННЫМИ ЗЛОКАЧЕСТВЕННЫМИ НОВООБРАЗОВАНИЯМИ МАЛОГО ТАЗА

An analysis of surgical treatment of 154 patients with locally advanced and recurrent malignant tumors of the pelvic organs with secondary lesions of the bladder was performed. Described surgical technique used for resection and reconstructive stages of surgery. In 73.4 % of the volume of the intervention was complete or anterior pelvic exenteration. Morbidity after operations was 30.5 %, postoperative mortality — 7.8 %. The perspective of large-scale interventions to improve outcomes of patients with tumors of the pelvic localization is marked.Проведен анализ хирургического лечения 154 больных местно-распространенными и рецидивными злокачественными новообразованиями органов малого таза с вторичным поражением мочевого пузыря. Описан дифференцированный подход на резекционном и реконструктивном этапах хирургического вмешательства у данной категории пациентов. В 73,4 % случаев объемом вмешательства была полная или передняя эвисцерация малого таза, в 26,6 % удалось ограничиться комбинированным вмешательством с резекцией мочевого пузыря. Ранние послеоперационные осложнения развились у 30,5 % пациентов. Умерли 12 (7,8 %) больных. Отмечена перспективность масштабных вмешательств в улучшении результатов лечения больных с опухолями тазовой локализации

What has GWAS done for HLA and disease associations?

The major histocompatibility complex (MHC) is located in chromosome 6p21 and contains crucial regulators of immune response, including human leucocyte antigen (HLA) genes, alongside other genes with nonimmunological roles. More recently, a repertoire of noncoding RNA genes, including expressed pseudogenes, has also been identified. The MHC is the most gene dense and most polymorphic part of the human genome. The region exhibits haplotype-specific linkage disequilibrium patterns, contains the strongest cis- and trans-eQTLs/meQTLs in the genome and is known as a hot spot for disease associations. Another layer of complexity is provided to the region by the extreme structural variation and copy number variations. While the HLA-B gene has the highest number of alleles, the HLA-DR/DQ subregion is structurally most variable and shows the highest number of disease associations. Reliance on a single reference sequence has complicated the design, execution and analysis of GWAS for the MHC region and not infrequently, the MHC region has even been excluded from the analysis of GWAS data. Here, we contrast features of the MHC region with the rest of the genome and highlight its complexities, including its functional polymorphisms beyond those determined by single nucleotide polymorphisms or single amino acid residues. One of the several issues with customary GWAS analysis is that it does not address this additional layer of polymorphisms unique to the MHC region. We highlight alternative approaches that may assist with the analysis of GWAS data from the MHC region and unravel associations with all functional polymorphisms beyond single SNPs. We suggest that despite already showing the highest number of disease associations, the true extent of the involvement of the MHC region in disease genetics may not have been uncovered