Maxim B. Freidin

Leprosy and the adaptation of human toll-like receptor 1.

Leprosy is an infectious disease caused by the obligate intracellular pathogen Mycobacterium leprae and remains endemic in many parts of the world. Despite several major studies on susceptibility to leprosy, few genomic loci have been replicated independently. We have conducted an association analysis of more than 1,500 individuals from different case-control and family studies, and observed consistent associations between genetic variants in both TLR1 and the HLA-DRB1/DQA1 regions with susceptibility to leprosy (TLR1 I602S, case-control Pu200a=u200a5.7×10−8, ORu200a=u200a0.31, 95% CIu200a=u200a0.20–0.48, and HLA-DQA1 rs1071630, case-control Pu200a=u200a4.9×10−14, ORu200a=u200a0.43, 95% CIu200a=u200a0.35–0.54). The effect sizes of these associations suggest that TLR1 and HLA-DRB1/DQA1 are major susceptibility genes in susceptibility to leprosy. Further population differentiation analysis shows that the TLR1 locus is extremely differentiated. The protective dysfunctional 602S allele is rare in Africa but expands to become the dominant allele among individuals of European descent. This supports the hypothesis that this locus may be under selection from mycobacteria or other pathogens that are recognized by TLR1 and its co-receptors. These observations provide insight into the long standing host-pathogen relationship between human and mycobacteria and highlight the key role of the TLR pathway in infectious diseases.

Genome-wide association study of body mass index in 23 000 individuals with and without asthma

Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co‐morbidity between these conditions.

Meta-analysis identifies seven susceptibility loci involved in the atopic march

Eczema often precedes the development of asthma in a disease course called the ‘atopic march. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10−8) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10−9). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.

Circulating Tumor DNA Outperforms Circulating Tumor Cells for KRAS Mutation Detection in Thoracic Malignancies

BACKGROUNDnCirculating biomarkers, such as circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), are both considered for blood-based mutation detection, but limited studies have compared them in a head-to-head manner. Using KRAS (Kirsten rat sarcoma viral oncogene homolog), we performed such a comparison in patients who underwent surgery for suspected lung cancer.nnnMETHODSnWe recruited 93 patients, including 82 with lung cancer and 11 with benign diseases of the lung. Mutations were detected in codons 12 and 13 of KRAS in DNA extracted from CTCs, plasma, and matched tumors or lung tissues with custom-designed coamplification at lower denaturation temperature (COLD)-PCR assays, high-resolution melt analysis (HRM), and commercial assays (Roche Cobas(®) KRAS mutation test and Qiagen Therascreen(®) pyrosequencing KRAS kit).nnnRESULTSnWith the Cobas mutation test, we identified KRAS mutations in 21.3% of tumors. Mutation analysis in matched CTC DNA and ctDNA samples by COLD-PCR/HRM assay revealed mutations in 30.5% (ctDNA) and 23.2% (CTC DNA) of patients with lung cancer. Combined results of different tests revealed KRAS-positive cases for 28% of tumors. The diagnostic sensitivity and specificity of KRAS mutation detection in tumors achieved with ctDNA was 0.96 (95% CI 0.81-1.00) and 0.95 (0.85-0.99), respectively. The diagnostic test performance was lower for CTC DNA, at 0.52 (0.34-0.73) and 0.88 (0.79-0.95).nnnCONCLUSIONSnOur results support ctDNA as a preferential specimen type for mutation screening in thoracic malignancies vs CTC DNA, achieving greater mutation detection than either CTCs or limited amounts of tumor tissue alone.

BAI3, CDX2 and VIL1: a panel of three antibodies to distinguish small cell from large cell neuroendocrine lung carcinomas.

Discriminating small‐cell lung carcinoma (SCLC) from large‐cell neuroendocrine carcinoma (LCNEC) rests on morphological criteria, and reproducibility has been shown to be poor. We aimed to identify immunohistochemical markers to assist this diagnosis.

An assessment of diagnostic performance of a filter-based antibody-independent peripheral blood circulating tumour cell capture paired with cytomorphologic criteria for the diagnosis of cancer

OBJECTIVESnCirculating tumour cells (CTCs) are reported to be predictive for prognosis and response to treatment in advanced lung cancer. However, the clinical utility of the CTCs detection remains unknown for early stage lung cancer as the number of CTCs is reported as low, providing challenges in identification. We have evaluated diagnostic performance of filtration-based technology using cytomorphologic criteria in patients undergoing surgery for lung cancer.nnnMATERIAL AND METHODSnWe processed blood from 76 patients undergoing surgery for known or suspected lung cancer using ScreenCell(®) Cyto filter devices. Captured cells were stained using haematoxylin and eosin and independently assessed by two pathologists for the presence of atypical cells suspicious for cancer. Diagnostic performance was evaluated against pathologist reported diagnoses of cancer from surgically obtained specimens.nnnRESULTSnCancer was diagnosed in 57 patients (77.0%), including 32 with primary lung cancer (56.1%). The proportion of patients with early stage primary lung cancer in which CTCs were identified was 18 and 21 (56.3% and 65.6%, respectively) as reported by two pathologists. The agreement between the pathologists was 77.0% corresponding to a kappa-statistic of 53.7% indicating moderate agreement. No significant differences were found for the percentage of CTCs for primary and metastatic cancer as well as for cancer stages. On sensitivity weighted analysis, a sensitivity and specificity were 71.9% (95% CI 60.5-83.0) and 52.9% (95% CI 31.1-77.0), respectively. On specificity weighted analysis, a sensitivity and specificity were 50.9% (95% CI 39.3-64.4) and 82.4% (60.4-96.2), respectively.nnnCONCLUSIONnThe performance of the tested filter-based antibody-independent technology to capture CTCs using standard cytomorphologic criteria provides the potential of a diagnostic blood test for lung cancer.

The C718T polymorphism in the 3′-untranslated region of glutathione peroxidase-4 gene is a predictor of cerebral stroke in patients with essential hypertension

In the present study we have investigated the association of three single nucleotide polymorphisms in glutathione peroxidase (GPx) genes GPX1 rs1050450 (P198L), GPX3 rs2070593 (G930A) and GPX4 rs713041 (T718C) with the risk of cerebral stroke (CS) in patients with essential hypertension (EH). A total of 667 unrelated EH patients of Russian origin, including 306 hypertensives (the EH–CS group) who suffered from CS and 361 people (the EH–CS group) who did not have cerebrovascular accidents, were enrolled in the study. The variant allele 718C of the GPX4 gene was found to be significantly associated with an increased risk of CS in hypertensive patients (odds ratio (OR) 1.53, 95% confidence interval (CI) 1.23–1.90, Padj=0.0003). The prevalence of the 718TC and 718CC genotypes of the GPX4 gene was higher in the EH–CS group than the EH-alone group (OR=2.12, 95%CI 1.42–3.16, Padj=0.0018). The association of the variant GPX4 genotypes with the increased risk of CS in hypertensives remained statistically significant after adjusting for confounding variables such as sex, body mass index (BMI), blood pressure and antihypertensive medication use (OR=2.18, 95%CI 1.46–3.27, P=0.0015). Multiple logistic regression analysis did not reveal any interaction between various combinations of GPX1, GPX3 and GPX4 genotypes regarding the risk of CS in patients with EH. The study demonstrated for the first time that the C718T polymorphism in the 3′-untranslated region of the GPX4 gene could be considered as a genetic marker of susceptibility to CS in patients with EH.

Association between the 1188 A/C polymorphism in the human IL12B gene and Th1-mediated infectious diseases

gene andtuberculosis and salmonellosis in Russians. Both case-control and family-based association studies data suggestthat this gene variant is a risk factor of common suscepti-bility to infection due to intracellular bacteria.Interleukin-12 (IL-12) is the key cytokine of Th1-mediated immunity in humans. It is secreted by antigen-presenting dendritic cells and phagocytes and activatesCD4+ T cells to differentiate to Th1, IFN- γ-secreting cells,associated with cellular immune responses. IL-12 plays acrucial role in immunity to intracellular bacteria, such as

A Comparison of Genome-Wide DNA Methylation Patterns between Different Vascular Tissues from Patients with Coronary Heart Disease

Epigenetic mechanisms of gene regulation in context of cardiovascular diseases are of considerable interest. So far, our current knowledge of the DNA methylation profiles for atherosclerosis affected and healthy human vascular tissues is still limited. Using the Illumina Infinium Human Methylation27 BeadChip, we performed a genome-wide analysis of DNA methylation in right coronary artery in the area of advanced atherosclerotic plaques, atherosclerotic-resistant internal mammary arteries, and great saphenous veins obtained from same patients with coronary heart disease. The resulting DNA methylation patterns were markedly different between all the vascular tissues. The genes hypomethylated in athero-prone arteries to compare with atherosclerotic-resistant arteries were predominately involved in regulation of inflammation and immune processes, as well as development. The great saphenous veins exhibited an increase of the DNA methylation age in comparison to the internal mammary arteries. Gene ontology analysis for genes harboring hypermethylated CpG-sites in veins revealed the enrichment for biological processes associated with the development. Four CpG-sites located within the MIR10B gene sequence and about 1 kb upstream of the HOXD4 gene were also confirmed as hypomethylated in the independent dataset of the right coronary arteries in the area of advanced atherosclerotic plaques in comparison with the other vascular tissues. The DNA methylation differences observed in vascular tissues of patients with coronary heart disease can provide new insights into the mechanisms underlying the development of pathology and explanation for the difference in graft patency after coronary artery bypass grafting surgery.

Opisthorchiasis: an overlooked danger

1 Siberian State Medical University, Tomsk, Russian Federation, 2 Tropical Disease Research Laboratory, Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand, 3 Laboratory of Molecular Mechanisms of Pathological Processes, Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation, 4 Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland, 5 University of Basel, Basel, Switzerland, 6 Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland, 7 Department of Microbiology, Immunology and Tropical Medicine, and Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, GeorgeWashington University, Washington, D.C., United States of America, 8 Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands, 9 Department of Chemistry, Tomsk State University, Tomsk, Russian Federation, 10 Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany, 11 Academic Division of Thoracic Surgery, Royal Brompton Hospital, London, United Kingdom, 12 Population Genetics Laboratory, Research Institute for Medical Genetics, Siberian Branch of Russian Academy of Medical Sciences, Tomsk, Russian Federation, 13 Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russian Federation, 14 ReMedys Foundation, Geneva, Switzerland, 15 External R&D Innovation, Pfizer Russia, Moscow, Russian Federation, 16 Department of Parasitology and Leiden Parasite Immunology Group, Leiden University Medical Center, Leiden, the Netherlands