Modeling Haplotype-Haplotype Interactions in Case-Control Genetic Association Studies

Haplotype analysis has been increasingly used to study the genetic basis of human diseases, but models for characterizing genetic interactions between haplotypes from different chromosomal regions have not been well developed in the current literature. In this article, we describe a statistical model for testing haplotype-haplotype interactions for human diseases with a case-control genetic association design. The model is formulated on a contingency table in which cases and controls are typed for the same set of molecular markers. By integrating well-established quantitative genetic principles, the model is equipped with a capacity to characterize physiologically meaningful epistasis arising from interactions between haplotypes from different chromosomal regions. The model allows the partition of epistasis into different components due to additive × additive, additive × dominance, dominance × additive, and dominance × dominance interactions. We derive the EM algorithm to estimate and test the effects of each of these components on differences in the pattern of genetic variation between cases and controls and, therefore, examine their role in the pathogenesis of human diseases. The method was further extended to investigate gene-environment interactions expressed at the haplotype level. The statistical properties of the models were investigated through simulation studies and its usefulness and utilization validated by analyzing the genetic association of sarcoidosis from a human genetics project

Hit-hard and early versus step-up treatment in severe sarcoidosis

Purpose of reviewThe treatment of sarcoidosis remains uncertain, despite 70 years of study. The conventional approach is to initiate corticosteroids in individuals who require treatment. The position of more aggressive regimes is unknown.Recent findingsRecent recognition that many patients will require prolonged therapy, and the observation that corticosteroids lead to overt and insidious toxicities, have led to suggestions that steroid-sparing medications be used earlier in the management of sarcoidosis. Individuals with poor prognostic features, designated as 'high-risk' sarcoidosis may, especially benefit from a broader palette of therapeutic options in the initial treatment regimen. An even more aggressive approach, known as 'top-down' or 'hit-hard and early' therapy has emerged in the fields of gastroenterology and rheumatology in the past 15 years, on the premise that highly effective early control of inflammation leads to better outcomes. These regimens typically involve early initiation of biologic therapies.SummaryFor certain subpopulations of sarcoidosis patients, 'top-down' therapy could be helpful. Severe pulmonary sarcoidosis, neurosarcoidosis, cardiac sarcoidosis and multiorgan sarcoidosis are phenotypes that may be most relevant for revised therapeutic algorithms. Precision medicine approaches and randomized trials will be necessary to confirm a role for top-down therapy in the routine management of sarcoidosis

Peroxisome Proliferator-Activated Receptor-γ Regulates the Expression of Alveolar Macrophage Macrophage Colony- Stimulating Factor

Macrophage CSF (M-CSF) regulates monocyte differentiation, activation, and foam cell formation. We have observed that it is elevated in human pulmonary alveolar proteinosis (PAP) and in the GMCSF knockout mouse, a murine model for PAP. A potential regulator of M-CSF, peroxisome proliferator-activated receptor-γ (PPARγ), is severely deficient in both human PAP and the GM-CSF knockout mouse. To investigate the role of PPARγ in alveolar macrophage homeostasis, we generated myeloidspecific PPARγ knockout mice using the Lys-Cre method to knock out the floxed PPARγ gene. Similar to the GM-CSF-deficient mouse, absence of alveolar macrophage PPARγ resulted in development of lung pathology resembling PAP in 16-wk-old mice, along with excess M-CSF gene expression and secretion. In ex vivo wild-type alveolar macrophages, we observed that M-CSF itself is capable of inducing foam cell formation similar to that seen in PAP. Overexpression of PPARγ prevented LPS-stimulated M-CSF production in RAW 264.7 cells, an effect that was abrogated by a specific PPARγ antagonist, GW9662. Use of proteasome inhibitor, MG-132 or a PPARγ agonist, pioglitazone, prevented LPS-mediated M-CSF induction. Using chromatin immunoprecipitation, we found that PPARγ is capable of regulating M-CSF through transrepression of NF-κB binding at the promoter. Gel-shift assay experiments confirmed that pioglitazone is capable of blocking NF-κB binding. Taken together, these data suggest that M-CSF is an important mediator of alveolar macrophage homeostasis, and that transcriptional control of M-CSF production is regulated by NF-κB and PPARγ

Hepatitis B assays in serum, plasma and whole blood on filter paper

BACKGROUND: Screening and determining the immune status of individuals for hepatitis B is usually done by detecting hepatitis B surface antigen (HBsAg) and hepatitis B surface antigen-specific antibodies (HBsAb). In some countries with the highest viral burden, performing these assays is currently impractical. This paper explores the use of filter paper as a blood specimen transport medium. METHODS: Samples, chosen from routine clinical laboratory pool, were applied and dried onto filter paper. Eluates, from the paper samples, were analyzed as routine clinical specimens on ADVIA Centaur 5634® immunoassay analyzers using the standard HBsAg and HBsAb kits. Dried blood samples were subjected to a range of environmental conditions in order to assess stability. RESULTS: After drying and elution the assays showed linearity and precision comparable to clinical assays performed on fresh serum. Elutions at various times during a 149 day incubation period showed very little variability in the Index numbers. All analytes were temperature stable except for a decrease in the HBsAg signal at 42°C. CONCLUSIONS: Filter paper is an acceptable storage and transport medium for serum to be used in the detection of hepatitis B markers if atmospheric variability can be controlled. HBsAg, HBsAb and HBcAb are all stable for at least five months under storage conditions below room temperature. Drying specimens, particularly serum, on filter paper at remote locations, offers a reasonable solution to the problem of hepatitis surveillance in underdeveloped regions, although some attempt at temperature control might be desirable

The long-term Illinois rivers fish population monitoring program 2014

This report presents a summary of those data collected during segment 26(2014-15) of the Long-term Illinois Rivers Fish Population Monitoring Program(LTEF), an annual survey executed by members of the Illinois Natural History Survey with funds administered by the U.S. Fish and Wildlife Service and the Illinois Department of Natural Resources. Sampling for the LTEF program was conducted on: six reaches of the Illinois River Waterway, six segments or pools of the Mississippi River, and navigable portions of the Iroquois and Kankakee Rives. In all segments of the LTEF program, all fish species collected were accurately identified, tallied, measured, and weighed. The catch rates of sportfish species were calculated as the number of individuals collected per hour (CPUEN± standard error). Structural indices [Proportional Size Distribution (PSD) and Relative Weight (Wr)] were also calculated for species of interest to regional managers. Catch rates and species richness varied greatly among all sampling locations and sampling periods. Emerald Shiners and Gizzard Shad comprised the majority of the individuals caught, and Silver Carp and Common Carp accounted for the greatest proportion of the biomass collected in most sampling areas of the survey. The analysis of CPUEN and PSD trends in sportfish populations sampled by the program may indicate inter-annual recruitment patterns in sportfish populations around the state. Both Shovelnose Sturgeon and Blue Catfish were the two species most commonly encountered in the gill net surveys.IDNR Division of Fisheries Project F-101-R, Segment 26unpublishednot peer reviewe

A Targeted Genetic Association Study of Epithelial Ovarian Cancer Susceptibility

BACKGROUND: Genome-wide association studies have identified several common susceptibility alleles for epithelial ovarian cancer (EOC). To further understand EOC susceptibility, we examined previously ungenotyped candidate variants, including uncommon variants and those residing within known susceptibility loci. RESULTS: At nine of eleven previously published EOC susceptibility regions (2q31, 3q25, 5p15, 8q21, 8q24, 10p12, 17q12, 17q21.31, and 19p13), novel variants were identified that were more strongly associated with risk than previously reported variants. Beyond known susceptibility regions, no variants were found to be associated with EOC risk at genome-wide statistical significance (p \u3c5x10(-8)), nor were any significant after Bonferroni correction for 17,000 variants (p\u3c 3x10-6). METHODS: A customized genotyping array was used to assess over 17,000 variants in coding, non-coding, regulatory, and known susceptibility regions in 4,973 EOC cases and 5,640 controls from 13 independent studies. Susceptibility for EOC overall and for select histotypes was evaluated using logistic regression adjusted for age, study site, and population substructure. CONCLUSION: Given the novel variants identified within the 2q31, 3q25, 5p15, 8q21, 8q24, 10p12, 17q12, 17q21.31, and 19p13 regions, larger follow-up genotyping studies, using imputation where necessary, are needed for fine-mapping and confirmation of low frequency variants that fall below statistical significance

WASOG statement on the diagnosis and management of sarcoidosis-associated pulmonary hypertension

Sarcoidosis-associated pulmonary hypertension (SAPH) is an important complication of advanced sarcoidosis. Over the past few years, there have been several studies dealing with screening, diagnosis and treatment of SAPH. This includes the results of two large SAPH-specific registries. A task force was established by the World Association of Sarcoidosis and Other Granulomatous disease (WASOG) to summarise the current level of knowledge in the area and provide guidance for the management of patients. A group of sarcoidosis and pulmonary hypertension experts participated in this task force. The committee developed a consensus regarding initial screening including who should undergo more specific testing with echocardiogram. Based on the results, the committee agreed upon who should undergo right-heart catheterisation and how to interpret the results. The committee felt there was no specific phenotype of a SAPH patient in whom pulmonary hypertension-specific therapy could be definitively recommended. They recommended that treatment decisions be made jointly with a sarcoidosis and pulmonary hypertension expert. The committee recognised that there were significant defects in the current knowledge regarding SAPH, but felt the statement would be useful in directing future studies

Double-blind randomized proof-of-concept trial of canakinumab in patients with COVID-19 associated cardiac injury and heightened inflammation

AIMS: In coronavirus disease 2019 (COVID-19), myocardial injury is associated with systemic inflammation and higher mortality. Our aim was to perform a proof of concept trial with canakinumab, a monoclonal antibody to interleukin-1β, in patients with COVID-19, myocardial injury, and heightened inflammation. METHODS AND RESULTS: This trial required hospitalization due to COVID-19, elevated troponin, and a C-reactive protein concentration more than 50 mg/L. The primary endpoint was time to clinical improvement at Day 14, defined as either an improvement of two points on a seven-category ordinal scale or discharge from the hospital. The secondary endpoint was mortality at Day 28. Forty-five patients were randomly assigned to canakinumab 600 mg ( CONCLUSION: There was no difference in time to clinical improvement at Day 14 in patients treated with canakinumab, and no safety concerns were identified. Future studies could focus on high dose canakinumab in the treatment arm and assess efficacy outcomes at Day 28

The DIAMORFOSIS (DIAgnosis and Management Of lung canceR and FibrOSIS) survey. International survey and call for consensus

Background: Currently there is major lack of agreement on the diagnostic and therapeutic management of patients with idiopathic pulmonary fibrosis (IPF) and lung cancer. Our aim was to identify variations in diagnostic and management strategies across different institutions and provide rationale for a consensus statement on this issue. Methods: This was a joint-survey by European Respiratory Society (ERS) Assemblies 8, 11 and 12. The survey consisted of 25 questions. Results: Four hundred and ninety-four (n=494) physicians from 68 different countries and five continents responded to the survey. Ninety-four per cent of participants were pulmonologists, 1.8% thoracic surgeons and 1.9% oncologists; 97.7% were involved in multidisciplinary team approaches on diagnosis and management. Regular low-dose high-resolution computed tomography (HRCT) scan was used by 49.5% of the respondents to screen for lung cancer in IPF. Positron emission tomography (PET) scan and endobronchial ultrasound (EBUS) is performed by 60% and 88% to diagnose nodular lesions with mediastinal lymphadenopathy in patients with advanced and mild IPF, respectively. Eighty-three per cent of respondents continue anti-fibrotics following lung cancer diagnosis; safety precautions during surgical interventions including low tidal volume are applied by 67%. Stereotactic radiotherapy is used to treat patients with advanced IPF (diffusing capacity of the lung for carbon monoxide (D LCO) <35%) and otherwise operable nonsmall cell lung cancer (NSCLC) by 54% of respondents and doublet platinum regimens and immunotherapy for metastatic disease by 25% and 31.9%, respectively. Almost all participants (93%) replied that a consensus statement for the management of these patients is highly warranted. Conclusion: The diagnosis and management of IPF-lung cancer (LC) is heterogeneous with most respondents calling for a consensus statement