Insights into the molecular underpinning of type 2 diabetes complications.

Type 2 diabetes (T2D) complications pose a significant global health challenge. Omics technologies have been employed to investigate these complications and identify the biological pathways involved. In this review, we focus on four major T2D complications: diabetic kidney disease, diabetic retinopathy, diabetic neuropathy, and cardiovascular complications.

Disentangling the consequences of type 2 diabetes on targeted metabolite profiles using causal inference and interaction QTL analyses.

Circulating metabolite levels have been associated with type 2 diabetes (T2D), but the extent to which T2D affects metabolite levels and their genetic regulation remains to be elucidated. In this study, we investigate the interplay between genetics, metabolomics, and T2D risk in the UK Biobank dataset using the Nightingale panel composed of 249 metabolites, 92% of which correspond to lipids (HDL, IDL, LDL, VLDL) and lipoproteins. By integrating these data with large-scale T2D GWAS from the DIAMANTE meta-analysis through Mendelian randomization analyses, we find 79 metabolites with a causal association to T2D, all spanning lipid-related classes except for Glucose and Tyrosine.

Multi-omics characterization of type 2 diabetes associated genetic variation.

Discerning the mechanisms driving type 2 diabetes (T2D) pathophysiology from genome-wide association studies (GWAS) remains a challenge. To this end, we integrated omics information from 16 multi-tissue and multi-ancestry expression, protein, and metabolite quantitative trait loci (QTL) studies and 46 multi-ancestry GWAS for T2D-related traits with the largest, most ancestrally diverse T2D GWAS to date. Of the 1,289 T2D GWAS index variants, 716 (56%) demonstrated strong evidence of colocalization with a molecular or T2D-related trait, implicating 657 -effector genes, 1,691 distal-effector genes, 731 metabolites, and 43 T2D-related traits.

Bridging the diversity gap: Analytical and study design considerations for improving the accuracy of trans-ancestry genetic prediction.

Genetic prediction of common complex disease risk is an essential component of precision medicine. Currently, genome-wide association studies (GWASs) are mostly composed of European-ancestry samples and resulting polygenic scores (PGSs) have been shown to poorly transfer to other ancestries partly due to heterogeneity of allelic effects between populations. Fixed-effects (FETA) and random-effects (RETA) trans-ancestry meta-analyses do not model such ancestry-related heterogeneity, while ancestry-specific (AS) scores may suffer from low power due to low sample sizes.

Unravelling the genetic architecture of human complex traits through whole genome sequencing.

Whole genome sequencing has enabled new insights into the genetic architecture of complex traits, especially through access to low-frequency and rare variation. This highlights the key contributions from this technology and discusses considerations for its use and future perspectives.

Ravages: An R package for the simulation and analysis of rare variants in multicategory phenotypes.

Current software packages for the analysis and the simulations of rare variants are only available for binary and continuous traits. Ravages provides solutions in a single R package to perform rare variant association tests for multicategory, binary and continuous phenotypes, to simulate datasets under different scenarios and to compute statistical power. Association tests can be run in the whole genome thanks to C++ implementation of most of the functions, using either RAVA-FIRST, a recently developed strategy to filter and analyse genome-wide rare variants, or user-defined candidate regions.

Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases.

Testing for association with rare variants in the coding and non-coding genome: RAVA-FIRST, a new approach based on CADD deleteriousness score.

Rare variant association tests (RVAT) have been developed to study the contribution of rare variants widely accessible through high-throughput sequencing technologies. RVAT require to aggregate rare variants in testing units and to filter variants to retain only the most likely causal ones. In the exome, genes are natural testing units and variants are usually filtered based on their functional consequences.

RAVAQ: An integrative pipeline from quality control to region-based rare variant association analysis.

Next-generation sequencing technologies have opened up the possibility to sequence large samples of cases and controls to test for association with rare variants. To limit cost and increase sample sizes, data from controls could be used in multiple studies and might thus be generated on different sequencing platforms. This could pose some problems of comparability between cases and controls due to batch effects that could be confounding factors, leading to false-positive association signals.

Cooperative -Regulatory Elements in Intestinal Cells.

About 8% of the human genome is covered with candidate -regulatory elements (cCREs). Disruptions of CREs, described as "-ruptions" have been identified as being involved in various genetic diseases. Thanks to the development of chromatin conformation study techniques, several long-range cystic fibrosis transmembrane conductance regulator () regulatory elements were identified, but the regulatory mechanisms of the gene have yet to be fully elucidated.

Extension of SKAT to multi-category phenotypes through a geometrical interpretation.

Rare genetic variants are expected to play an important role in disease and several statistical methods have been developed to test for disease association with rare variants, including variance-component tests. These tests however deal only with binary or continuous phenotypes and it is not possible to take advantage of a suspected heterogeneity between subgroups of patients. To address this issue, we extended the popular rare-variant association test SKAT to compare more than two groups of individuals.

Principal component analysis, a useful tool to study cyclin-dependent kinase-inhibitor's effect on cerebral ischaemia.

Stroke is a leading cause of acute death related in part to brain oedema, blood-brain barrier disruption and glial inflammation. A cyclin-dependant kinase inhibitor, (S)-roscovitine, was administered 90 min after onset on a model of rat focal cerebral ischaemia. Brain swelling and Evans Blue tissue extravasation were quantified after Evans Blue injection.

Rare variant association testing in the non-coding genome.

The development of next-generation sequencing technologies has opened-up some new possibilities to explore the contribution of genetic variants to human diseases and in particular that of rare variants. Statistical methods have been developed to test for association with rare variants that require the definition of testing units and, in these testing units, the selection of qualifying variants to include in the test. In the coding regions of the genome, testing units are usually the different genes and qualifying variants are selected based on their functional effects on the encoded proteins.

Rare variant association testing for multicategory phenotype.

Genetic association studies have provided new insights into the genetic variability of human complex traits with a focus mainly on continuous or binary traits. Methods have been proposed to take into account disease heterogeneity between subgroups of patients when studying common variants but none was specifically designed for rare variants. Because rare variants are expected to have stronger effects and to be more heterogeneously distributed among cases than common ones, subgroup analyses might be particularly attractive in this context.

New route for fast detection of antibodies against zoonotic pathogens in sera of slaughtered pigs by means of flow-through chemiluminescence immunochips.

The research on fast screening methods for antibodies against zoonotic pathogens in slaughter animals is important for food safety in farming and meat-processing industries. As a proof-of-concept study, antibodies against the emerging zoonotic pathogen hepatitis E virus (HEV) and enteropathogenic Yersinia spp. were analyzed in parallel using immobilized recombinant antigens (rAgs) of HEV genotypes 1 and 3 and Yersinia outer protein D (YopD) on a flow-through chemiluminescence immunochip.

Tumor-associated gene expression in disseminated tumor cells correlates with disease progression and tumor stage in colorectal cancer.

Background: A possible correlation of disease progression and tumor stage in colorectal cancer patients with tumor-associated gene expression in disseminated tumor cells (DTC) was evaluated. Detection of DTC and expression of tumor-associated genes might be of clinical value with respect to individual patient prognosis, monitoring of therapy and as a surrogate tumor staging parameter.

Patients And Methods: In a multicenter study, a total of 196 peripheral blood samples were collected from 76 patients with tumor stage Dukes' A to D and analyzed using a DTC detection assay consisting of immunomagnetic selection and expression analysis of the tumor-associated genes CEA, EGFR and GA733-2.

Heterogeneous expression of tumor-associated genes in disseminated breast cancer cells.

Background: Gene expression profiles were determined to demonstrate heterogeneity of viable disseminated tumor cells (DTC) in the blood of breast cancer patients.

Patients And Methods: All patients (n = 48) suffered from metastatic disease (M1) and were treated with chemotherapy and/or Herceptin, respectively. Blood samples were analyzed by a DTC detection assay consisting of immunomagnetic tumor cell selection combined with expression profiling of the tumor-associated transcripts GA733-2, MUC-1, HER-2 and Claudin-7.

The clinical significance of circulating tumour cells in breast cancer and colorectal cancer patients.

Background: Circulating tumour cells (CTC) in the blood of cancer patients indicate disease progression. Their presence reflects a relapse or metastasising process since CTC survive only a short time in the circulation.

Materials And Methods: Test systems developed by AdnaGen have been used for the sensitive and specific analysis of CTC.

Quantitative real-time RT-PCR of disseminated tumor cells in combination with immunomagnetic cell enrichment.

Detection of disseminated tumor cells in the blood circulation is important in assessing tumor progression. The objective of this examination was to develop a highly specific and sensitive quantitative realtime reverse transcriptase-polymerase chain reaction (qRT-PCR) assay for the detection of relevant tumor-associated transcripts in patients' blood. The qRT-PCR assays detect the human epidermal growth factor receptor 2 (HER2) and CK20 transcripts of two tumor cells spiked into 5 mL of blood after an immunomagnetic tumor cell enrichment.

Combination of immunomagnetic enrichment with multiplex RT-PCR analysis for the detection of disseminated tumor cells.

Background: A highly specific and sensitive tumor cell detection assay is reported, which combines immunomagnetic enrichment with multiplex RT-PCR analysis.

Materials And Methods: The effect on the recovery rate of breast, testicular and colorectal cancer cells using single antibodies and combinations of them for IMS was examined by fluorescence microscopy and multiplex RT-PCR. The clinical utility of a tumor cell detection assay using IMS with multiplex RT-PCR was tested by examination of colorectal cancer blood samples and by comparing the results with CEA serum protein levels.

Detection of disseminated tumor cells in peripheral blood.

Metastases are the major cause of cancer-related deaths in patients with solid epithelial malignancies, such as breast, colorectal and prostate carcinomas. Hematogenous spreading of tumor cells from a primary tumor can be considered as a crucial step in the metastasis cascade leading eventually to the formation of clinically manifest metastases. Consequently, as shown in recent studies, the detection of disseminated tumor cells in peripheral blood might be of clinical relevance with respect to individual patient prognosis and staging or monitoring of therapy.