TTC7B Emerges as a Novel Risk Factor for Ischemic Stroke Through the Convergence of Several Genome-Wide Approaches

Abstract

We hereby propose a novel approach to the identification of ischemic stroke (IS) susceptibility genes that involves converging data from several unbiased genetic and genomic tools. We tested the association between IS and genes differentially expressed between cases and controls, then determined which data mapped to previously reported linkage peaks and were nominally associated with stroke in published genome-wide association studies. We first performed gene expression profiling in peripheral blood mononuclear cells of 20 IS cases and 20 controls. Sixteen differentially expressed genes mapped to reported whole-genome linkage peaks, including the TTC7B gene, which has been associated with major cardiovascular disease. At the TTC7B locus, 46 tagging polymorphisms were tested for association in 565 Portuguese IS cases and 520 controls. Markers nominally associated in at least one test and defining associated haplotypes were then examined in 570 IS Spanish cases and 390 controls. Several polymorphisms and haplotypes in the intron 5-intron 6 region of TTC7B were also associated with IS risk in the Spanish and combined data sets. Multiple independent lines of evidence therefore support the role of TTC7B in stroke susceptibility, but further work is warranted to identify the exact risk variant and its pathogenic potential.

Attenuation of Myeloid-Specific TGFβ Signaling Induces Inflammatory Cerebrovascular Disease and Stroke

“…Representative type 2 cytokines such as IL4 and IL10 were not detected in plasma from either wt or Tgfbr2 Myeko mice (Figure 3A). This enhanced type 1, and deficient type 2 polarization is also observed in vascular inflammation and atherosclerotic plaque formation 20,21 .…”

“…Tgfbr2 Myeko post- stroke mice showed a unique cytokine profile that overlapped with that from pre-stroke mice (Figure 4A). A human RNA dataset of peripheral blood mononuclear cells (PBMC) from patients 6 months post ischemic stroke 20 , who are at high risk for subsequent stroke 21 , revealed increased expression of inflammatory cytokines, including TNF (Figure 4B). Ingenuity pathway analysis (IPA) of significantly altered pro-inflammatory genes from the human dataset, revealed striking similarity to our mouse pre-stroke cytokine signature (Online Figure IV).…”

Genome-wide association study identifies four SNPs associated with response to platinum-based neoadjuvant chemotherapy for cervical cancer

“…Tetratricopeptide repeats consist of tandem arrays of highly degenerate 34-amino acid repeats that are predicted to form extended superhelical arrangements23. These TPR domains function as protein–protein interaction modules for macromolecular complexes involved in numerous cellular processes, including transcriptional regulation, mRNA processing, protein folding, and translocation24.…”

RIFS: a randomly restarted incremental feature selection algorithm

“…Five more recent datasets, i.e . Mye (accession: GDS531) 40 , Gas (accession: GSE37023) 41 , Gas1/Gas2 (accession: GSE29272) 42 , T1D (accession: GSE35725) 43 and Stroke (accession: GSE22255) 44 , were publicly available at the NCBI Gene Expression Omnibus (GEO) database. The raw data from the NCBI GEO database was normalized into the gene expression matrix with the default parameters of the RMA algorithm 45 , and all the other datasets were downloaded as the normalized data matrix.…”