title: Genome-wide SNP analysis of the Systemic Capillary Leak Syndrome (Clarkson disease).
abstract: The Systemic Capillary Leak Syndrome (SCLS) is an extremely rare, orphan disease that resembles, and is frequently erroneously diagnosed as, systemic anaphylaxis. The disorder is characterized by repeated, transient, and seemingly unprovoked episodes of hypotensive shock and peripheral edema due to transient endothelial hyperpermeability. SCLS is often accompanied by a monoclonal gammopathy of unknown significance (MGUS). Using Affymetrix Single Nucleotide Polymorphism (SNP) microarrays, we performed the first genome-wide SNP analysis of SCLS in a cohort of 12 disease subjects and 18 controls. Exome capture sequencing was performed on genomic DNA from nine of these patients as validation for the SNP-chip discoveries and de novo data generation. We identified candidate susceptibility loci for SCLS, which included a region flankingCAV3(3p25.3) as well as SNP clusters inPON1(7q21.3),PSORS1C1(6p21.3), andCHCHD3(7q33). Among the most highly ranked discoveries were gene-associated SNPs in the uncharacterizedLOC100130480gene (rs6417039, rs2004296). Top case-associated SNPs were observed inBTRC(rs12355803, 3rs4436485),ARHGEF18(rs11668246),CDH13(rs4782779), andEDG2(rs12552348), which encode proteins with known or suspected roles in B cell function and/or vascular integrity. 61 SNPs that were significantly associated with SCLS by microarray analysis were also detected and validated by exome deep sequencing. Functional annotation of highly ranked SNPs revealed enrichment of cell projections, cell junctions and adhesion, and molecules containing pleckstrin homology, Ras/Rho regulatory, and immunoglobulin Ig-like C2/fibronectin type III domains, all of which involve mechanistic functions that correlate with the SCLS phenotype. These results highlight SNPs with potential relevance to SCLS.
authors.affiliation: Molecular Signal Transduction Section; NIAID/NIH; Bethesda, MD USA.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Computational Biology Section; Bioinformatics and Computational Biosciences Branch; OCICB; NIAID/NIH; Bethesda, MD USA.
authors.forename: Vijayaraj
authors.initials: V
authors.lastname: Nagarajan
authors.affiliation: Genomics Unit, Research Technologies Section; Rocky Mountain Laboratories; NIAID/NIH, Hamilton, MT USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Sturdevant
authors.affiliation: Molecular Signal Transduction Section; NIAID/NIH; Bethesda, MD USA.
authors.forename: Shoko
authors.initials: S
authors.lastname: Iwaki
authors.affiliation: Molecular Signal Transduction Section; NIAID/NIH; Bethesda, MD USA.
authors.forename: Eunice
authors.initials: E
authors.lastname: Chan
authors.affiliation: Molecular Signal Transduction Section; NIAID/NIH; Bethesda, MD USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Wisch
authors.affiliation: Clinical Research Directorate/CMRP; SAIC-Frederick, Inc; Frederick National Laboratory for Clinical Research; Frederick, MD USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Young
authors.affiliation: Molecular Signal Transduction Section; NIAID/NIH; Bethesda, MD USA.
authors.forename: Celeste M
authors.initials: CM
authors.lastname: Nelson
authors.affiliation: Genomics Unit, Research Technologies Section; Rocky Mountain Laboratories; NIAID/NIH, Hamilton, MT USA.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Porcella
authors.affiliation: Molecular Signal Transduction Section; NIAID/NIH; Bethesda, MD USA.
authors.forename: Kirk M
authors.initials: KM
authors.lastname: Druey
keywords: cell adhesion; cell junction; cytoskeleton; genetics, genome-wide SNP study; systemic capillary leak syndrome; vascular permeability