Summary To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of three genome-wide association studies (GWAS) and two independent datasets genotyped on the Immunochip, involving 10,588 cases and 22,806 controls in total. We identified 15 new disease susceptibility regions, increasing the number of psoriasis-associated loci to 36 for Caucasians. Conditional analyses identified five independent signals within previously known loci. The newly identified shared disease regions encompassed a number of genes whose products regulate T-cell function (e.g. RUNX3, TAGAP and STAT3). The new psoriasis-specific regions were notable for candidate genes whose products are involved in innate host defense, encoding proteins with roles in interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C), and NF-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.

The specialized epithelial cell of the kidney, the podocyte, has a complex actin-based cytoskeleton. Dynamic regulation of this cytoskeleton is required for efficient barrier function of the kidney. Podocytes are a useful cell type to study the control of the actin cytoskeleton in vivo, because disruption of components of the cytoskeleton results in podocyte damage, cell loss, and a prototypic injury response called focal segmental glomerulosclerosis (FSGS). Searching for actin regulatory proteins that are expressed in podocytes, we identified a RhoA-activated Rac1 GTPase-activating protein (Rac1-GAP), Arhgap24, that was upregulated in podocytes as they differentiated, both in vitro and in vivo. Increased levels of active Rac1 and Cdc42 were measured in Arhgap24 knockdown experiments, which influenced podocyte cell shape and membrane dynamics. Consistent with a role for Arhgap24 in normal podocyte functioning in vivo, sequencing of the ARHGAP24 gene in patients with FSGS identified a mutation that impaired its Rac1-GAP activity and was associated with disease in a family with FSGS. Thus, Arhgap24 contributes to the careful balancing of RhoA and Rac1 signaling in podocytes, the disruption of which may lead to kidney disease.

FSGS is characterized by segmental scarring of the glomerulus and is a leading cause of kidney failure. Identification of genes causing FSGS has improved our understanding of disease mechanisms and points to defects in the glomerular epithelial cell, the podocyte, as a major factor in disease pathogenesis. Using a combination of genome-wide linkage studies and whole-exome sequencing in a kindred with familial FSGS, we identified a missense mutation R431C in anillin (ANLN), an F-actin binding cell cycle gene, as a cause of FSGS. We screened 250 additional families with FSGS and found another variant, G618C, that segregates with disease in a second family with FSGS. We demonstrate upregulation of anillin in podocytes in kidney biopsy specimens from individuals with FSGS and kidney samples from a murine model of HIV-1-associated nephropathy. Overexpression of R431C mutant ANLN in immortalized human podocytes results in enhanced podocyte motility. The mutant anillin displays reduced binding to the slit diaphragmassociated scaffold protein CD2AP. Knockdown of the ANLN gene in zebrafish morphants caused a loss of glomerular filtration barrier integrity, podocyte foot process effacement, and an edematous phenotype. Collectively, these findings suggest that anillin is important in maintaining the integrity of the podocyte actin cytoskeleton.

To further evaluate the nature of the HLA association with psoriasis, HLA haplotypes of 60 patients with type 1 (early onset, positive family history) and 30 patients with type II (late onset, no family history) psoriasis were investigated by polymerase chain reaction sequence-specific oligonucleotide hybridization (HLA class II) and serology (HLA class I). Ethnically matched blood donors (146) served as controls. In type I, but not type II psoriasis, the Caucasian HLA extended haplotype (EH) Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303 named according to the B allele EH-57.1 was highly significantly overrepresented (p cor= 0.00021). This particular EH was present in 35% of type I psoriatics but only 2% of controls. EH-57.1+ individuals therefore carry a 26 times higher risk of developing type I psoriasis than individuals who are EH-57.1-negative Further analysis of individual HLA alleles revealed that within EH-57.1, HLA class I antigens (Cw6-B57) were associated to a much higher extent with type I psoriasis than the HLA class II alleles (DRB1*0701-DQA1*0201-DQB1* 0303). Pedigree analysis of three multiply affected families over three generations revealed a cosegregation of disease with EH-57.1. These results strongly suggest that a gene for familial psoriasis is associated with the class I side of the extended haplotype Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303.

Psoriasis is a common chronic inflammatory skin disease with a strong genetic component. Few psoriasis-susceptibility loci have been reported, and only two have been confirmed in independent data sets. This article reports results of a genomewide scan that was performed, using 370 microsatellite markers, for psoriasis-susceptibility loci in 32 German extended families, comprising 162 affected and 195 unaffected individuals. Nonparametric linkage analysis of all families provided strong evidence for a novel psoriasis-susceptibility locus on chromosome 19p (Zlr=3.50; P=.0002). Parametric analysis revealed a heterogeneity LOD score of 4.06, corresponding to a genomewide significance level of.037, under the assumption of a recessive model with high disease-allele frequency and 66% as the proportion of linked families. This study confirms linkage of psoriasis to the HLA region on chromosome 6p and suggests additional regions on chromosomes 8q and 21q for further investigations.