PATJ Low Frequency Variants Are Associated With Worse Ischemic Stroke Functional Outcome

Abstract

Rationale: Ischemic stroke (IS) is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome. Objective: Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest genome-wide association study (GWAS) in IS recovery to date. Methods and Results: A 12-cohort, two-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent IS cases. Functional outcome was recorded using 3-month modified Rankin Scale (mRS). Analyses were adjusted for confounders such as discharge NIHSS. A gene-based burden test was performed. The discovery phase (n=1,225) was followed by open (n=2,482) and stringent joint-analyses (n=1,791). Those cohorts with mRS recorded at timepoints other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in Pals1-Associated Tight Junction (PATJ) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, beta=0•40, p=1•70×10 −9). Conclusions: Our results identify a set of common variants in PATJ gene associated with 3month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci.

Cell Polarity Protein Pals1-Associated Tight Junction Expression Is a Favorable Prognostic Marker in Clear Cell Renal Cell Carcinoma

“…Previous studies showed that epithelial-mesenchymal transition (EMT) markers SANIL and ZEB1 could transcriptionally inhibit PATJ expression in MDCK and MDA-MB-231 cells (Aigner et al, 2007;Whiteman et al, 2008). PATJ SNP variants were associated with worse outcomes in ischemic stroke patients (Mola-Caminal et al, 2019). However, the cause of PATJ downregulation in ccRCC requires future investigation.…”

Genetic Aspects of Inflammation and Immune Response in Stroke

“…Recently, about long-term stroke outcome, two GWAS studies have been published with remarkable results. The GODS (Genetic contribution to functional Outcome and Disability after Stroke) study detected that PATJ (Pals1-associated tight junction) low-frequency variants were associated with worse IS functional outcome [ 43 ]. In the GISCOME study, with more than 6000 participants, it was showen that intronic variant rs1842681 in LOC105372028 had a significant association with functional outcomes 60–90 days after stroke [ 44 ].…”

Clinical Variables and Genetic Risk Factors Associated with the Acute Outcome of Ischemic Stroke: A Systematic Review

“…Additionally, in reference to long-term stroke outcome, two GWAS (Genetic contribution to functional Outcome and Disability after Stroke [GODS] [7] and Genetics of Ischemic Stroke functional outCOME [GISCOME] [8] studies, with 1,791 and 6,165 participants, respectively) have been recently published with remarkable results. One study [7] had found a locus located within a candidate gene, confirmed by an external replication. These studies are beginning to clarify the influence of genetics on patient recovery, which can help us to understand all the mechanisms involved.…”

“…Several genome-wide association studies (GWAS) have found genes associated with stroke risk and have been confirmed in independent studies [4-6]. However, with the exception of two recent GWAS [7,8], the studies performed to find genetic variables associated with stroke outcome are candidate gene studies that have not been consistently replicated [9].…”