Abstract 17477: NCKAP1L

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Introduction: Variable response to PAH therapeutics suggests that genetic differences may influence survival. As such, we hypothesized that enhanced activation of RhoBTB1 is associated with increased mortality in PAH patients

Methods: A GWAS was performed on 670 PAH patients with matching clinical and genomic sample treated with ERAs enrolled prospectively from 45 US and Canadian PAH centers or retrospectively from global sites participating in the Sitaxsentan To Relieve Impaired Exercise (STRIDE) trials. GWAS was conducted using an Illumina 1 million SNP chip with outcome survival. Quality control of the GWAS data was conducted using the R programming language. Genotypes were imputed using IMPUTE2 software with the phase 3-reference panel. Survival analyses were performed on the imputed genotypes using ProbABEL software.

Results: Among 670 patients, 79 % were female (mean age 52 ± 16 years). Patients were followed over average of 9.5 years. There were 249 deaths. Out of 925,436 autosomal loci, 170,597 (18.5%) were monogenic; 325,426 (35.1%) had mono allele frequency (MAF) < 0.05; 6,227 had HWE p-values < 0.001 (0.6%). A total of 595,897 passed both the 0.05 MAF and the 0.001 thresholds for HWE p-value.

Using recessive modeling of inheritance, four SNPs were significantly associated with higher mortality; the locus rs61304036 was SNV (P= 6.64E-06); the locuses rs1013705, rs76526069 and rs73266037 had P= 8.22E-06; P=2.72E-06; and P= 2.30E-06 respectively. All were within the intronic region of RhoBTB1 gene on chromosome 10 regions and gene expression microarray studies suggest RHOBTB1 is up-regulated in PAH lung tissue. These SNPs had a MAF of 0.03, which is consistent for these alleles in the European population.

Conclusion: Genetic variations in the RhoBTB1 gene are associated with higher mortality in PAH and may be linked to an increased expression of RhoBTB1 gene. This altered genetic association may affect RhoA/Rho kinase activity level with a subsequent imbalance of vasoconstrictor and vasodilator responses as recent findings have suggested that loss of Cullin3 expression led to increase in RhoA/Rho kinase activity level and agonist-mediated contraction. This novel pathway should serve as a future area of exploration into PAH pathogenesis

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