Identification of novel genetic variants, including PIM1 and LINC01491, with ICD-10 based diagnosis of pulmonary arterial hypertension in the UK Biobank cohort

Abstract

Pulmonary arterial hypertension (PAH) is characterized by remodeling and narrowing of the pulmonary vasculature which results in elevations of pulmonary arterial pressures. Here, we conducted a genome-wide association study (GWAS) using the UK Biobank, analyzing the genomes of 493 individuals diagnosed with primary pulmonary hypertension, based on ICD-10 coding, compared to 24,650 age, sex, and ancestry-matched controls in a 1:50 case-control design. Genetic variants were analyzed by Plink’s firth logistic regression and assessed for association with primary pulmonary hypertension. We identified three linked variants in the PIM1 gene, which encodes a protooncogene that has been garnering interest as a potential therapeutic target for PAH, that were associated with PAH with genome wide significance, one (rs192449585) of which lies in the promoter region of the gene. We also identified 15 linked variants in the LINC01491 gene. These results provide genetic evidence supporting the role of PIM1 inhibitors as a potential therapeutic option for PAH.

Multi-biobank summary data Mendelian randomisation does not support a causal effect of IL-6 signalling on risk of pulmonary arterial hypertension

“…To maximise our power to detect an association we extracted summary data from all publicly available genetic studies containing PAH patients: 1) a 2019 meta-analysis of four international case–control studies of PAH, with 2085 cases and 9659 controls, all of European ancestry [ 7 ]; 2) a GWAS of PAH in the UK Biobank using 493 medical record-identified cases and 24 650 age-, sex- and ancestry-matched controls [ 10 ]; and 3) FinnGen round 9 (n=377 277), including 234 individuals with medical record-identified PAH (ID: I9_HYPTENSPUL) [ 11 ]. FinnGen does not overlap with either the UK Biobank or the 2019 meta-analysis.…”