KLK1 – Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy characterized by pathologic remodeling of small pulmonary arterioles, leading to increased pulmonary vascular resistance, right ventricular hypertrophy, and eventual right heart failure. Despite therapeutic advances, PAH carries high mortality, underscoring the need to define genetic contributors. Pathogenic variants in BMPR2 and other genes underlie familial forms, but most idiopathic cases lack a defined molecular etiology. Recent exome sequencing in a large PAH Biobank has identified new candidate genes, including KLK1, implicating tissue kallikrein in disease pathogenesis. KLK1 encodes tissue kallikrein 1, a serine protease involved in kinin generation and vascular tone regulation. Its perturbation may predispose to vascular remodeling.

KLK1-associated PAH appears to follow an autosomal dominant inheritance pattern with reduced penetrance, as indicated by the enrichment of heterozygous rare variants in affected individuals. No multigenerational pedigrees with segregating KLK1 variants have been reported to date. The discovery in unrelated European cases suggests sporadic occurrence. Phenotypic spectrum includes later age of onset and moderate disease severity compared to BMPR2 patients. Affected individuals typically present in mid-adulthood. Right ventricular hypertrophy (HP:0001667) and congestive heart failure (HP:0001635) are common clinical features.

In a case–control gene-based burden analysis of exome sequences, rare predicted deleterious KLK1 variants were identified in approximately 0.4% of PAH Biobank cases among 1832 unrelated European patients ([PMID:31727138]) compared to 12 771 controls ([PMID:31727138]). The analysis included 2572 total PAH individuals ([PMID:31727138]), controlling for population stratification. Empirical P values from permutation testing surpassed the Bonferroni-corrected threshold. The excess burden of rare loss-of-function and damaging missense KLK1 alleles achieved genome-wide significance. Although individual variant segregation data are lacking, the aggregated burden supports KLK1 as a PAH risk gene. This case–control evidence meets ClinGen criteria for moderate genetic evidence.

Specific KLK1 variants underlying the association were not detailed in the PAH report; however, rare loss-of-function and deleterious missense changes are implicated. One coding variant, c.230G>A (p.Arg77His), has been observed to reduce kallikrein activity in other disease contexts ([PMID:35873600]). Functional annotation suggests that such variants impair kinin generation, aligning with vascular dysfunction. The variant spectrum likely spans nonsense, frameshift, and critical missense mutations. No recurrent founder alleles have been described in PAH cohorts. Population allele frequencies were below 0.01%, consistent with a rare disease model.

KLK1 encodes tissue kallikrein 1, which generates kinins critical for vasodilation and endothelial homeostasis. Reduced KLK1 activity impairs kinin-mediated vasodilation, plausibly contributing to pulmonary arteriolar remodeling observed in PAH. Although no dedicated animal or cellular models of KLK1 deficiency in pulmonary vasculature have been published, studies in KLK1-deficient mice demonstrate compromised arterial function and renal tubular transport ([PMID:18627303]). These models indicate essential roles of kallikrein in vascular hemodynamics. Concordance between predicted KLK1 loss-of-function and vascular phenotypes supports a haploinsufficiency mechanism. This evidence provides limited functional support for KLK1 in PAH pathogenesis.

In summary, genetic association and mechanistic data implicate KLK1 as a novel risk gene for pulmonary arterial hypertension. Case–control exome sequencing in a large cohort identified a significant burden of rare deleterious variants, reaching genome-wide significance. Functional plausibility is supported by the known role of kallikrein in vascular tone regulation. Additional family segregation and targeted functional studies are needed to further bolster the clinical validity. Nonetheless, current evidence positions KLK1 as a moderate-strength PAH gene. Key take-home: screening for rare KLK1 variants may refine genetic risk assessment in PAH patients.

References

• Genome medicine • 2019 • Novel risk genes and mechanisms implicated by exome sequencing of 2572 individuals with pulmonary arterial hypertension. PMID:31727138
• Biological chemistry • 2008 • Genetic deficiency in tissue kallikrein activity in mouse and man: effect on arteries, heart and kidney. PMID:18627303
• Frontiers in allergy • 2022 • Searching for Genetic Biomarkers for Hereditary Angioedema Due to C1-Inhibitor Deficiency (C1-INH-HAE). PMID:35873600

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