GGCX – Pulmonary Arterial Hypertension

Gamma-glutamyl carboxylase (GGCX) has been identified as a candidate risk gene for group 1 pulmonary arterial hypertension (PAH) through a large exome-sequencing case-control study. Using 1,832 unrelated European PAH cases and 12,771 matched controls, rare deleterious variants in GGCX were significantly enriched, accounting for approximately 0.9% of PAH Biobank cases ([PMID:31727138]).

In total, burden testing implicated four rare missense variants in 16 probands (e.g., c.1465G>A (p.Val489Met)) within catalytic or substrate-binding domains, yielding genome-wide significance (Bonferroni-corrected) with empirical p-values determined by permutation analyses ([PMID:31727138]). Segregation data are lacking for familial cases, suggesting an incomplete picture of heritability. No multigenerational segregation or linkage analyses have yet been reported.

The inheritance pattern of GGCX variants in PAH appears consistent with an autosomal dominant model with reduced penetrance. Variant spectrum is limited to missense substitutions affecting vitamin K binding and enzyme activity; no loss-of-function or splice variants were reported in this cohort. No recurrent or founder alleles were annotated for population subgroups.

Mechanistically, GGCX catalyzes γ-carboxylation of vitamin K-dependent proteins involved in vascular homeostasis and remodeling. However, direct functional validation of PAH-associated GGCX variants in pulmonary vascular cells or animal models is currently absent; existing functional studies focus on coagulation factor carboxylation and general enzyme processivity in heterologous systems, not on pulmonary vascular pathology.

There are no conflicting genetic or functional data disputing GGCX’s role in PAH to date. Nonetheless, additional segregation studies and in vivo modeling are needed to clarify penetrance and pathogenic mechanisms.

In summary, rare missense variants in GGCX demonstrate a moderate level of clinical validity for association with Pulmonary Arterial Hypertension, supporting inclusion of GGCX in comprehensive genetic risk panels for PAH. Key Take-home: Screening for pathogenic GGCX variants can uncover a moderate but non-negligible contributor to PAH etiology, guiding risk assessment and potential exploration of vitamin K–modulating therapies.

References

• Genome Medicine • 2019 • Novel risk genes and mechanisms implicated by exome sequencing of 2,572 individuals with pulmonary arterial hypertension. PMID:31727138

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