Researchers from the IDIBAPS, UPF and the Israel Institute of Technology - Technion have identified a region in the genome that could contribute to increased susceptibility to suffering pulmonary arterial hypertension among carriers of a mutation in the gene BMPR2, which is responsible for the heritable form of the disease. The study was published in Journal of Medical Genetics. 

Heritable pulmonary arterial hypertension (HPAH) is a rare disease characterized by an abnormal increase in the average blood pressure in the lung. This disorder is mainly caused by mutations in the gene BMPR2. However, identifying mutations in certain genes is often not enough to understand the genetic basis of rare heritable diseases. In fact, some carriers of the disease have been seen not even to develop the disease, a phenomenon known as incomplete penetrance. In recent years this phenomenon has appeared to be far more significant and widespread than had been imagined in previous decades.    

“In the clinical setting, it is important to identify a biomarker to determine which patients carrying a mutation develop the disease. In such cases, clinical monitoring of patients carrying the mutation but with a lower risk of suffering the disease would be less exhaustive”, says Irene Madrigal, senior specialist of the Biochemistry and Molecular Genetics Service at Hospital Clínic de Barcelona, a researcher at the IDIBAPS and coordinator of the study.

They have studied which genetic modifiers can explain this difference between healthy and diseased carriers.

“Our task has been to study which genetic modifiers can explain this difference between healthy and diseased carriers”, explains Robert Castelo, tenured lecturer at the Department of Experimental and Health Sciences (DCEXS) at UPF.

The researchers carried out the study in a family affected by HPAH in which about 40% of the carriers of the mutation have developed the disease. The family studied includes 65 individuals from five different generations, of whom 22 are carriers of the mutation and eight have been diagnosed with HPAH.

“By analysing their genetic profiles, we have managed to identify a region in the genome that could potentially contribute to showing susceptibility to the disease among carriers of the mutation”, says Pau Puigdevall, first author of the article.

This result may help to advance in understanding genetic modifiers that affect the mutations that cause HPAH.

This result may help to advance in understanding genetic modifiers that affect the mutations that cause HPAH. “However, additional efforts will be needed to identify the specific genetic and molecular mechanism responsible for this susceptibility in order to be able to diagnose it with total reliability”, says Castelo, who is also head of the Functional Genomics group of the Research Programme on Biomedical Informatics (GRIB, a mixed group of the Hospital del Mar Medical Research Institute and UPF).

Also participating are the Biomedical Research Networking Centre on Respiratory Diseases (CIBERES) and the Biomedical Research Networking Centre on Rare Diseases (CIBERER). The study was made possible thanks to funding from the Carlos III Health Institute, the European Regional Development Fund (ERDF), the AGAUR, MINECO/ERDF and María de Maeztu.

Reference article:

Puigdevall P, Piccari L, Blanco I, et al Genetic linkage analysis of a large family identifies FIGN as a candidate modulator of reduced penetrance in heritable pulmonary arterial hypertension Journal of Medical Genetics Published Online First: 20 March 2019. doi: 10.1136/jmedgenet-2018-105669.