Genetic Variants Near Two Genes Linked to PAH Risk, Large Study Reports

Genetic variants close to the SOX17 and the HLA-DPB1 genes are linked to pulmonary arterial hypertension (PAH), according to the findings of the largest genetic study to date in PAH patients.

The study, “Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis,” was published in the journal The Lancet Respiratory Medicine.

While previous studies have shown that rare genetic variants increase the risk for PAH, the contribution of more common variations within the genome to the disease and to patient’s treatment responses remained unknown.

To take a closer look at these potential associations, researchers at the Imperial College London and international colleagues conducted the large-scale genetic analysis, pooling data from four international studies in North America and Europe, including the U.K.

The U.K. data was from the National Institute for Health Research BioResource — Rare Diseases and the British Heart Foundation Pulmonary Arterial Hypertension study.

In total, the genome-wide association study (GWAS) included 11,744 individuals, of whom 2,085 were diagnosed with PAH.

The analysis identified three genetic regions linked with PAH, two of which were located near the SOX17 gene (genetic variants rs10103692 and rs13266183) and the other within the HLA-DPB1 gene (genetic variant rs2856830).

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“This is the first study at the scale required to look at how common genetic variations influence PAH, which could help us understand variations in how the disease presents itself and how patients respond to treatments,” Christopher Rhodes, PhD, the study’s first author, said in a press release.

“Out of the 23,000 genes in the whole genome we have found that PAH has significant associations with two genes, SOX17 and HLA-DPB1, providing strong evidence that these genes play an important role in PAH. This opens up exciting possibilities for future research into new therapies,” added Rhodes, who is the British Heart Foundation’s intermediate basic science fellow.

SOX17 provides instructions to make a protein involved in embryonic development, determination of cell fate, and in the development of endothelial cells (those lining the inside of blood vessels in the lungs). Consequently, variations in the SOX17 gene may lead to structural changes that may, in turn, affect a patient’s risk for developing PAH.

A recent study identified SOX17 as a potential contributing factor to PAH associated with congenital heart disease, as well as to idiopathic and/or familial PAH.

“The discovery of a common variant that operates through a gene, SOX17, that is mutated in a few patients with the disease suggests that SOX17 may be more commonly involved in pulmonary hypertension than previously thought. This has implications for the development of new treatments that might come from further work on SOX17,” said Martin Wilkins, MD, head of the Department of Medicine at Imperial College London and the study’s lead author.

The HLA-DPB1 gene provides instructions for the production of a key protein that helps the immune system distinguish the body’s own proteins from proteins made by foreign organisms, such as viruses and bacteria.

Researchers identified different variants of the HLA-DPB1 gene and found they correlated differently with patient survival. Specifically, they found that the median survival after PAH diagnosis of patients with one particular variant (C/C genotype) was 13.5 years, roughly twice that of patients with variant number two (T/T genotype), whose median survival was seven years.

“This study represents the enormous efforts of an international collaboration and the generous participation of many patients, making it the largest genetic study of PAH to date,” Wilkins said. “The findings raise the importance of including the genotype as a factor when interpreting the results of clinical studies, as it may be that some patients deteriorate at a rate determined by their genotype, rather than at a rate determined by a new treatment.”

Further studies are now needed to confirm the association among these genetic variants, PAH risk, and patient survival.

“This international team has made real gains in our understanding of PAH by identifying two important genes which contribute to its development, laying the essential groundwork we need to develop new treatments in future,”  said professor Metin Avkiran, PhD, associate medical director at the British Heart Foundation.