A study published in the American Journal of Respiratory and Critical Care Medicine in September 2018 found that a gene on the Y chromosome regulates the expression of a different gene, BMPR2. BMPR2 is known to be important in the pathogenesis of pulmonary arterial hypertension (PAH).
Germline mutations in BMPR2 (bone morphogenetic protein reception type 2) are present in approximately 70 percent of patients with heritable PAH and about 20 percent of idiopathic PAH patients. In addition, BMPR2 expression is reduced in the lungs of patients with multiple different types of PAH, further highlighting the crucial role of this gene in PAH. Intriguingly, female patients with BMPR2 mutations are three times more likely to develop PAH as males with the same mutations—42 percent of females with BMPR2 mutations develop PAH versus 14 percent of males.
“PAH has long been recognized as a disease more likely to afflict females than males, although the underlying reasons for this difference remain unclear,” said Eric Austin, M.D., associate professor of Pediatrics and Director of the Vanderbilt Pediatric Pulmonary Hypertension Program. “While our team typically studies the potential role of sex hormones in this disparity, we became interested in non-hormonal factors including the most obvious difference between males and females: XY versus XX sex chromosomes.”
Y chromosome’s protective effect
This study—carried out by researchers in Vanderbilt University Medical Center’s Divisions of Pediatric Pulmonary, Allergy, and Immunology Medicine and Medical Genetics—builds on work that previously showed the Y chromosome has a protective effect in hypoxia-induced pulmonary hypertension in mice.
The research focused on the sex-determining region Y (SRY) gene, which is located on the Y chromosome. They found that SRY binds to and positively regulates BMPR2 expression. This finding provides a potential explanation for why males are less likely to develop PAH, particularly given that reduced BMPR2 is such a strong contributor to PAH. The SRY gene is found exclusively in males.
“We previously found that, in general, males express higher levels of BMPR2 than females,” explained Austin. “We thus hypothesized that factors specific to the Y chromosome enhance BMPR2 expression. As a transcription factor, SRY was a high value target for study given its potential ability to regulate the expression of other genes.”
SRY expression was analyzed in several cell types for the study. While SRY expression was low in multiple different lung vascular cell lines, it was robustly expressed in fibroblast cell lines from multiple control and PAH patients.
SRY expression test in female cell line
The researchers also tested SRY expression in a female cell line, which under normal conditions would not express SRY. Overexpression of SRY in that female cell—a HEK293 cell line—resulted in around a 20 percent increase in BMPR2 expression.
“It is likely that multiple factors—genetic, hormonal, and others—contribute to PAH susceptibility, and resiliency.”
SRY was also shown in the study to directly bind to BMPR2 promotor sequences.
The study did find that SRY’s positive effect on BMPR2 has an upper limit and led researchers to postulate that there are multiple factors that contribute to BMPR2 expression, and not just SRY, leaving the door open for more research in the area.
Taken together, the results of this latest research provide a greater understanding of the potential role played by the Y chromosome as it relates to BMPR2 expression, and PAH.
“The higher susceptibility of females to PAH remains a puzzle, but we hope that his work adds another piece to our understanding,” Austin said. “It is likely that multiple factors—genetic, hormonal, and others—contribute to PAH susceptibility, and resiliency. Our group continues to explore these factors in the hope that understanding the sex discrepancy will soon advance therapies for this devastating disease.”
