May 14, 2001

A gene microarray analysis of lung tissue from patients with primary pulmonary hypertension (PPH) suggests that there is more than one way to develop the rare, often fatal disease. Researchers found that expression levels of key genes differed between patients with inherited and sporadic PPH. The latter cases appeared to involve a more tumor-like process.

The genes identified should help clarify what causes PPH, a disorder in which blood vessels feeding the lungs become severely damaged. The investigators evaluated lung samples of two patients with inherited PPH and four patients thought to have sporadic PPH. One of the four, an orphan, had a genetic signature more like the inherited cases of PPH. Control tissue was obtained from six patients with normal lungs.

Using RNA from the tissue samples, the researchers compared the activity of several thousand genes. A difference in the expression pattern of 307 genes existed between the control and PPH samples. The results support the theory that genes involved in cell growth and cell death play a role in PPH. The study is reported in a recent issue of Circulation Research.

In addition, the investigators identified a dozen or so genes whose expression differed markedly between the known inherited and sporadic cases of the lung disease. The gene expression pattern of inherited PPH looked more like that of normal tissue than sporadic PPH. And the genetic features of sporadic cases resembled the poorly regulated cell growth associated with tumors.

The findings call into question a theory that defects in a single gene underlie PPH, such as the recently identified gene for the type II bone morphogenetic protein receptor (BMPR2). The BMPR2 gene has been linked to 6 percent of inherited cases and more than a third of sporadic cases of the disease.

In PPH, muscle cells that encircle arteries in the lung plump up, and endothelial cells lining the vessels' inside surface begin growing out of control. These changes block blood flow through the arteries, raising blood pressure and making it harder for the heart to pump blood to the lungs. Heart failure frequently results within a few years.

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Geraci, M.W. et al. Gene expression patterns in the lungs of patients with primary pulmonary hypertension. Circ Res 88, 555-562 (March 30, 2001).

Aldred, M. et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet 26, 81-84 (September 2000).

Deng, Z. et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 67, 737-744 (September 2000).

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