Interstitial Lung Disease: Pathophysiology and Genetic Predisposition

Penelope A. Lympany, PhD, and Roland M. du Bois, MD, Imperial College of Science, Technology and Medicine, London, UK

In This Article

Pulmonary Hypertension

Pulmonary hypertension occurs in rheumatologic diseases, normally as a consequence of diffuse lung disease. In scleroderma it can occur as primary hypertension without diffuse lung disease and is then similar to primary pulmonary hypertension.

Primary pulmonary hypertension may occur independently (without rheumatologic disease); the female-to-male ratio is 1.7:1. There is evidence of common ancestry in sporadic primary pulmonary hypertension, suggesting that the disease has a genetic basis and that familial primary pulmonary hypertension may be more common than previously recognized. It appears that in families with this condition, successive generations are more likely to develop the disease at an earlier age (a phenomenon known as genetic anticipation).[97] Specific genes including those of the MHC[98,99] and genes on chromosome 2q[100,101] have been implicated in primary pulmonary hypertension and appear to be associated with the disease.

Pulmonary hypertension in scleroderma is a consequence of lone vascular disease and is normally found in patients with limited, rather than diffuse, SSc. ACA have been detected in 43% of patients with limited SSc, and although they are not absolutely predictive of pulmonary hypertension, this result suggests a possible immunogenetic association.[54] Because primary pulmonary hypertension may be regarded as an autoimmune disease, the candidate genes of interest have been those of the MHC. Differences in the frequency of HLA alleles have been found in children (HLA-DR3, DR52, DQ2) with primary pulmonary hypertension and adults with familial primary pulmonary hypertension.[102] This finding is substantiated by the observation that pulmonary hypertension in adults with scleroderma is associated with an increased frequency of HLA-DR52.[103]

These data suggest that there is a genetic basis to pulmonary hypertension, but it is clear that further studies are required to determine the exact nature of that predisposition. One hypothesis is that TGF-beta contributes to pulmonary vascular hypertension via its action on fibroblasts and matrix deposition.[104] This theory is supported by findings of Cambien and coworkers,[105] suggesting that genetic polymorphisms within the promoter region of TGF-beta 1 may be associated with myocardial infarction and hypertension.


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