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End-Organ Dysfunction in Cystic Fibrosis

Association with Angiotensin I Converting Enzyme and Cytokine Gene Polymorphisms

Academic Unit of Child Health, Booth Hall Children's Hospital, and School of Biological Sciences, University of Manchester; Department of Clinical Genetics, Royal Manchester Children's Hospital; and Bradbury Cystic Fibrosis Unit, Wythenshawe Hospital, Manchester, United Kingdom

Correspondence and requests for reprints should be addressed to Peter D. Arkwright, M.D., Senior Lecturer in Paediatric Immunology, Booth Hall Children's Hospital, Charlestown Road, Manchester M9 7AA, UK. E-mail: peter_arkwright{at}lineone.net

The clinical course of patients with cystic fibrosis (CF) with functionally similar mutations in the CF transmembrane conductance regulator gene is variable and must therefore relate to secondary genetic and environmental factors. We examined the hypothesis that polymorphisms of certain inflammatory mediator and regulatory genes affect clinical outcome by influencing the degree of end-organ damage. By studying the possible association between clinical outcome and angiotensin I-converting enzyme (ACE) and cytokine genotypes by amplification refractory mutation system-polymerase chain reaction, using stored DNA from 261 white patients with CF, we found that ultrasound features of cirrhosis occurred more frequently in patients with the high-producer (DD) rather than the low-producer (II) ACE genotype (odds ratio [95% confidence interval], 3.7 [1.2 to 12]). Moreover, significant pulmonary dysfunction (age at which FEV₁ < 50%) was associated with the high-producer ACE genotype (2.3 [1.2 to 4.5]) and transforming growth factor–ß₁ genotype (2.6 [1.0 to 6.8]) as well as with age at first colonization with Pseudomonas aeruginosa (9.1 [1.1 to 72]). We conclude that the high-producer ACE genotype predicts patients with CF who have an increased chance of developing portal hypertension; and high-producer ACE and TGF-ß₁ genotypes are secondary genetic factors contributing to pulmonary dysfunction in these patients.

Key Words: angiotensin I converting enzyme • cirrhosis • cystic fibrosis • lung • transforming growth factor–ß₁

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