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A Polymorphism in the Tumor Necrosis Factor- Gene Promoter Region May Predispose to a Poor Prognosis in COPD^*

^* From the Department of Medicine and Therapeutics (Drs. Keatings, Henry, O’Connor, and FitzGerald), University College Dublin, Ireland; and Division of Clinical Chemistry, School of Clinical Laboratory Sciences (Ms. Cave, Drs. Morgan and Kalsheker), Queens Medical Center, University of Nottingham, Nottingham, UK.

Correspondence to: Vera M. Keatings, MD, Department of Medicine, St Vincent’s Hospital, Elm Park, Dublin 4, Ireland; e-mail: vera.keatings{at}ucd.ie

Study objectives: To determine whether the adenine (A)-guanine (G) substitution polymorphism at position - 308 on the tumor necrosis factor- gene confers susceptibility to COPD or to the development of a more severe form of disease.

Design: A cross-sectional study was undertaken to compare the frequency of the A allele in a group of 106 patients with COPD with that in a control population (n = 99). Patients were followed up prospectively for a period of 2 years.

Participants and setting: Participants included 106 COPD patients recruited from a respiratory outpatient clinic and 99 control subjects recruited from patients admitted for cardiac catheterization.

Measurements and results: DNA was extracted from venous blood, and each subject was genotyped for the polymorphism by polymerase chain reaction amplification and restriction digestion using Nco1. There was no increased frequency of the A allele in patients compared to control subjects. AA homozygous patients had less reversible airflow obstruction (p < 0.05) and a significantly greater mortality (both all-cause and respiratory deaths) on follow-up (p < 0.001), despite a shorter cigarette smoking history.

Conclusions: This study suggests that homozygosity for this A allele predisposes to more severe airflow obstruction and a worse prognosis in COPD.

Key Words: COPD • polymorphism • susceptibility • tumor necrosis factor-

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