To the Editors:
In a recent issue of the European Respiratory Journal, Meysman 1 suggested that in studies on the effects of angiotensin-converting enzyme (ACE) blockers in patients with chronic obstructive pulmonary disease (COPD), stratification for ACE gene polymorphism could potentially affect the outcomes under investigation. We have shown previously that the insertion (I)/deletion (D) polymorphism at intron 16 of the ACE gene is linked to pulmonary artery pressure (Ppa) in patients with COPD 2. In addition, in our recent study, increases in Ppa were associated with higher serum levels of high-sensitivity C-reactive protein (hsCRP), raising the possibility of a pathogenetic role of low-grade systemic inflammation in the pathogenesis of pulmonary hypertension secondary to COPD 3. Since activation of the renin–angiotensin system is likely to contribute to inflammatory processes 4, we performed a post hoc analysis on the potential relationship between the I/D ACE gene polymorphism and circulating hsCRP levels in 72 patients with clinically stable COPD (56 male, mean±sd age 65.1±10.5 yrs, forced expiratory volume in one second (FEV1) 45.8±17.4% predicted, arterial oxygen tension (Pa,O2) 8.2±1.8 kPa) who were participants in our previous studies 2, 3. The I/D ACE polymorphism was determined as previously described 2. Serum hsCRP levels were assessed in samples of peripheral venous blood drawn from the antecubital vein by chemiluminescent immunoassay (Randox, Crumlin, UK).
Serum hsCRP differed significantly between the II, ID, and DD groups (median (25th–75th percentile): 1.4 (0.9–2.7) versus 2.7 (1.5–6.1) versus 3.8 (1.8–10.4) mg·L−1, respectively; ANOVA on ranks, p<0.05). Moreover, the I/D ACE polymorphism predicted serum log hsCRP levels (p<0.05) independently of age, sex, FEV1 or Pa,O2.
In vitro studies on human vascular smooth muscle cells indicate that angiotensin II mediates a variety of proinflammatory effects through pleiotropic activation of nuclear factor-κB transcription factors 4. Importantly, angiotensin II receptor blockade significantly reduced serum hsCRP and tumour necrosis factor-α in patients with systemic hypertension 5, suggesting that the renin–angiotensin system, and probably its genetic determinants, plays an important role in vascular microinflammation. On one hand, it is well known that carriers of the D allelle of the I/D ACE gene polymorphism have higher serum and tissue ACE activities 6. On the other hand, however, the potential relationships between the ACE genotype and inflammatory cytokines have not been analysed previously in COPD patients. Our pilot study revealed a significant relationship between the I/D ACE gene polymorphism and circulatory CRP levels in patients with stable COPD: serum hsCRP increased from the homozygous II to the heterozygous ID and then to the homozygous DD ACE genotype group, and the I/D ACE gene polymorphism predicted serum log hsCRP levels independently of age, sex, FEV1 or Pa,O2. This finding might be meaningful, particularly in the light of recently published data indicating the clinical importance and predictive value of CRP in patients with COPD 7, 8. High CRP levels correlate with poorer performance in the 6-min walk test 7 and, in addition, they relate to increased mortality 8.
Animal studies are needed to shed more light on the mechanisms related to the induction and/or potentiation of inflammatory processes by the renin–angiotensin system. Moreover, future clinical studies are necessary to assess the potential relationships between the genetic determinants of the renin–angiotensin system and systemic complications in chronic obstructive pulmonary disease.
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