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+9/+9 Homozygosity of the bradykinin receptor gene polymorphism is associated with reduced fat-free mass in chronic obstructive pulmonary disease ^1,2,3

¹ From the Respiratory Muscle Laboratory, Royal Brompton Hospital, London, United Kingdom (NSH, AHN, and MIP); the Department of Cardiovascular Genetics, Rayne Institute, London, United Kingdom (KIE, JP, EH, and HM); the Respiratory Muscle Laboratory, Guy's, King's and St Thomas' School of Medicine, King's College Hospital, London, United Kingdom (JM); and the UCL Institute for Human Health and Performance, London, United Kingdom (HM)

Background:The etiology of muscle wasting in chronic obstructive pulmonary disease (COPD) is incompletely understood. We previously showed that the D rather than the I polymorphic variant of the angiotensin-converting enzyme (ACE) gene is associated with preserved quadriceps strength in COPD. If the ACE D allele influences skeletal muscle through increased ACE-related kinin degradation [and reduced activity at the bradykinin type 2 receptor (BK₂R)], we might expect a similar association with the +9 BK₂R genotype in this population as well.

Objective:The objective was to test the hypothesis that the BK₂R gene polymorphism is a determinant of fat-free mass and quadriceps strength in patients with COPD.

Design:In a cross-sectional design we determined BK₂R genotype, fat-free mass, and quadriceps strength in 110 COPD patients with a mean (±SD) predicted forced expiratory volume in 1 s of 34.3 ± 16.4% and in 104 healthy age-matched control subjects.

Results:The mean (±SD) fat-free mass index (in kg/m²) was significantly lower in 37 patients homozygous for the +9 allele than in carriers of the –9 allele (15.7 ± 1.8 compared with 16.7 ± 2.3; P = 0.038); the same pattern was true for quadriceps maximal voluntary force (30.8 ± 10.4 and 36.4 ± 12.8 kg; P = 0.02), respectively. No significant effect of BK₂R genotype on inspiratory muscle strength or on any variable in control subjects was observed. There was no interaction between the effect of the BK₂R and ACE genotypes on quadriceps strength.

Conclusions:The genotype associated with reduced BK₂R expression is associated with reduced fat-free mass and quadriceps strength in COPD. However, alterations in the activity at the BK₂R do not seem to account for the previously identified association of quadriceps strength with ACE genotype.

Key Words: Gene polymorphism • bradykinin • angiotensin-converting enzyme • respiratory muscle • quadriceps • magnetic stimulation

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