Single nucleotide polymorphisms within oxidative stress genes affect arterial compliance: gene function relationships

R Drummond; M Brosnan; C Tan; A Kirk; C Hamilton; J Connell; A Dominiczak

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Endocrine Abstracts (2004) 7 P46

BES2004 Poster Presentations Diabetes, metabolism and cardiovascular (43 abstracts)

Single nucleotide polymorphisms within oxidative stress genes affect arterial compliance: gene function relationships

RS Drummond ¹ , MJ Brosnan ¹ , C Tan ² , A Kirk ¹ , CA Hamilton ¹ , JMC Connell ¹ & AF Dominiczak ¹

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¹1 BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Western Infirmary Glasgow, UK; ²Department of Cardiothoracic Surgery, Western Infirmary Glasgow, UK.

Background and Hypothesis:- A common NOS3 Single nucleotide polymorphisms (SNP) (894 G/T) which encodes a Glu298Asp amino acid substitution in endothelial NO synthase has been associated with cardiovascular disorders in which NO bioactivity is impaired. The gene coding for p22phox, a critical component of the NADH/NAD(P)H oxidase enzyme system, a major source of vascular SO, is CYBA. Among the allelic polymorphisms reported in CYBA is C242T, associated with progression of coronary atherosclerosis. Consistent characteristic changes in the pressure pulse waveshape have been associated with ageing, risk factors for cardiovascular disease and impaired NO bioactivity. Therefore pulse waveform analysis (PWA) can be utilized to quantify arterial compliance as well as dynamic changes in NO bioactivity. We hypothesise that the two SNPs within oxidative stress genes influence vascular compliance in patients with CAD.

Methods:- We recruited 100 patients with angiographically documented coronary artery disease. Genotypes were determined with polymerase chain reaction and restriction digestion. Radial artery pressure waveforms were recorded using a calibrated tonometer. Windkessel based diastolic pressure decay analysis was then used to generate large (C1) and small (C2) artery compliance values. Differences between genotype groups were analysed using unequal variance unpaired Student's t tests.

Results:- The distribution of the genotypes in either gene did not differ significantly from that expected under Hardy Weinberg equilibrium. Homozygosity for a common NOS3 polymorphism (894 G/T) was associated with decreased small artery compliance (p= 0.006) but not with large artery compliance or blood pressure. In contrast the CYBA 242T allele was associated with decreased large artery compliance (p=0.042) and increased systolic (p=0.005) and pulse pressure (p=0.001).

Conclusion:- We confirmed our hypothesis that SNPs in the NOS3 and CYBA genes contribute to vascular compliance thus implicating the PWA as a cardiovascular intermediate phenotype.