Genetic approach to the role of cysteine proteases in the expansion of abdominal aortic aneurysms.
BACKGROUND
The elastinolytic cysteine proteases, including cathepsins S and K, are overexpressed at sites of arterial elastin damage. Cystatin C, an inhibitor of these enzymes, is expressed in arterial smooth muscle cells; an imbalance in cystatin C has been implicated in the aortic wall degeneration observed in abdominal aortic aneurysms (AAAs). The aim of the study was to investigate the impact of a polymorphism in the signal peptide of the cystatin C gene on the growth of small AAAs.


METHODS
Some 424 patients with a small AAA (4.0-5.5 cm) were monitored for AAA growth by ultrasonography and provided a DNA sample for analysis of the + 148 G > A polymorphism in the cystatin C signal peptide and the-82 G > C polymorphism in the gene promoter. The median length of follow-up was 2.8 years and AAA growth rates were calculated by linear regression analysis.


RESULTS
For patients of + 148 GG (n = 263), GA (n = 147) and AA (n = 20) genotypes, the mean(s.d.) AAA growth rates were 0.37(0.29), 0.37(0.23) and 0.30(0.26) cm, and initial diameters were 4.58(0.35), 4.58(0.35) and 4.62(0.36) cm, respectively. Patients of + 148 AA genotype had a slower aneurysm growth rate (unadjusted P = 0.058; after adjustment for age, sex, initial AAA diameter and smoking, P = 0.027). There also was a trend for the rare homozygotes of the-82 C allele to have slower AAA growth (adjusted P = 0.055). Smoking history had a stronger association with aneurysm growth (P = 0.003).


CONCLUSIONS
There was a weak association between variation in the cystatin C gene and AAA growth. Medical strategies to limit AAA growth might include the inhibition of cysteine proteases.
Eriksson
P
P
Atherosclerosis Research Unit, King Gustaf V Research Institute, Department of Medicine, Karolinska Institute, Stockholm, Sweden.
Jones
K G
KG
Brown
L C
LC
Greenhalgh
R M
RM
Hamsten
A
A
Powell
J T
JT
D000368:Aged; D017544:Aortic Aneurysm, Abdominal / Q000201:enzymology* / Q000235:genetics; D003546:Cysteine Endopeptidases / Q000235:genetics*; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics; D012907:Smoking / Q000235:genetics
D003546:Cysteine Endopeptidases