1. There is a familial tendency to abdominal aortic aneurysms. We have followed up a previous report of a weak association between the haptoglobin 2-1 phenotype and aortic aneurysm and investigated polymorphisms of the haptoglobin gene and neighbouring cholesterol ester transfer protein gene on the long arm of chromosome 16 in patients with atherosclerotic abdominal aortic aneurysm, patients with stenosing aortic atherosclerosis and healthy control subjects. The protein polymorphism of haptoglobin results from variant α-chains, α1 and α2, the phenotype nomenclature describing the two α-chains. We have also investigated whether the different haptoglobin phenotypes influence the degradation of aortic connective tissue.
2. The frequency of the haptoglobin α1 allele was increased in patients with aneurysms compared with healthy control subjects (0.51 versus 0.35, P < 0.05). Patients homozygous for the α2 allele had the highest mean age at aneurysm resection. The frequency of a rare polymorphism at the cholesterol ester transfer protein locus was also increased in aneurysm patients (0.15 versus 0.05 in control subjects, P < 0.01). These two genetic markers appear to act independently. Haptoglobins containing an α1-chain accelerated two-to fourfold the degradation by elastases of aortic elastin in vitro.
3. Genetic variation in the haptoglobin and cholesterol ester transfer protein genes appears to influence dilatation of the abdominal aorta. Variation at the haptoglobin locus could have a direct effect on the degradation of elastin in atherosclerotic aorta, whereas variation at the cholesterol ester transfer protein locus could affect lipid metabolism and promote atherosclerosis. These results indicate that a gene on chromosome 16 is associated with aortic aneurysm, although this may be an as yet unidentified gene in linkage disequilibrium with the haptoglobin and cholesterol ester transfer protein genes.